Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOCC>[O:15]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(Br)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(Oc2ccccc2)n1
Temperature: 210 °C
Yield: 124.3 %

Procedure:
A mixture containing 50.28 g of 6-bromo-2-picoline, 83.01 g of phenol and 120.86 g of potassium carbonate under an atmosphere of nitrogen was heated in an oil bath maintained at 210° C. for 20 hrs. After cooling to room temperature, the reaction mixture was dissolved in 1000 ml of H2O and 500 ml of ether. The layers were then separated and the aqueous layer extracted with ether. The combined etheral extracts were washed three times with 5% NaOH and then once with H2O. After drying the etheral layer over anhydrous Na2SO4, removal of the solvents afforded 67.3 g of an orange oil. Distillation afforded 44.32 g of colorless oil, b.p. 80°-85° at 5 mm.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=O)[CH2:13]Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]([NH2:19])=[S:18].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:19][C:17]1[S:18][CH:13]=[C:12]([C:6](=[N:5][O:4][CH2:3][CH2:2][Cl:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCCCl)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCCCl)c1csc(N)n1
Yield: 45.7 %

Procedure:
Ethyl 2-(2-chloroethoxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 68 g.), thiourea (20.2 g.), sodium acetate trihydrate (36.2 g.), ethanol (270 ml.) and water (170 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetate (syn isomer, 33.7 g.), mp 126° to 128° C.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]([C:12]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[S:14][CH:13]=1)=[O:11])[CH2:6]2.C(N(S(F)(F)[F:34])CC)C>C(Cl)Cl>[F:34][C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]([C:12]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[S:14][CH:13]=1)=[O:11])[CH2:6]2
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1CC2CCC(C1)C2(O)c1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CC2CCC(C1)C2(F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(8-Hydroxy-8-phenyl-3-aza-bicyclo[3.2.1]oct-3-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]methanone (0.05 g, 0.12 mmol) in DCM (2 mL) was cooled to −78° C. under an atmosphere of nitrogen. Diethylaminosulphur trifluoride (0.05 mL) was added and the mixture stirred for 0.25 hour and allowed to warm to room temperature over 1 hour. The mixture was diluted with DCM and washed with water then dried over magnesium sulphate, filtered and the solvent removed by evaporation. The residue was purified by reverse phase HPLC and the fractions containing the desired products were combined and the solvent removed by lyophilisation to give the title compound as a white solid (0.02 g). LCMS m/z 382.1 [M+H]+. RT.=4.25 min (Analytical Method 2).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O.CCOC(C)=O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH3:15])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(-n2nccc2N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-n2nccc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaOH (107 mg, 2.67 mmol) was added to a stirred solution of 2-p-tolyl-2H-pyrazol-3-ylamine (for reference procedure see WO 2009/150614, which is incorporated herein by reference in its entirety, 346 mg, 2.00 mmol) in water (1 mL) and EtOAc (4 mL). The mixture was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (385 μL, 2.80 mmol) added. Stirring was continued for 30 min at 0° C. and then for 2 h at RT. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine and concentrated to dryness in vacuo to give the title compound as an orange residue. LCMS (Method 3): Rt 3.90 min, m/z 348, 350 [MH+].
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([OH:41])[CH2:20][O:21][C:22]([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:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:42][N:43]=[C:44]=[O:45]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([S:17][CH2:18][CH:19]([O:41][C:44](=[O:45])[NH:43][CH3:42])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Reaction time: 72 h

Procedure:
To a solution of 1-hexadecylthio-3-trityloxy-2-propanol c1 4.6 g (8.0 mmol) in dichloromethane 100 ml are added 4-dimethylaminopyridine 1.17 g (9.6 mmol) and methyl isocyanate 4.72 ml (80 mmol). The solution is allowed to stand at room temperature for 72 hr and concentrated. The residue is chromatographed on SiO2 (46 g) and eluted with ethyl acetate:hexane (1:5) to give 1-hexadecylthio-2-methylcarbamoyloxy-3-trityloxypropane c2 as a crude oil (5.6 g). The oil is dissolved in dichloromethane 100 ml and boron trifluoride-methanol complex 1.68 ml (15.5 mmol) is added under cooling. The resulting yellow solution is stirred at 0° C. for 15 min and then at room temperature for 1 hr. Sodium carbonate aq solution is added to neutralize the reaction mixture and an organic layer is separated. The organic layer is subjected to SiO2 (80 g) column chromatography and eluted with ethyl acetate:hexane (1:1) to afford crude crystals 2.07 g. The crystals are triturated and washed with pentane to yield the titled compound V c1 1.205 g. The mother liquor is purified by Lobar column chromatography with the same solvent as described above to give additional V c1 0.321 g (49% total yield), mp. 53°-55° C.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu][C:21]#N.C[Li]>CCOCC.O>[OH:13][CH:8]([C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21])[C:9]([O:11][CH3:12])=[O:10]
Reactant: N#C[Cu]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in 10 ml of absolute ether were added dropwise to a cup-rate solution which had been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normal methyllithium solution and had been cooled to −78° C. The solution was stirred at −78° C. for 1 h and then allowed to warm to room temperature. It was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with sodium bicarbonate solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate mixtures to result in 250 mg (16%) of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].FC1C=CC(CC(O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=C(O)Cc1ccc(F)cc1
Product: O=Cc1c(F)cccc1F

