Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:53]CN(C(C)C)C(C)C.[CH3:62][O:63][CH2:64][CH2:65][NH:66][CH3:67]>C1COCC1>[CH:44]([OH:45])=[O:63].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][CH:50]=[C:51]([CH2:67][N:66]([CH2:65][CH2:64][O:63][CH3:62])[CH3:53])[CH:52]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: CNCCOC
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(C)Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 13.7 %

Procedure:
To a solution of Intermediate 167b (0.19 mmol) in THF (2 mL) was added DIPEA (130 μL, 0.75 mmol) and N-(methoxyethyl)methylamine (81 μL, 0.75 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (20 mg, 14%). LCMS (Method 5): Rt 3.65 min, m/z 720 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.48 (2H, m), 1.58-1.67 (2H, m), 1.72-1.92 (4H, m), 1.96-2.12 (2H, m), 2.12 (3H, s), 2.49 (2H, t, J=6.0 Hz), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J=12.1, 4.3 Hz), 3.16 (3H, s), 3.39 (2H, t, J=6.0 Hz), 3.50 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.02 (1H, d, J=8.6 Hz), 7.14 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.25-7.30 (2H, m), 7.30-7.35 (2H, m), 7.38 (1H, s), 7.40 (1H, t, J=7.7 Hz), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.07 (1H, s), 8.28 (0.2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(diethylamino)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1-diethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.55 (s, 1H), 8.48 (s, 1H), 8.10 (d, 1H), 7.56 (s, 1H), 7.47-7.50 (m, 1H), 7.33 (s, 1H), 7.10-7.14 (m, 2H), 3.44 (t, 2H), 3.25 (t, 2H), 3.08-3.14 (m, 4H), 2.62-2.72 (m, 4H), 2.42 (s, 3H), 2.27 (s, 3H), 1.05 (t, 6H). LRMS [M+H]=470.3
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[C:13]2[N:14]([C:18]([Br:22])=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:6])=[O:4].C(O)(=O)C.[O-:32][C:33]#[N:34].[Na+]>O>[Br:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:9]3[C:23]([Cl:26])=[CH:24][CH:25]=[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH2:34])=[O:32])[C:8]=3[Cl:27])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: N#C[O-]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(N)=O)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (100 mg), acetic acid (0.5 ml) and water (1.0 ml) was added an aqueous solution (1 ml) of sodium cyanate (138 mg) at 40° C. The mixture was stirred at the same temperature for 1 hour and evaporated in vacuo. The residue was partitioned into dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) followed by crystallization from ethyl acetate-diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(ureidoacetyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (72 mg) as crystals.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]1([S:21](Cl)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 1-naphthalenesulfonyl chloride (2.27 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.15 g, 68%). 1H-NMR (300 MHz, CDCl3) δ 8.79 (d, J=8.5 Hz, 1H), 8.14 (d, J=7.0 Hz, 2H), 7.98 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 1H), 6.17 (s, 1H), 2.14 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[OH:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.[C:28](=[O:31])([O-:30])[O-].[K+].[K+]>CN(C)C=O>[C:21]([OH:23])(=[O:22])/[CH:20]=[CH:19]/[C:28]([OH:30])=[O:31].[C:10]1([CH2:9][N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=3)[CH2:4]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CN(Cc3ccccc3)CCO2)cc1
Product: O=C(O)/C=C/C(=O)O
Temperature: 110 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of 11.3 parts of 2-chloromethyl-4-(phenylmethyl)morpholine (described in Synth. Comm. 1980, 10(1), 59-73), 8.3 parts of ethyl 4-hydroxybenzoate, 6.9 parts of potassium carbonate and 141 parts of N,N-dimethylformamide was stirred overnight at 110° C. The reaction mixture was evaporated and water was added to the residue. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into the (E)-2-butenedioate salt in 2-propanol, yielding 9.5 parts (40.3%) of ethyl 4-[[4-(phenylmethyl)-2-morpholinyl]methoxy]benzoate (E)-2-butenedioate(1:1); mp. 174.4° C. (interm. 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:24]1([N:30]2[C:6]3=[N:7][C:2]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:3][CH:4]=[C:5]3[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCCC3)C2=O)cc1
Temperature: 25 °C

