Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[Br:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=1[CH2:12]Br.CN(C=[O:26])C>CCOC(C)=O.O>[Br:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=1[CH2:12][N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:26]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1OCCN1Cc1cc(C(F)(F)F)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 2-oxazolidone (0.110 g, 1.26 mmol) in DMF (4 mL) was added sodium hydride (60% in mineral oil; 0.056 g, 1.39 mmol), and the mixture was stirred at 0° C. for 10 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.420 g, 1.26 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. The mixture was diluted with EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([C:10](=[CH:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)[CH3:9].[S:28](Cl)(Cl)=O>CN(C=O)C>[CH2:8]([C:10](=[CH:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11](=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:28][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCC(=CSc1ccccc1)C(=O)Nc1ccccc1
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(=CSc1ccccc1)C(=Nc1ccccc1)Sc1ccccc1

Procedure:
Toluene (20 mL) was added to 2-ethyl-N-phenyl-3-(phenylthio)acrylamide (3.68 g), and then thionyl chloride (1.9 mL) and DMF (10 mg) were added thereto. The mixture was stirred with heating under reflux for 1 hour. The mixture was concentrated under reduced pressure. To the concentrate was added DMF (35 mL), and then, phenylmercaptan sodium salt (2.0 g) was added portionwise thereto under ice-cooling. The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added tert-butyl methyl ether, and then a 1 N aqueous sodium hydroxide solution was added, thereby the solution was separated. The organic layer was washed with water three times, dried and then concentrated. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain phenyl 2-ethyl-N-phenyl-3-(phenylthio)thioacrylimidate (2.03 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1.[CH3:43][C:44]1([CH3:52])[O:48][CH:47]([CH2:49][O:50][NH2:51])[CH2:46][O:45]1>C(OCC)(=O)C.O1CCCC1>[CH3:43][C:44]1([CH3:52])[O:48][CH:47]([CH2:49][O:50][NH:51][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=2[NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH2:46][O:45]1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OCC(CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (4.52 g, 11.5 mmol) in freshly distilled tetrahydrofuran (20 mL) at −15° C. was added diphenylphosphinic chloride (2.85 mL, 14.95 mmol). The resultant reaction mixture was stirred for 30 minutes at −15° C. N-Methylmorpholine (1.26 mL, 11.5 mmol) was added and stirring was continued for 90 minutes at −15° C. The reaction was then charged with O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (2.03 g, 13.8 mmol) and allowed to stir at −15° C. for 30 minutes. N-methylmorpholine (1.9 mL, 17.25 mmol) was added and the reaction was allowed to warm to room temperature. After 17 hours, the mixture was diluted with ethyl acetate and partitioned twice with saturated NaHCO3 solution, then twice with water, and twice with saturated brine solution. Organic layers were collected, dried over sodium sulfate, filtered and concentrated in vacuo. The afforded residue was purified by silica column chromatography in 3:1 hexanes/ethyl acetate. The corresponding fractions were collected, dried in vacuo, and crystallized from ethyl acetate/hexanes affording N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (4.12 g, 68.6%) as light brown solid: m.p.=114-115° C.; 1NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.62 (s, 1H), 7.53-7.55 (m, 1H), 7.31-7.37 (m, 2H), 7.17 (dd, 1H, J=16.9, 9.3), 6.60-6.65 (m, 1H), 4.22 (t, 1H, J=6.1), 3.96 (t, 1H, J=8.3), 3.76-3.77 (m, 2H), 3.63 (t, 1H, J=4.9), 1.26 (s, 3H), 1.21 (s, 3H); MS(APCI+)=522.9; Anal.calcd/found for C19H18F3IN2O4: C, 43.70/43.88; H, 3.47/3.43; N, 5.36/5.20; F, 10.91/10.87.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(F)cc2)c1
Yield: 67.3 %

Procedure:
Reaction of 4-(4-fluoro-phenyl)-1H-imidazole (573 mg, 3.53 mmol), 95% NaH (100 mg, 4.0 mmol), and SEMCl (650 mg, 3.90 mmol) followed by purification of the crude material on silica gel (50% EtOAc/hexanes) gave the title compound as yellow crystals (695 mg, 67%). 1H NMR (CDCl3) □−0.01 (s, 9H), 0.93 (m, 2H), 3.52 (m, 2H), 5.29 (s, 2H), 7.07 (m, 2H), 7.28 (s, 1H), 7.62 (s, 1H), 7.75 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cccc(Cl)c1
Product: Cc1cc(Nc2cccc(Cl)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-chloroaniline (50.8 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (99 mg, 84%). 1H NMR (CDCl3): 8.59 (d, J=4.2 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.80 (br, 1H), 7.67 (t, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.19 (m, 1H), 7.10 (m, 2H), 6.91 (m, 1H), 6.41 (s, 1H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[OH:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C@@H:6]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>CC(C)=O>[CH3:1][O:2][C:3]([C@H:5]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C@@H:6]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)OC)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A 1 L 3 necked round-bottom flask equipped with an air driven stirrer, and a nitrogen inlet/outlet was charged with 49.0 g (102.8. mmol) of methyl-(1S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate, 490 mL of acetone, 71.0 g of potassium carbonate and 17.3 g (110 mmol) of methyl bromoacetate. The resulting slurry was stirred at ambient temperature under an atmosphere of nitrogen while the progress of the reaction was monitored by HPLC. The reaction was deemed to be complete when all the starting material had been converted to the title compound. The slurry was filtered through 50 g of Aluminium oxide rinsing with 1250 mL of acetone. The resulting filtrate was concentrated under reduced pressure to a volume of approximately 100 mL. The concentrate was diluted with 500 mL of t-butyl methyl ether then washed with 2×300 mL portions of 5% aqueous citric acid followed by drying over anhydrous magnesium sulphate. The resulting solution was concentrated under reduced pressure to afford 49.2 g of the title compound as an oil. HPLC analysis indicated 97.8% PAR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20](N(CC)C(C)C)(C)C.[CH2:29]([O:33][C:34]1[CH:40]=[CH:39][C:37](N)=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH3:32]>C(O)CO>[CH2:29]([O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:7][C:2]2[CH:20]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Solvent: OCCO
Product: CCCCOc1ccc(Nc2cc(Nc3ccc4c(c3)OCCO4)c(F)cn2)cc1
Temperature: 185 °C
Yield: 49.4 %

