Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:18]1([C:21]2[NH:25][N:24]=[C:23]([NH2:26])[CH:22]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][C:23]2[CH:22]=[C:21]([CH:18]3[CH2:20][CH2:19]3)[NH:25][N:24]=2)[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(Cl)cc(Nc2cc(C3CC3)[nH]n2)c1=O
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a mixture of 110a (2.38 g, 7.00 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (905 mg, 7.35 mmol), in 1,4-dioxane (40 mL) in a 100 mL single-neck round-bottomed flask was added cesium carbonate (6.84 g, 21.0 mmol). The mixture was purged with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (641 mg, 0.700 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (688 mg, 1.19 mmol) were then added. The flask was connected to a nitrogen-purged condenser and the mixture was refluxed for 6 h under nitrogen. The mixture was cooled to room temperature and filtered. The filter cake was suspended in ethyl acetate (30 mL) and water (10 mL) and filtered through Celite®. The layers were separated. The combined organic layers were dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient 0 to 50% ethyl acetate in heptane to afford 6-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (111a) (1.58 g, 59%).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:31])[C:11](=[O:30])[NH:12][CH:13]1[C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15][C:14]1=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:33][C:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][N:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[O:36]1[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:34]([CH2:33][N:15]2[C:14](=[O:29])[C@@H:13]([NH:12][C:11](=[O:30])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH3:31])[C:19]3([CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[O:18][C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]2=3)=[N:35]1
Reactant: BrCc1noc2ccccc12
Reactant: C[C@@H](C(=O)NC1C(=O)Nc2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2noc3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.8 %

Procedure:
A mixture of tert-butyl methyl((2S)-1-oxo-1-(4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-yl)carbamate (156 mg, 360 μmol), 3-(bromomethyl)benzo[d]isoxazole (83.9 mg, 396 μmol), Cs2CO3 (141 mg, 432 μmol) and NaI (64.7 mg, 432 μmol) in DMF (900 μL) was stirred at RT for 18 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, and the filtrate concentrated to give a residue that was purified by silica gel chromatography. The resulting material was purified by supercritical fluid chromatography (SFC) to provide tert-butyl (S)-1-((S)-5-(benzo[d]isoxazol-3-ylmethyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (54.5 mg, 27%) as a white foam.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:20][CH:21]=[CH2:22])([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH:7]=[CH2:8])C>CO.[OH-].[Na+]>[CH2:6]([C:5]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH2:20][CH:21]=[CH2:22])[C:4]([OH:23])=[O:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(CC=C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-Allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid was prepared starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester (2.2 g, 6.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:16]([Mg]Br)[CH3:17].[Cl-].[NH4+]>CCOCC>[OH:2][CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[CH:5][CH:4]=1)[CH2:16][CH3:17]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in ether (300 ml), followed by the dropwise addition of ethylmagnesium bromide (3M ethereal solution, 33 ml) under cooling with ice. The obtained mixture was stirred to complete a reaction. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic phase was distilled to remove the solvent and the obtained residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 22.3 g of t-butyl 4-(1-hydroxypropyl)benzoate. This product was dissolved in petroleum ether (500 ml), followed by the addition of active manganese dioxide (165 g). The obtained mixture was heated under reflux for 30 hours to complete a reaction. The reaction mixture was filtered and the filtrate was concentrated to give 21.1 g of t-butyl 4-propionylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Br:11][C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:11][C:12]1[C:13]([NH:19][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: COc1ccc(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: COc1ccc(Cl)cc1Nc1ncc(C)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
In a oven dried 50 mL round bottom flask were sequentially added 4-chloro-2-iodo-1-methoxybenzen (1.13 g, 4.2 mmol), 3-bromo-5-methylpyridin-2-amine (945 mg, 5.05 mmol), Pd2(dba)3 (192 mg, 0.21 mmol), xantphos (146 mg, 0.06 mmol) and NatBuO (605 mg, 6.3 mmol) at room temperature. The solid materials were kept under vacuum for 5 min. and then refilled with nitrogen. This process was repeated thrice before adding dry, degassed dioxane (10 mL). The heterogeneous mixture was stirred at room temperature for 15 min. and then at 100° C. for 1 h. Finally upon completion of the reaction, it was diluted with ether and filtered through a small pad of silica gel with several washings. All the washings and filtrate concentrated in vacuum and the crude residue was further purified by flash chromatography to provide title compound (1.16 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2C[CH2:12][N:11]([CH3:14])[CH2:10]2)=[O:7])=[CH:4][C:3]=1[O:17][CH3:18].CN(C)CCNC(=O)C1C=CC([N+]([O-])=O)=C(OC)C=1>>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:12])[CH3:14])=[O:7])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Agent: COc1cc(C(=O)NCCN(C)C)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)NCCN(C)C)ccc1N