Procedure:
A solution of [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine (200 mg, 0.70 mmol) (from Example 1d supra) in anhydrous tetrahydrofuran (24 mL) was treated with n-butyllithium (1.6 M solution in hexanes, 0.53 mL, 0.84 mmol) (Aldrich) at −78° C. This was followed by addition of cyclohexyl isocyanate (90 μL, 88 mg, 0.70 mmol) (Aldrich). The resulting mixture was stirred and slowly warmed up to room temperature within a period of 2 hours. The reaction mixture was then partitioned between ethyl acetate and brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography with a silica gel column using a 0–60% ethyl acetate in hexanes gradient. The intermediate that was obtained from this purification was dissolved in aniline (2 mL) (Aldrich), a catalytic amount of 4-(dimethylamino)pyridine (Aldrich) was added and the mixture was then heated at 100° C. After stirring overnight the mixture was cooled, and purified by silica gel column chromatography with a 0–60% ethyl acetate in hexanes gradient. The solid obtained from this purification was dissolved in tetrahydrofuran and then precipitated with excess of pentane to give 1-cyclohexyl-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a beige solid. (Yield 78 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O.O>[OH:13][C:12]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[O:16][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=1[C:9]([OH:10])=[O:8]
Reactant: Cc1cccc2c1C(=O)OC2
Reactant: Oc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cccc(O)c2)c1C(=O)O
Temperature: 140 °C
Reaction time: 21 h
Yield: 77.7 %

Procedure:
7-Methylphthalide (30.1 g, 203 mmol), resorcinol (45.3 g, 407 mmol) and potassium tert-butoxide (47.6 g, 424 mmol) are suspended in 300 ml of N-methylpyrrolidone (NMP) and stirred at 140° C. for 21 h. After this time, a second amount of potassium tert-butoxide (2.4 g, 21.4 mmol) is added and stirring is continued at 140° C. for 2.5 h. The reaction mixture is cooled, 800 ml of water are added, and the mixture is acidified to pH=2 at 20° C. with concentrated hydrochloric acid. After stirring at 3 to 5° C. for 2 hours, the pale beige solid is filtered off with suction, washed with water and then dried. The isolated product contains 2-(3-hydroxyphenoxymethyl)-6-methylbenzoic acid and N-methylpyrrolidone as solvate molecule in a ratio of 1:1. Yield 77.7%, melting point 98 to 99° C.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[CH:13](Cl)(Cl)Cl.[CH3:17][C:18]([CH3:20])=[O:19]>>[OH:19][C:18]1[CH:20]=[C:8]2[C:9]([C:10]([CH3:12])=[C:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[O:7]2)=[CH:13][CH:17]=1
Reactant: CCCC(C(C)=O)C(=O)OCC
Reactant: CC(C)=O
Reactant: ClC(Cl)Cl
Product: CCCc1c(C)c2ccc(O)cc2oc1=O
Yield: 37 %

Procedure:
This was prepared from 9 (1.72 g) in a similar manner to the preparation of 3. The yellow/brown crude product that obtained was fractionated by flash chromatography (chloroform/acetone, 20:1 to 1:1 gradient). The product that isolated was further purified by recrystallisation from ethyl acetate/hexane (2:3) to give 10 as creamy crystals (813 mg, 3.73 mmol, ca. 37%); mp 160–173° C. [Lit. [73] 171–173° C. (aq. ethanol)]; δH (400 MHz, DMSO-d6) 0.92 (3H, t, J=7.3 Hz, CH3), 1.45 (2H, sextet, J=7.5 Hz, —CH2CH2CH3), 2.36 (3H, s, C4-CH3), 2.51 (2H, t, J=7.7 Hz, —CH2CH2CH3), 6.67 (1H, d, J=2.4 Hz, C8-H), 6.79 (1H, dd, J=2.4 and 8.4 Hz, C6-H), 7.60 (1H, d, J=8.8 Hz, C5-H) and 10.38 (1H, br s, exchanged with D2O, OH); MS (FAB+) m/z (rel. intensity) 437.2[10, (2M+H)+], 219.2[100, (M+H)+]; MS (FAB−) m/z (rel. intensity) 435.2[12, (2M−H)−], 371.1[15, (M+NBA)−], 217.1[100, (M−H)−]; HRMS (FAB+) m/z 219.10300 [(M+H)+], calcd for C13H15O3 219.10212. Found: C, 71.7; H, 6.49; C13H14O3 requires C, 71.53; H, 6.47%.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].Br[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>O1CCCC1>[CH2:12]([O:11][CH:10]([O:14][CH2:15][CH3:16])[CH2:9][O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOCC(OCC)OCC
Temperature: 68 °C
Reaction time: 0.5 h