Procedure:
The title compound was synthesized according to methods described for the preparation of 51.2. Here, commercially available 2,6-difluorobenzoic acid was utilized instead of 2-(4-fluorophenyl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([C:20]1[N:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[C:22]([CH:29]=O)[CH:21]=1)[CH2:18][CH3:19]>>[C:25]([N:24]1[C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][C:22]([CH2:29][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[N:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Product: CCCc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1C(C)(C)C
Yield: 76.5 %

Procedure:
Compound 75 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:8](=[O:20])[O:7]1)(=O)C>C1COCC1.CO.[Sn]>[Si:13]([O:12][C@@H:10]1[CH2:11][C@@H:6]([CH2:5][OH:4])[O:7][C:8](=[O:20])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: [Sn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Reaction time: 8 h
Yield: 29.3 %

Procedure:
((2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-yl)methyl acetate (VI) (0.625 g, 80% purity, 1.65 mmol) was dissolved in THF (8 mL) and MeOH (8 mL). Tin catalyst (tBu2SnClOH)2 (94 mg, 0.1 eq) was added and the reaction was stirred overnight. Reaction was concentrated and purified by flash chromatography to give pure (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (VII) (126 mg, 30%). VII was found to contain less than 0.1% of enantiomer.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10]
Reactant: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Yield: 27 %

Procedure:
To a rapidly and efficiently stirred mixture of 5-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (4.21 g, 13.0 mmol) in benzene (300 mL), was added 1,3-propanediol (3.81 mL, 52 mmol, 4 eq) and p-toluenesulfonic acid (0.989 g, 5.2 mmol, 0.4 mole % ) and the reaction was refluxed with a Dean Stark Trap for 4.5 hours under a dry N2 atmosphere. After cooling to room temperature the reaction was washed with sat. aq. NaHCO3 (3×), water (3×), brine (3×), dried over MgSO4, and concentrated. The crude product was purified on Biotage KP silica gel eluting with 50/50 Pet ether/EtOAc to give the title compound as a white solid (1.34 g, 27% yield). NMR (400 MHz, DMSO-d6): consistent; MS: (API-ES−) m/z 381 [M−H]. MS: (API+ES+) m/z 383 [M+H].
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1CCC(n2cnc([N+](=O)[O-])c2)CC1

Procedure:
4-nitroimidazole was alkylated with 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester to provide the title compound: C13 NMR (100 MHz, CDCl3) 28.5, 33.2, 42.7, 56.8, 80.7, 117.5, 134.4, 154.5; MS 297.1 m/z (M+1).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:20]2[CH3:23])=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:15]=1>>[CH:1]([C:4]1[N:5]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-isopropylbenzimidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 195. LCMS m/z: 533.3 (MH+). 1H-NMR (DMSO-d6): 7.89 (m, 1H), 7.64 (m, 1H), 7.24 (m, 2H), 4.25 (s, br, 4H), 4.00 (s, 1H), 3.92 (m, 1H), 3.81 (s, 3H), 3.77 (t, 4H), 3.73 (s, 2H), 2.91 (d, 2H), 2.00 (t, 2H), 1.67 (t, 2H), 1.35 (d, 6H), 1.22 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[N:13]=1)(=O)C.[OH-].[Li+]>>[OH:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[N:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)nn(C)c3=O)cc2C1
Yield: 63.4 %