Procedure:
The title compound was prepared in quantitative yield by an analogous method to the preparation of Intermediate 187, on a 2 g scale utilising N-(2-dimethylaminoethyl)-3-methoxy-4-nitro-benzamide (Intermediate 195).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])[NH2:52].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:55][CH3:56])([O:57][CH3:58])=[O:54])[NH:52][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])=[CH:34][C:26]=1[Cl:25]
Reactant: O=C(NCc1ccc2cc[nH]c2c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:28]([CH3:31])([O-:30])=[O:29].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:31][N+:28]([O-:30])=[O:29])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1OCc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])ccc1OCc1cccc2ccccc12

Procedure:
36 g of 3-methoxy-4-(naphthalen-1-ylmethoxy)-benzaldehyde, 8.7 9 of ammonium acetate and 10 ml of nitromethane are together heated at reflux for 5 hours in 140 ml of glacial acetic acid. After cooling, the reaction mixture is introduced into 1.5 liters of water. Extraction is carried out twice using 1 liter of ethyl acetate each time. The organic phases are washed 4 once with 500 ml of water and three times using 400 ml of 2N potassium hydrogen carbonate solution each time, dried over magnesium sulfate and concentrated, yielding 1-[2-methoxy-4-(2-nitro-vinyl)-phenoxymethyl]-naphthalene, which can be purified by chromatography on silica gel with ethyl acetate/n-hexane 1:4 and recrystallisation in ethyl acetate/n-hexane, m.p. 120-123° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(C(=O)C=Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Acetylbenzonitrile (14.5 g, 0.1 mol) and 4-fluorobenzaldehyde (12.1 g, 0.1 mol) are dissolved in methanol (150 ml) and solid sodium hydroxide is added to make the solution alkaline. The mixture is stirred in room temperature for 6 hours. The product is filtered off and washed with methanol.
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[O:7]=[S:8]1(=[O:26])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C:14]12[CH2:22][CH:18]3[CH2:19][CH:20]([CH2:21]1)[C:16]([C:23](=[O:25])C)([CH2:17]3)[CH2:15]2.CC(O)=[O:29]>O1CCOCC1.O>[O:26]=[S:8]1(=[O:7])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][C:14]12[CH2:22][CH:18]3[CH2:19][CH:20]([CH2:21]1)[C:16]([C:23]([OH:25])=[O:29])([CH2:17]3)[CH2:15]2
Reactant: CC(=O)O
Reactant: CC(=O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(CN1CCCS1(=O)=O)(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To a stirred mixture of NaOH (1.2 g, 27.8 mmol), H2O (8 mL), and 1,4 dioxane (1 mL) at ice bath temperature was added Br2 (0.56 mL, 10.4 mmol) and the mixture was stirred for 15 minutes. The resulting hypobromite solution was added drop-wise to a stirred solution of the compound obtained in step II (0.55 g, 1.85 mmol) in 1,4-dioxane (3 mL) at ice bath temperature. The reaction mixture was gradually warmed to room temperature and after stirring for 1 h; it was cooled to ice bath temperature and quenched by adding AcOH (1.7 mL, 27.8 mmol). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-[(1,1-dioxidoisothiazolidin-2-yl)methyl]tricyclo[3.3.1.03,7]nonane-3-carboxylicacid (0.39 g) in 70% yield. m/z (M−1) 298; 1H NMR (CDCl3) 300 MHz δ 3.32 (t, J=6.8 Hz, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.95 (s, 2H), 2.80-2.73 (m, 1H), 2.43-2.41 (m, 1H), 2.40-2.29 (m, 2H), 2.10-2.0 (m, 2H), 1.82-1.72 (m, 3H), 1.67-1.54 (m, 4H), 1.46 (dd, J=3.2, 11.0 Hz, 1H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([NH:20][C@@:21]3([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH2:25][C@@H:24]([O:26][CH3:27])[CH2:23][C@H:22]3[CH2:28]O)=[S:19])C3C(=CC=CC=3)C=2C=CC=1>CO>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@:21]12[CH2:25][C@@H:24]([O:26][CH3:27])[CH2:23][C@H:22]1[CH2:28][S:19][C:18]([NH2:17])=[N:20]2
Reactant: CO[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Solvent: CO
Product: CO[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl({[(1S*,2R*,4S*)-1-(2-fluorophenyl)-2-(hydroxymethyl)-4-methoxycyclopentyl]amino}carbonothioyl)carbamate (330 mg) in methanol (20 mL)-concentrated hydrochloric acid (1 mL) was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 mL) and piperidine (1 mL) were added to the residue at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The resulting crude product was purified by NH-silica gel column chromatography to obtain the title compound (170 mg).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:23])=[CH:9][C:10]=3[N+:16]([O-:18])=[O:17])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc[n+]([O-])c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-bromo-4-nitro-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide (90 mg, 0.267 mmol) in 1 mL of dry DMF was added dropwise to a solution of phosphorus oxychloride (44.0 μL, 0.481 mmol) in 0.2 mL of DMF and 0.5 mL of toluene at 0° C. After stirring at 0° C. for 0.5 h, the reaction was quenched with saturated NaHCO3 and extracted with ethyl acetate (5×5 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=100:3) gave 8-bromo-2-chloro-4-nitro-10H-chromeno[3,2-b]pyridin-10-one as a light yellow solid.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[CH:43][C:38]([C:35](=[O:37])[CH3:36])=[CH:39][CH:40]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C(C)=O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-acetylphenylboronic acid (97 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (26 mg, yield 52%).
Reaction SMILES: [Na].[CH2:2]([NH:6][C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][CH3:5].C([O:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16])C>C(O)C>[CH2:2]([N:6]1[C:15](=[O:16])[CH2:14][C:13](=[O:12])[NH:9][C:7]1=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCN1C(=O)CC(=O)NC1=O
Yield: 68.8 %