Procedure:
A solution of but-3-en-1-ol (96%, 28.0 mL, 312 mmol) in tetrahydrofuran (150 mL) was added to a suspension of sodium hydride (60% in mineral oil, 59.9 g, 1.50 mol) in tetrahydrofuran (700 mL) at 0° C. After the reaction mixture had stirred for 30 minutes at this temperature, a solution of 2-bromo-1,1-diethoxyethane (97%, 72.6 mL, 468 mmol) in tetrahydrofuran (150 mL) was added at 0° C., and the reaction mixture was heated to 68° C. for 66 hours. The reaction mixture was cooled to 0° C., slowly quenched with water (150 mL), and concentrated in vacuo to remove tetrahydrofuran. After three extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as an oil, which was taken directly to the following step. Yield: 77 g. 1H NMR (400 MHz, CDCl3), product peaks only: δ 1.23 (t, J=7.0 Hz, 6H), 2.32-2.38 (m, 2H), 3.50 (d, J=5.3 Hz, 2H), 3.53-3.62 (m, 4H), 3.67-3.75 (m, 2H), 4.63 (t, J=5.3 Hz, 1H), 5.02-5.06 (m, 1H), 5.07-5.13 (m, 1H), 5.77-5.88 (m, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH3:13]O>>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Product: COC(=O)C(O)[C@@H](N)CC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 110 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoic acid in 10 ml of methanol with stirring, and the mixture was stirring overnight, and the mixture was evaporated to dryness under reduced pressure to obtain 150 mg of methyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder. [IR (KBr): νco 1740 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[Mg].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
2-(3,4-Dichlorophenyl)ethyl bromide (5 g, 19.7 mmol) was added slowly to a suspension of magnesium turnings (0.48 g, 19.7 mmol) in ether (30 ml). After spontaneous reflux had finished the mixture was stirred under reflux for 15 minutes and allowed to cool to room temperature. The mixture was added dropwise via cannula to a stirred, cooled (-25° C.) solution of diethyl oxalate (3 g, 20.7 mmol) in THF (15 ml). The mixture was stirred at -10° C. for 30 minutes and allowed to warm to room temperature. Hydrochloric acid (2M, 15 ml) was added and the mixture was extracted with ether (2×20 ml). The combined organic fractions were washed with water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90) to give the title compound (0.7 g).
Reaction SMILES: Cl.Cl[C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)C>CC#N>[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[S:4][C:5]3[C:6]([N:11]=2)=[N:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: Clc1nc2ncccc2s1
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Yield: 87.4 %

Procedure:
A mixture of 2-chloro[1,3]thiazolo[4,5-b]pyridine hydrochloride (863 mg, 4.17 mmol), 4-(2-bromo-ethoxy)-phenol (905 mg, 4.17 mmol), and Cs2CO3 (5.88 g, 16.67 mmol) was stirred in CH3CN (42 mL) for 16 h. After filtration through diatomaceous earth, the organic filtrate was partitioned with 1 M NaOH (3×10 mL) and satd. aq. NaCl (1×10 mL). The organic layer was dried and concentrated to yield a red oil. Additional desiccation under high vacuum yielded a brown solid in red oil. Diethyl ether was added, and the mixture was sonicated for 20 min to give a homogenous suspension. The pink solid was filtered and discarded, and the ether solution was concentrated to yield the title compound as a yellow solid (1.28 g, 87%). 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.67 1H), 7.38-7.34 (m, 2H), 7.21 (dd, J=7.9, 4.8, 1H), 7.01-6.97 (m, 2H), 4.33 (t, J=6.2, 2H), 3.68 (t, J=6.2, 2H). MS (ESI): mass calcd. for C14H11BrN2O2S, 349.97; m/z found, 351.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][O:37][C:36]4=[O:40])[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)Cc1cc(Cl)ccc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1

