Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[C:14](=[O:23])[C:13]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]([OH:20])[C:18]([CH3:21])([N:15]2[C:14](=[O:23])[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:12]([CH3:11])[O:17][CH2:16]2)[CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)c2cc(F)cc(F)c2)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.4 %

Procedure:
3,5-Difluorobromobenzene (2.9 g) was added to a suspension of magnesium (0.41 g) in tetrahydrofuran, under an inert atmosphere at 20° C., slowly, to initiate reaction, then at a rate to maintain gentle reflux. After refluxing for 1 hour, the mixture was added to a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (2.59 g) in tetrahydrofuran at -78° C. The solution was warmed to ambient temperature and stirred for 18 hours. Ammonium chloride and ethyl acetate were added and the organic phase dried (magnesium sulphate) and evaporated to give 1-(3,5-difluorophenyl)-2-methyl-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-propan-1-ol (1.32 g), m.p. 87.6-89.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[S:11])=[C:7]([O:13][CH3:14])[N:6]=[CH:5][N:4]=1.[CH3:15]C[O-].[Na+]>>[CH2:1]([O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[S:11])=[C:7]([O:13][CH3:14])[N:6]=[CH:5][N:4]=1)[CH3:15]
Reactant: CC[O-]
Reactant: COc1ncnc(OC)c1NC(N)=S
Agent: [Na+]
Product: CCOc1ncnc(OC)c1NC(N)=S
Yield: 56.4 %

Procedure:
3.0 g N-(4,6-dimethoxy-5-pyrimidyl)-thiourea are mixed with a sodium-ethylate solution (0.317 g sodium in 30 ml absolute ethanol) and heated for 3 hours under reflux. After cooling the mixture is neutralized. The reaction product is vacuum treated and purified chromatographically on silica gel (developer; chloroform/methanol 95:5). 0.6 g N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea having a melting point of 186° to 187° C. are obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:26]([OH:25])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:28][CH2:29]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Product: CN(CC(CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(hydroxydiphenylmethyl)piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:13]([C@@H:15]1[O:17][CH2:16]1)[Cl:14]>CCO.O>[Cl:14][CH2:13][C@H:15]([OH:17])[CH2:16][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: ClC[C@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: O
Solvent: CCO
Product: O=C1CSc2ccc(NC[C@@H](O)CCl)cc2N1
Yield: 81 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (18.39 g, 102 mmol; commercial) and (R)-epichlorohydrin (8.0 mL, 1 eq.) in EtOH/H2O (9:1; 450 mL) was heated at 80° C. overnight. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/EA followed by filtration. The filtrate containing the product was concentrated under reduced pressure to afford the title intermediate as a beige solid (22.52 g, 81% yield) which was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)([O-:16])=[O:15]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1

Procedure:
In 20 volume parts of ethanol is dissolved 2.16 parts of o-nitrobenzyl chloride, followed by the addition of 1.02 parts of N-methyl piperazine and 1.3 parts of potassium carbonate. The mixture is reacted under reflux for 1 hour. The reaction mixture is then filtered and the solvent is removed from the filtrate by distillation under reduced pressure. The residue is extracted with water-ether (1:1). The ethereal layer is taken and dried over anhydrous sodium sulfate and the solvent is then distilled off. This procedure gives N1 -methyl-N4 -(2-nitrobenzyl)piperazine as a brown colored oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8][CH2:7]1.Cl[C:19]1[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH3:13])[C:19]2[N:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:10][CH2:11]1
Reactant: CNC1CCN(Cc2ccc(F)c(F)c2)CC1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccc(C(F)(F)F)nn1)C1CCN(Cc2ccc(F)c(F)c2)CC1