Procedure:
Hydrolysis of 133b (160 mg 0.267 mmol) with lithium hydroxide afforded 133 as a white solid (94 mg, 63%). LCMS: [M+H]+ 556. 1H NMR (500 MHz, CDCl3) δ 8.55 (d, J=5.0, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.43 (d, J=5.0, 1H), 6.87 (s, 1H), 5.94 (s, 1H), 4.57 (s, 3H), 4.47 (s, 1H), 4.11-4.15 (m, 4H), 3.89 (s, 3H), 3.87 (s, 1H), 3.61 (d, J=4.0, 2H), 2.90 (s, 2H), 2.61 (d, J=4.0, 2H), 2.57 (t, J=6.0, 2H), 2.49 (s, 3H), 1.89-1.91 (m, 2H), 1.79-0.80 (m, 2H)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.7° (c=1.04, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH3:18])=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1ccccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccc3C)nc2c1
Temperature: 60 °C
Yield: 27.6 %

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.060 g, 0.306 mmol), 2-methylbenzaldehyde (0.037 g, 0.306 mmol), NaHSO3 (0.032 g, 0.306 mmol), and p-TsOH.H2O (0.00370 g, 0.021 mmol) in DMA (5.00 mL) was heated at 60° C. overnight. The mixture was cooled to room temperature, water (50.0 mL) and EtOAc (50.0 mL) was added. The layers were separated and the organic layer was washed with water (2×50 mL), brine (50 mL), dried and concentrated. The crude solid was purified via CombiFlash provide 5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one (0.025 g, 28%) as yellow solid. Selected data: 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H), 7.53 (dd, J=5.92, 3.07 Hz, 1H), 7.46-7.36 (m, 1H), 7.32 (dd, J=9.04, 4.60 Hz, 2H), 6.81 (d, J=2.29 Hz, 1H), 6.49 (d, J=2.28 Hz, 1H), 3.95 (s, J=7.48 Hz, 3H), 3.94-3.88 (s, 3H), 2.51 (s, 3H); MS (APCI) m/z 297 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-])=O)([O-])=O.Cl[Sn]Cl>Cl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1NCCOCCOCCNc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1ccccc1NCCOCCOCCNc1ccccc1N

Procedure:
26.1 g N,N'-bis(2-nitrophenyl)-1,8-diamino-3,6-dioxaoctane is dissolved in 100 ml concentrated HCl and stirred while 92.5 g SnCl2 dissolved in 100 ml concentrated HCl are added during approximately two minutes. The reaction is exothermal and the temperature rises to 90° C. at the same time as the colour changes from light orange through dark to light green, whereafter a product starts to precipitate. After one hour the reaction mixture is cooled on an ice bath. The crystalline product is filtered off and dissolved in 150 ml water and added to 50 g NaOH in 300 ml ice water. A greenish oil is separated. The product is extracted with 100+50 ml CH2Cl2, dried over MgSO4, and evaporated under vacuum. Yield: 21.7 g (57.9 mmol, N,N'-bis(2-aminophenyl)-1,8-diamino-3,6-dioxaoctane.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.[Br:18]Br>CC(O)=O>[Br:18][C:7]1[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1]
Reactant: BrBr
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 102.1 %

Procedure:
To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (0.75 g, 3.1 mmol) in AcOH (12 mL) was added a solution of bromine (0.2 mL, 3.5 mmol) in AcOH (6 mL), and the reaction mixture was stirred 10 min. The solvent was removed under reduced pressure to afford 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as a white solid (1.0 g, 100%): ESI MS m/z 299 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>O>[CH3:1][N:2]([CH:3]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4]1)[C:21](=[O:23])[CH3:22]
Reactant: CNC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(C)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 8-methylamino-6-nitro-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione (0.5 g. 1.6 mmol), acetic anhydride (0.5 g, 5 mmol), triethylamine (0.5 g, 5 mmol) in water (5 mL) was stirred for 15 min at room temperature. The solid was collected by filtration, washed with 2N HCl, then washed with diethyl ether and dried (0.5 g). Calc'd for C14 H14N4O5 : C, 52.83; H, 4.43; N, 17.60; found: C, 48.62; H, 4.26; N, 15.50.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.I[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:33][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:35][CH2:36][CH3:37])=[CH:7][CH:6]=2)[C:13](=[O:14])[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 1-iodopropane (1.1 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.91 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:22]([NH2:24])[CH3:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:24][CH2:22][CH3:23])[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)c1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
0.2 g (0.00061 mol) of 4-amino-N-(6-chloro-2-dimethylamino-pyrimidin-4-yl)-benzenesulfonamide were dissolved in 20 ml of ethanol, treated with 4.2 ml (0.061 mol) of ethylamine and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.082 g (40%) of 4-amino-N-(2-dimethylamino-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 237-238° C.