Procedure:
To a solution of 23 g (1g-atom) sodium metal in 500 ml absolute ethanol were added at room temperature 35 g (0.3 mole) butyl-urea and 48 g (0.3 mole) malonic acid-diethylester. The alcohol was then distilled off in an oil bath held at 120° C and the residue maintained at this temperature for about 16 hours. The residue was then cooled and dissolved in about 300 ml water, stirred with activated carbon and the solution filtered. The clear filtrate was acidified by the addition of concentrated hydrochloric acid to produce 38 g 1-butyl-barbituric acid, representing a yield of 68%. The substance had, after recrystallization from benzene, a melting point of 107°-108° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(O)(=O)CCC(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>ClCCl.O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:21][CH2:22]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCC2CCN(c3ccc(C)nn3)CC2)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
A mixture of 10.4 parts of 3-chloro-6-methylpyridazine, 22.4 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate butanedioate (1:1), 8.6 parts of sodium carbonate and 0.9 parts of N,N-dimethylformamide was stirred for 3 hours in an oil bath at ±150° C. After cooling, water and dichloromethane were added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone (75:25 by volume). The precipitated product was filtered off and dried, yielding 17 parts (56.8%) of ethyl 4-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]-ethoxy]benzoate; mp. 130.1° C. (comp. 1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:4]=1[NH2:5].[S-:16][C:17]#[N:18].[K+].[OH-].[Na+].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)(=O)C.BrBr.C(OCC)C.O>[CH3:1][N:2]([CH3:15])[C:3]1[C:4]2[N:5]=[C:17]([NH2:18])[S:16][C:6]=2[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: N#C[S-]
Reactant: CN(C)c1cc(OC(F)(F)F)ccc1N
Agent: BrBr
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CN(C)c1cc(OC(F)(F)F)cc2sc(N)nc12
Yield: 27.8 %

Procedure:
The procedure is as in Example 1, starting with 2-dimethylamino-4-trifluoromethoxyaniline (2 g), potassium thiocyanate (3.5 g) dissolved in acetic acid (30 cc) and bromine (1.45 g; 0.47 cc). Stirring is maintained for 12 hours at this temperature. The mixture is evaporated to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is taken up with water (100 cc) and the pH is brought to 9-10 with concentrated sodium hydroxide (10N). After extraction with ethyl acetate (2×50 cc), washing of the combined phases with water (2×20 cc), drying over anhydrous magnesium sulphate and evaporating to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa), a brown oil is isolated, which oil is purified by flash chromatography on a column of silica under a stream of nitrogen at moderate pressure (0.5-1.5 bars), with a dichloromethane/methanol mixture (99:1 by volume). A solid is isolated, which is dissolved in ethyl ether (30 cc), and ethereal hydrogen chloride (6.2N) is added until precipitation is complete. 4-Dimethylamino-6-trifluoromethoxy-2-benzothiazolamine (0.7 g) is thereby isolated in the form of a dihydrochloride, m.p. 184° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[Cl:12][C:13]1[C:19]([CH2:20][OH:21])=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[C:19]([CH2:20][OH:21])=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)c(CO)c1
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(CO)c1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To 50 ml of acetic acid, 2.47 g of 3,4,5,6-tetrahydrophthalic anhydride and2.56 g of 4-chloro-5-hydroxymethyl aniline were added and the mixture was heated to reflux under stirring for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, benzene/ethyl acetate=10/1 (v/v)) to obtain 1.82 g of the desired product.