Procedure:
A solution of D5 (480 mg, 2 mmol), 3-chloro-6-trifluoromethylpyridazine (182 mg, 1 mmol) and diisopropylethylamine (260 mg, 2 mmol) in n-butanol (4 ml) was heated at 190° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 2 h. After this period, the reaction mixture was evaporated in vacuo and the residue extracted with dichloromethane. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, dried (MgSO4) and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E12 (210 mg, 54%). C18H19F5N4 requires 386; Found 387 (MH+). 1H NMR (CDCl3) δ 1.74 (br.d, J=12.0 Hz, 2H), 1.88 (qd, J=12.0, 3.9 Hz, 2H), 2.17 (td, J=11.8, 2.5 Hz, 2H), 2.96 (br.d, J=11.6 Hz, 2H), 3.00 (s, 3H), 3.47 (s, 2H), 4.85 (t, J=12.1 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.99-7.05 (m, 1H), 7.10 (dt, J=10.2, 8.1 Hz, 1H), 7.20 (ddd, J=11.4, 7.8, 2.1 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 3-fluorophenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz): δ 1.272 (s, 9H), 1.700 (bs, 2H), 1.742 (bs, 2H), 2.520-2.818 (bs, 3H), 3.379 (bs, 2H), 6.478 (s, 1H), 6.710 (d, J=10.0 Hz, 1H), 7.228 (s, 1H), 7.264 (m, 1H), 7.420 (m, 2H), 7.618 (t, J=7.6 Hz, 1H), 7.722 (m, 2H), 7.975 (d, J=10.0 Hz, 1H). Mass spectrum (ESI): 541.5 (M+1).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4]CC1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.[H-].[Na+]>CN(C=O)C>[N:16]1([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(n2cncn2)CC1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
A solution of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (567 mg, 2.40 mmol) and 1,2,4-triazole (232 mg, 3.36 mmol) in dry DMF (5.00 mL) is treated with sodium hydride 60% (125 mg, 3.12 mmol) at room temperature under nitrogen. The resulting mixture is stirred at 65° C. for 72 h. It is poured in ice water (75 mL), extracted 3 portions of 75 mL of EtOAc. The organic portions are combined, dried over anhydrous Na2SO4 and concentrated. The solid is purified by silica gel column chromatography using a gradient from 100% EtOAc to 5% MeOH:EtOAc as eluent to furnish the final compound I-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole as a white solid.
Reaction SMILES: [Na:1].CC1(C)COC(C[O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])OC1.[CH3:31][C:32]1([CH3:41])[CH2:37][O:36][CH:35]([CH2:38][CH2:39]O)[O:34][CH2:33]1>>[Na:1].[CH3:31][C:32]1([CH3:41])[CH2:37][O:36][CH:35]([CH2:38][CH2:39][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])[O:34][CH2:33]1
Reactant: CC1(C)COC(CCO)OC1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using 5,5-dimethyl-1,3-dioxane-2-ethanol (1.00 g, 6.24 mmol) to obtain the title compound (138 mg, 0.31 mmol) as a beige solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.O.NN>CO.[Ni]>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2
Reactant: CNc1ccc2nccnc2c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CNc1ccc2nccnc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a solution of N-methyl-5-nitroquinoxalin-6-amine (1.3 g, 6.4 mmol) in MeOH (100 mL) was added hydrazine hydrate (1.27 g, 25.5 mmol) and Raney Ni (0.2 g). The mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filtrate was concentrated under reduce pressure to give N6-methylquinoxaline-5,6-diamine as a black solid (1.14 g, yield 100%). ESI MS: m/z 175.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[F:51][C:52]1[CH:57]=[CH:56][C:55]([Mg]Br)=[CH:54][CH:53]=1>C1COCC1>[F:51][C:52]1[CH:57]=[CH:56][C:55]([C:13]2([OH:43])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:45])([C:9]4=[O:44])[C:7]4[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=[C:14]2[NH:30][C@@H:31]2[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]2)=[CH:54][CH:53]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4(O)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (200 mg, 0.28 mmol) in THF (5 mL) was added 4-fluorophenylmagnesium bromide (4.30 mL, 1.0 M solution in THF, 4.30 mmol) at −30° C. The mixture was stirred under nitrogen for 30 min. The reaction mixture was quenched with water (0.30 mL), the reaction was brought to room temperature and pH was adjusted to 7 with 1N HCl. The reaction mixture was extracted with dichloromethane (3×50 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford (6R,6aS,14aR)-methyl 12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate as a diastereomer A (13 mg, 7%) and as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.58-7.55 (m, 2H), 7.53 (s, 1H), 7.13-7.07 (m, 2H), 6.60 (s, 1H), 5.69 (s, 1H), 4.93 (br s, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.58-3.46 (m, 5H), 3.37-3.33 (m, 2H), 3.25-3.21 (m, 1H), 2.92 (t, J=9.0 Hz, 1H), 2.41 (s, 3H), 1.35-1.25 (m, 2H), 1.17 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 794 (M+H); HPLC 95.4% (AUC), tR 13.49 min.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[CH3:11][O:12][CH:13](Cl)Cl.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:12][C:13]1[C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[CH:7][C:8]=1[CH:3]=[O:2]
Reactant: COc1ccc(C)cc1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C)cc1C=O
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of 1-methoxy-2,4-dimethylbenzene (8.00 g, 58.7 mmol) and 1,1-dichloromethyl methyl ether (7.40 g, 64.7 mmol) in methylene chloride (30 mL) was added titanium tetrachloride (20.0 g, 105 mmol) at 0° C. and the mixture was stirred at that temperature for 20 minutes. This reaction mixture was poured into iced water and the organic layer was taken, washed with saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.40 g of the title compound. Yield 98%. Oil.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N+:7]([C:10]1[O:14][C:13]([CH:15]=[CH:16][C:17]2[NH:26][C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>P(Cl)(Cl)(Cl)=O>[N+:7]([C:10]1[O:14][C:13]([CH:15]=[CH:16][C:17]2[N:26]=[C:25]([Cl:2])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C=Cc2ccc([N+](=O)[O-])o2)nc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Yield: 67 %