Procedure:
19 G. of 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)piperazine are together with 15 g. of pulverized potassium carbonate, 0.3 g of potassium iodide and 150 ml. of toluene reacted with 20.4 g of N-(beta-chloroethyl)-oxazolidinone and heated under reflux conditions for 20 hours. The reaction mixture is poured over water and diluted with benzene. The organic phase is thereafter washed with saturated, aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 3-{2-[4-(2-chloro-8-fluoro-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which is treated with maleic acid to form the corresponding maleate which has a melting point of 164°-166°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=CC=C[C:5]=1[CH:6]=[O:7])([O-])=O.CO[CH:14](OC)[C:15](=O)CC(OC)=O.C(O)(=[O:26])C.N1CCCCC1>C1C=CC=CC=1>[NH2:1]/[C:4](/[CH3:11])=[CH:5]\[C:6]([O:7][CH2:14][CH3:15])=[O:26]
Reactant: CC(=O)O
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)C(OC)OC
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C=C(/C)N
Yield: 575 %

Procedure:
A mixture of 2-nitrobenzaldehyde (6.8009 g), methyl 4,4-dimethoxyacetoacetate (8.7204 g), acetic acid (0.5405 g) and piperidine (0.4598 g) in benzene (30 ml) was heated to reflux for 2 hours under azeotropic dehydration. The reaction mixture was diluted with benzene (100 ml), washed twice with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.23 g). A mixture of thus obtained crude oil (15.23 g) and ethyl 3-aminocrotonate (6.6840 g) was heated at around 65° C. for 6 hours and then at 98° to 100° C. for 5 hours. The resultant viscous brown oil was dissolved in ethyl acetate, washed three times with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give brown oil (19.40 g). The residual oil was crystallized by trituration with methanol (10 ml) to give yellowish crystalline powder (12.77 g) of ethyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate. An additional 0.53 g of crystals was recovered from the mother liquor. Recrystallization from methanol gave yellowish granules, m.p. 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[N+:18]([O-])=O)=[CH:4][CH:3]=1>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[NH2:18])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCc1ccc(Cl)cc1
Solvent: CCO
Product: Cl
Product: Nc1cc(C(F)(F)F)ccc1NCc1ccc(Cl)cc1

Procedure:
A solution of 2-(4-chlorobenzylamino)-5-trifluoromethylnitrobenzene (70 g, 0.21 mmol) in ethanol (500 ml) was hydrogenated at a pressure of 4 bar. When the reaction was finished the product was filtered through a plug of celite into a flask containing 25 ml conc. HCl. After evaporation the product was suspended in petrol ether and filtered off. Yield 57 g.
Reaction SMILES: CC[C:3](O)=[S:4].[C:6]([C:13]1NC=CN=1)(C1NC=CN=1)=[O:7].[NH2:18][CH:19]1[CH:24]2[CH:20]1[CH2:21][N:22]([C:25]1[N:49]=[CH:48][C:28]3[N:29]=[CH:30][N:31]=[C:32]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][C:41]5[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=5)=[C:36]([CH3:47])[CH:35]=4)[C:27]=3[CH:26]=1)[CH2:23]2>C(Cl)Cl>[CH3:47][C:36]1[CH:35]=[C:34]([NH:33][C:32]2[C:27]3[CH:26]=[C:25]([N:22]4[CH2:21][CH:20]5[CH:24]([CH:19]5[NH:18][C:6](=[O:7])[CH2:13][S:4][CH3:3])[CH2:23]4)[N:49]=[CH:48][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:39]=[CH:38][C:37]=1[O:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCC(O)=S
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1cccnc1
Solvent: ClCCl
Product: CSCC(=O)NC1C2CN(c3cc4c(Nc5ccc(Oc6cccnc6)c(C)c5)ncnc4cn3)CC21
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
To a solution of 34 μL (0.39 mmol) of methylthioacetic acid in 1 mL of methylene chloride in a ice/brine bath was added 62.8 mg (0.39 mmol) of carbonyl diimidazole. The mixture was stirred for 15 minutes and 150 mg (0.353 mmol) of [6-(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyrido[3,4-d]pyrimidin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine was added along with additional methylene chloride to aid stirring. After stirring for 1 hour, the reaction was filtered and the precipitate was washed with methylene chloride and air dried. The solid was recrystallized from methanol/methylene chloride to afford 112 mg (62%) of the title compound. 1H NMR (CDCl3): δ 8.83 (s, 1), 8.35 (s, 1), 8.25 (m, 2), 7.72 (m, 1), 7.62 (m, 1), 7.24 (m, 2), 7.07 (s, 1), 6.91 (d, 1), 3.92 (d, 2), 3.52 (m, 2), 3.13 (s, 2), 2.48 (m, 1), 2.22 (s, 3), 2.10 (s, 3), 1.89 (m, 2), M.S. (m+1): 514. HPLC retention time (minutes): 5.154.