Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C([O-])(=O)C.[K+:12].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[K+:12].[C:13]1(=[O:18])[N:1]([CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])[C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: NCCS(=O)(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Yield: 84.1 %

Procedure:
A mixture containing 30 g of taurine, 25 g of potassium acetate and 90 ml of acetic acid is brought to reflux for 10 minutes and 37.8 g of phthalic anhydride are then added. The mixture is heated to reflux for two and a half hours and then filtered, and the product is washed with AcOH and then with 2-propanol; it is rinsed with ether and then dried under vacuum to obtain 59.14 g of the expected product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.O1CCOCC1.[ClH:24]>>[ClH:24].[CH3:16][C:13]1[N:12]=[C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)[O:15][N:14]=1
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1noc(C2(N)CC2)n1
Reaction time: 1 h

Procedure:
To a solution of N-boc-amino-cyclopropanecarboxylic acid (1.01 g, 5.00 mmol) in 2 mL of DMF was added carbonyldiimidazole (0.812 g, 5.01 mmol). This reaction mixture was stirred at room temperature for 6 h. N-Hydroxy-acetamidine (0.374 g, 5.05 mmol) was added. This reaction mixture was stirred at room temperature for 2 h then heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration was washed with acetonitrile and water, air-dried to give [1-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester as 1.05 g of white solid, m/z 240 [M+1]+. [1-(3-Methyl-1,2,4-oxadiazol-5-yl)-cyclopropyl]-carbamic acid tert-butyl ester (80 mg, 0.33 mmol) was dissolved in HCl in 1,4-dioxane (4.0 M, 1.0 mL, 4.0 mmol). After standing at room temperature for 1 h, the solvent was removed by a stream of nitrogen. The title compound was isolated and used without further purification.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:16][CH2:17][CH2:18][Cl:19])[CH:8]=[C:7]2[CH:13]=[O:14]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=Cc1cn(CCCCl)c2ccc(Cl)cc12
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred mixture of powdered potassium hydroxide (85%, 2.6 g, 39 mmol) in methyl sulfoxide (20 mL) was added dropwise a solution of 5-chloroindole-3-carboxaldehyde (3.5 g, 19 mmol) in methyl sulfoxide (5 mL). The mixture was stirred for 30 min and 1-bromo-3-chloropropane (2.9 mL, 29 mmol) was added dropwise. The mixture was stirred for 1 h and partitioned between ethyl acetate (3×40 mL) and water (100 mL). The combined organic extracts were washed (water, brine), dried (sodiurn sulfate) and concentrated in vacuo. The solid residue was recrystallised (2-propanol) to give the product as a white solid (4.1 g, 82%): mp 107-108° C.; Found: C, 56.51; H, 4.26; N, 5.44%. C12H11Cl2NO requires: C, 56.27; H, 4.33; N, 5.47%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][CH2:14][OH:15])[C:10]([NH2:12])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:17]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>C(Cl)Cl>[NH2:17][O:15][CH2:14][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]([NH2:12])=[O:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCON)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
To a solution of (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) in CH2Cl2 (150 mL) was added 2-hydroxyisoindolin-1,3-dione (5.1 g, 31.2 mmol) and triphenylphosphine (8.2 g, 31.2 mmol). The resultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate (6.0 ml, 31.2 mmol) was slowly added dropwise with an addition funnel under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was concentrated to provide clear oil, which was purified by flash chromatography (60% EtOAc-Hexane). The resultant pale yellow compound was dissolved in CH2Cl2 (60 ml). Hydrazine hydrate (670 μL, 8.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 8 h. The resultant solid was filtered off and the filtrate concentrated under reduced pressure to provide a clear yellow oil of (S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1.1 g, 4.4 mmol). [M+H] calc'd for C10H24N2O3Si, 249. found, 249.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: ClCCBr
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 93.8 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.0 g 9.96 mmol) and potassium carbonate (6.9 g, 50 mmol) in dry DMF (70 mL) is added 1-bromo-2-chloroethane (4.0 mL, 50 mmol). The mixture is heated to 85° C. for 8.25 h. The mixture is then partitioned between water and Et2O. The organic layer is separated and washed three times with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (200 mL silica) using CH2C2/hexanes (1/1) as eluent gave 3.4 g (94%) of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1(=O)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=[O:36])[O:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:23]4[C:27](=[O:28])[C:31]5[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29]4=[O:36])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6ccccc6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][CH:10]([Cl:14])[C:11](Cl)=[O:12].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:9][CH:10]([Cl:14])[C:11]([NH:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:12]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ncc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(Cl)cn1)C(Cl)Cl

Procedure:
To 2-amino-5-chloropyrimidine (1.30 g) dissolved in N,N-dimethylformamide (30 mL), dichloroacetyl chloride (1.44 mL) and sodium hydrogencarbonate (1.26 g) were added, and the resultant mixture was stirred at room temperature for 1 hour. The solvent was distilled away under reduced pressure. Methylene chloride and water were added to the residue for partitioning the mixture. The aqueous layer was extracted with methylene chloride. The organic layers were combined, and the resultant mixture was washed with water, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane ethyl acetate=1:1). The resultant white solid was slurry-washed with a solvent mixture of hexane-diethyl ether (4:1), followed by filtration to recover, to thereby give the title compound (1.24 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:45]=[O:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[BH3-]C#N.[Na+]>ClC(Cl)C.CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(C=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CO)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-formyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (36 mg, 0.05 mmol) in dichloroethane (2 mL) was added NaCNBH3 (1M in THF, 1 mL, 0.5 mmol), followed by a few drops of HOAc. The mixture was stirred at RT for 3 h then concentrated in vacuo. The residue was dissolved in MeOH and purified on reverse phase HPLC (MeOH/H2O/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(hydroxymethyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a sticky solid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1F.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[N:19]([CH2:20][CH3:21])[CH2:17][CH3:18]
Reactant: CCNCC
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(NC)c([N+](=O)[O-])cc1C(=O)OC