Procedure:
A 500 ml 3 necked flash fitted with a stirrer, reflux condenser and protected by a calcium chloride trap was charged with 9.0 g of phosphorus pentachloride (0.043 mole) and 70 ml of phosphorus oxychloride and the mixture stirred. To this 11.3 g (0.04 mole) of 2-[2-(5-nitro-2-furyl)vinyl] -4-(3H)quinazolinone was added and rinsed into the flask with 15 ml of phosphorus oxychloride. The mixture was heated under reflux for 4 hours, cooled in an ice bath and diluted with 150 ml of diethyl ether. The 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline which precipitated was collected by filtration, washed with 100-150 ml of diethyl ether, slurried in 100 ml of diethyl ether and then refiltered to obtain 8.09 g of the desired product melting at 252°-4°C with decomposition. The product was recrystallized from toluene (large volumes are required) or was extracted in a Soxhlet extractor with toluene to obtain yellow crystals of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline melting at 264°-5°C with decomposition.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN[C@H]1CC[C@H](O)CC1
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
In analogy to example 11.9D. trans-4-Methylamino-cyclohexanol and 4-bromobenzenesulfonylchloride were reacted to yield trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide as off-white solid, MS: 348 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:34][CH2:33]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 86.9 %

Procedure:
3-Methyl-4-nitrophenol (1.74 g, 11.4 mmol), triphenylphosphine (5.98 g, 22.8 mmol), and phenylmethyl 4-hydroxy-1-piperidinecarboxylate (3.99 g, 17.0 mmol) were dissolved in DCM with stirring and cooled to 0° C. Diisopropyl azodicarboxylate (3.35 mL, 17.0 mmol) was added via syringe. The reaction was stirred for 10 min and allowed to warm to rt. The reaction was stirred overnight and adsorbed onto silica gel. The crude material was purified by flash chromatography, and fractions containing product were concentrated in vacuo. The material was contaminated with 3-methyl-4-nitrophenol. The material was dissolved in diethyl ether and washed with 2N NaOH solution (3×), H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide 3.67 g (87%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=9.0 Hz, 1H), 7.42-7.24 (m, 5H), 7.06 (d, J=2.4 Hz, 1H), 7.01 (dd, J=9.1, 2.7 Hz, 1H), 5.07 (s, 2H), 4.76 (ddd, J=7.7, 4.2, 4.0 Hz, 1H), 3.81-3.64 (m, 2H), 3.31 (br. s., 2H), 2.52 (s, 3H), 2.01-1.88 (m, 2H), 1.63-1.49 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a stirred solution of 3-hydroxybenzylalcohol (1.0 g, 8 mmol, 1 equiv.) in 6.4N KOH solution (1.86 ml, 12 mmol, 1.5 equiv.) at r.t., ice (4 g) was added followed by acetic anhydride (0.95 ml, 10 mmol, 1.25 equiv.). The reaction mixture was stirred at r.t. for 3 h. Water (50 ml) was added and the mixture was stirred for 30 min, before extracting with CH2Cl2 (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The clear oil residue was purified by column chromatography on silica, eluted with EtOAc/hexane (1:2), to give the desired product as a clear oil (714 mg, 54% yield). HPLC-MS (method 1): m/z 165 [M−H]−. Rt=2.52 min.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:18]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:18]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:2]
Reactant: O=C1CCCC1
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), cyclopentanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 h at 100° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0434 g, 28%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:21]1([CH2:34][O:35][C:36]([NH:38][CH2:39][C:40](O)=[O:41])=[O:37])[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:40](=[O:41])[CH2:39][NH:38][C:36]([O:35][CH2:34][C:21]1[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:37])[CH2:9][CH2:10][N:11]1[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)OCc1cccc2c1Cc1ccccc1-2
Reactant: Cc1cn(CCNCC(=O)OC(C)(C)C)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cn(CCN(CC(=O)OC(C)(C)C)C(=O)CNC(=O)OCc2cccc3c2Cc2ccccc2-3)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
The product from Example 8 (3.78 g; 13 mmol) and N-(fluorenylmethyloxycarbonyl)glycine (5.9 g; 20 mmol) are dissolved in anhydrous N,N-dimethylformamide (160 ml) under a protective atmosphere of argon gas. N,N'-Dicyclohexylcarbodiimide (4.11 g; 20 mmol) is added in portions at 0° C. The mixture is stirred at room temperature for 21 h and the solid which has precipitated is subsequently filtered off with suction. The solution is then concentrated in vacuo, and subsequently distilled repeatedly with toluene, and the crude product is chromatographed on silica gel. (Eluent: toluene/ethanol, 30:1-20:1). Yield: 6.33 g (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2.[Br:17]Br>C(O)(=O)C>[Br:17][C:6]1([CH3:16])[CH2:5][C:4]2[C:8](=[CH:9][C:10]([S:11](=[O:13])(=[O:14])[NH2:12])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:15]
Reactant: CC1Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(Br)Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O

Procedure:
According to Example 1 (e), 9.7 g (0.037 mole) of 5-chloro-2-methyl-6-sulfamoyl-1-indanone and 5.97 g (0.037 mole) of bromine in a total of 95 ml of glacial acetic acid yield 2-bromo-5-chloro-2-methyl-6-sulfamoyl-1-indanone, which melts at a temperature of from 136° to 138° C. after reprecipitation from a mixture of ethyl acetate and petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: Fc1ccccc1S
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Sc3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 305 was used, starting from 2-fluoro-benzenethiol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenylsulfanyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 381 (MH+).