Procedure:
To a magnetically stirred solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at room temperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol) followed by 4-butoxyaniline (0.18 g, 1.1 mmol). The reaction mixture was heated to 185° C. for 5 h, cooled to room temperature, and partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine (0.18 g, 49%) as a tan solid: Rf 0.66 (silica gel, 4:1 chloroform/ethyl acetate); mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=3.2 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.7, 2.5 Hz, 1H) 6.90-6.81 (m, 4H), 6.60 (d, J=2.4 Hz, 1H), 4.27 (s, 4H), 3.94 (t, J=6.5 Hz, 2H), 1.80-1.71 (m, 2H), 1.55-1.42 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 155.1, 150.4, 143.6, 142.7, 140.3, 140.0, 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7, 110.8, 68.2, 64.7, 64.5, 31.6, 19.4, 14.0; IR (ATR) 3356 cm−1; ESI MS m/z 411 [C22H23FN4O3+H]+; HPLC (Method A)>99% (AUC), tR=17.3 min. Anal. Calcd for C22H23FN4O3: C, 64.38; H, 5.65; N, 13.65. Found: C, 62.64; H, 5.59; N, 13.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:26][O:27][CH3:28])[C:17]([NH:19][C:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23])=[O:18].O>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:16]([CH2:26][O:27][CH3:28])[C:17]([NH:19][C:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23])=[O:18])[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Chloro-5-hydroxypyridine (0.074 g), anhydrous potassium carbonate (0.087 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl)-3-methoxypropionamide (0.150 g) in dry N,N-dimethylformamide (3 ml) were stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature and stored for 2 days. The mixture was poured into water, extracted with ethyl acetate and the organic phases were combined, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to a gum. The gum was fractionated by chromatography (silica; ethyl acetate:hexane, 2:3 by volume) to give a colourless gum that was dissolved in diethyl ether and extracted with aqueous hydrochloric acid (3M). The aqueous acidic fraction was collected and treated with potassium carbonate until basic then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give the required product, 0.094 g, as a colourless gum.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.N([O-])=[O:14].[Na+]>O.S(=O)(=O)(O)O.[Cl-].[Na+].O>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([OH:14])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(-n2ncnn2)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-n2ncnn2)cc1
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
A suspension of 4-tetrazol-2-yl-phenylamine (5.4 g) in water (42 ml) and conc sulphuric acid (10 ml) was added slowly to a solution of sodium nitrite (2.3 g) in water (8.5 ml) at 5°. The resulting green solution was stirred at this temperature for ca. 30 min, treated with a mixture of water (50 ml) and conc. sulphuric acid (67 ml) and heated to 120° for 1 h. Water (170 ml) was added, the reaction mixture cooled, saturated with brine (100 ml) and extracted with dichloromethane (3×100 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (1.6 g). T.l.c. (Ethyl acetate/cyclohexane (1:1)), Rf 0.55.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:43])[CH:10]=1)#[N:2].[CH3:44][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[F:43][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:42])[N:18]([C@H:28]2[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][CH:36]([OH:37])[CH3:44])[CH2:32][CH2:33]2)[C:19]2[N:20]([N:25]=[CH:26][CH:27]=2)[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ccnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reaction time: 1 h

Procedure:
To a solution of 2-[(trans-4-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.30 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.73 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (6 mL), and sodium borohydride (0.020 g) was added at 0° C. After stirring at 0° C. for 30 min, ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.28 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O.O>C(OCC)(=O)C>[O:1]=[C:2]1[N:3]([NH:8][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:24]([NH2:23])=[O:25]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(NN1CCCNC1=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)N1CCCN(NC(=O)OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a suspension of (tetrahydro-2-oxo-1(2H)-pyrimidinyl)carbamic acid, phenylmethyl ester (35.5 g, 135.9 mmol) in 500 ml ethyl acetate, chlorosulfonyl isocyanate (24.0 g, 169.9 mmol) was added. The resulting solution was stirred for one hour and hydrolyzed by adding 175 ml water. The phases were separated, the organic phase washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and trituration of the residue with ether yielded 38.0 g of the desired product, melting point 135.6° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.[C:28]([CH:31]([CH:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32])([OH:30])=[O:29].ClC1C=CC(C2CCNCC3C=C(C4N=NC=CC=4)C=CC2=3)=CC=1>>[C:28]([CH:31]([CH:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32])([OH:30])=[O:29].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:13]=[C:12]([C:14]4[N:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:11]=[CH:10][C:5]2=3)=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Agent: Clc1ccc(C2CCNCc3cc(-c4cccnn4)ccc32)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: CN1CCC(Oc2ccc(Cl)cc2)c2ccc(-c3cccnn3)cc2C1

Procedure:
This compound was prepared from (−)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol from Step H in Example 1 and 4-chlorophenol, following the procedures of Steps J and K in Example 1. (+)-5-(4-Chlorophenyl)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (AUC HPLC>99%) is a white solid: mp 106-108° C.; 1H NMR (CD3OD, 500 MHz) δ 9.18 (d, J=5.0 Hz, 1H), 8.20-8.17 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.7, 3.8 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 5.73 (d, J=7.6 Hz, 1H), 4.92-4.84 (m, 1H), 4.52-4.46 (m, 1H), 4.42 (s, 3H), 3.90-3.80 (m, 1H), 3.56-3.50 (m, 1H), 2.86 (s, 3H), 2.46-2.37 (m, 2H); ESI MS m/z 366 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CNc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
2,4-Dichloropyrimidine (25 g, 0.16 moles) and 2,2-dimethyl-propylamine (25 ml, 0.21 moles) are dissolved in 250 ml of THF and K2CO3 (33.1 g, 0.24 mmoles) is added at rt. The mixture is refluxed at rt for 8 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 22 g of desired (2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 67% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Cu][C:16]#[N:17].C(N)CN>CN(C=O)C.[Cu]I>[OH:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc2c(c1)CCO[C@H]2CCO
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A suspension of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (300 g, 1.17 mol), copper(I) cyanide (209 g, 2.34 mol), and copper(I) iodide (33.3 g, 0.18 mol) in dry DMF (1.16 L), under an atmosphere of nitrogen, was heated to 140° C. After 8 h at this temperature, HPLC analysis of an aliquot indicated that the reaction was complete. The reaction mixture was cooled to room temperature and poured into an aqueous solution of ethylenediamine (3 L, v/v 3/1) then extracted into toluene. The combined organic layers were washed with water and concentrated in vacuo to give the crude title compound. This material is used without further purification in the subsequent step.
Reaction SMILES: [CH:1]1[C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=[CH:3][C:2]=1[C:17](=[O:19])[CH3:18].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl.O>[N+:20]([C:3]1[C:2]([C:17](=[O:19])[CH3:18])=[CH:1][C:6]2[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:5]=2[CH:4]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc2c(c1)OCCOCCOCCO2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCCOCCOCCO2
Temperature: 0 °C
Yield: 36.1 %

Procedure:
1-(6,7,9,10,12,13-Hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (200 mmol, 51.3 g) dissolved in DCM (750 ml) and the mixture cooled to 0° C. Nitric acid (90%, 300 mmol, 14 ml) was added dropwise to the cooled solution over 20 minutes. Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40 minutes at 0° C. Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20 minutes. The reaction mixture was diluted with water (300 ml) and wash with water (3×200 ml), Sat. NaHCO3 (4×200 ml, or until neutral). The organic layer was dried over Na2SO4 and concentrated. The crude mixture was recrystallized with DMF to give 22.5 g of the nitro product. The DMF layer was concentrated and recrystallized with ethyl acetate to give additional 8.75 g of the product. The ethyl acetate layer was concentrated and purified on silica column using 20% EtOAc/hexanes to give another 4.75 g of the product. Total yield is 36 g, (−60%). 1HNMR (400 MHz, DMSO) δ 7.82 (s, 1H), 7.61 (s, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 2.71 (s, 3H). LC/MS Calcd for (M+H)−312.3. found 312.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CCN(C(C)C)C(C)C.[Cl-].[CH:23]1([O:29][C:30]([C:32]2[N:33]=[C:34]([CH:37]3[CH2:42][CH2:41][NH2+:40][CH2:39][CH2:38]3)[S:35][CH:36]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:40]1[CH2:39][CH2:38][CH:37]([C:34]2[S:35][CH:36]=[C:32]([C:30]([O:29][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:31])[N:33]=2)[CH2:42][CH2:41]1)=[O:12]
Reactant: O=C(O)Cc1cc(Br)ccc1Br
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cc3cc(Br)ccc3Br)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,5-Dibromophenyl)acetic acid (323 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred at room temperature for 30 min. 4-{4-[(Cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 330 mg) is added, and the mixture is stirred for a further 5 min before bromotrispyrrolidinophosphonium hexafluorophosphate (559 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives cyclohexyl 2-{1-[(2,5-dibromophenyl)acetyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (250 mg, 43%).