Procedure:
2-Diethylamino-4-methylamino-5-nitro-benzoic acid methyl ester (1.2 g) was prepared by following General Procedure A starting from 2-fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (1.0 g) and diethylamine (683 uL) in DMF.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:11](=[O:15])[CH2:12][CH2:13]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)CCCl)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1ccc2c(c1)CCC2=O
Temperature: 95 °C

Procedure:
1-(4-tert-Butylphenyl)-3-chloro-1-propanone (22.25 g, 99 mmol) was dissolved in concentrated sulfuric acid (100 ml) and heated on a water bath at 95° C. for 2.5 hours. The reaction mixture was cooled, poured onto ice, and extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=[O:14])C>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:14][C@@H:9]2[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: OC/C=C/c1cccc(Br)c1
Product: OC[C@H]1O[C@@H]1c1cccc(Br)c1
Yield: 73 %

Procedure:
The title compound was prepared from trans-3-(3-bromophenyl)-2-propenol by a sequence analogous to that described above for compound (9a) but using D-(-)-diethyl tartrate. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 3:7) provided the title compound (73%) as a pale yellow oil. Distilled at 160°-185° C. at 0.1 mmHg. using a Kugelrohr short path distillation apparatus as a colourless oil; [α]D25 +37.6 (c=0.020 gml-1, CHCl3).
Reaction SMILES: [OH:1][C:2]1([CH2:17]N)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1>O.C(O)(=O)C>[CH:13]1[C:5]2[O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:17][C:2](=[O:1])[CH2:3][C:4]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC1(O)Cc2ccccc2Oc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2ccccc2Oc2ccccc2C1
Yield: 78.5 %

Procedure:
10,11-Dihydro-10-hydroxy-dibenz[b,f]oxepine-10-methanamine (46.6 g - as prepared in example A) was dissolved in a mixture of water (940 ml) and acetic acid (23 ml), and the solution was filtered and cooled below 5° C. To this cooled solution was quickly added a solution of sodium nitrite (20.5 g) in the minimum of water, the cooling was then removed, and the mixture was allowed to stand at ambient temperature for eighteen hours. The product was filtered, dissolved in dichloromethane, and the solution was filtered through silica, then evaporated. The residue was crystallised from 1,1'-oxybisethane/n-hexane to give pure 5H-dibenz[b,g]oxocin-6(7H)-one (34 g). M.P. 86° C. (Lit. 84.5° C. J.Org.Chem.34.1165(1969).
Reaction SMILES: [H][H].[C:3]1([C:9](O)([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(O)c1ccccc1
Reactant: [H][H]
Product: CC(C)c1ccccc1

Procedure:
The 6–20 mesh particles of reduced catalyst, prepared by the afore-mentioned procedure are loaded onto bed supports made of porous plate or screen in a distillation reactor in a nitrogen filled environment. Glass wool can also be used to support the catalyst particles. Hydrogen gas is added via a regulator to the apparatus to maintain a pressure between 0–450 psig, (typically between 0–150 psig). The flow rate is adjusted to maintain twice the amount of hydrogen required for the reaction stoichiometry. A feed stream containing alkylphenyl alcohol, such as a stream containing (e.g.10–40 weight %) of 2-phenyl-2-propanol (cumyl alcohol), is fed into the distillation reactor from below the catalyst beds. The bottom section of the distillation reactor is lowered into a heater and then the temperature is raised until the liquid refluxes in the distillation reaction zone containing the catalyst. Lower boiling alkylbenzene, such as cumene, and water are distilled out from the top of the column. Additional alkylphenyl alcohol, such as a cumyl alcohol-containing stream, is continually added with a slight molar excess of hydrogen to replace the amount of alkylphenyl alcohol, such as cumyl alcohol, that is converted to alkylbenzene, such as cumene, and distilled off. The alkyl benzene product, such as cumene, easily separates from the denser water phase. It is optionally dried further with molecular sieves or other suitable drying agents. The alkylbenzene, such as cumene, produced has a purity of more than 98 wt. %, preferably more than 99 wt. %. No measurable alkylphenyl alcohol, such as cumyl alcohol (<0.01 wt. %) is found in the alkylbenzene, such as cumene product. When desired, the bottoms can be removed, optionally diluted with cumene and sent to a fixed bed hydrogenation reactor to make additional alkyl benzene, such as cumene.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][O:3][CH2:2]1.[C:9]12([NH2:19])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2>ClCCl>[C:9]12([NH:19][C:5](=[O:6])[CH2:4][O:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:16][CH:15]3[CH2:14][CH:13]([CH2:12][CH:11]([CH2:17]3)[CH2:10]1)[CH2:18]2
Reactant: O=C1COCC(=O)O1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Product: O=C(O)COCC(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 3.67 h

Procedure:
In a similar operation, a solution of 11.56g (0.100 mole) of diglycolic anhydride in 1 liter of dichloromethane was added with stirring to a solution of 15.11 grams (0.100 mole) of 1-adamantanamine in 700 milliliters of dichloromethane during about 24 minutes at about 15° to 25° C., whereupon a reaction took place with the formation of heterogeneous milky white mixture. The mixture was stirred for 3.67 hours at temperatures of about 23°-25° C. to complete the reaction with the formation of the desired product in the reaction mixture. The mixture was then concentrated on a rotary evaporator to recover 32.7 grams of a white solid which after recrystallization from 1:1 isopropanol-water mixture yielded the desired [2-(1-adamantylamino)-2-oxoethoxy]acetic acid as white plates, m.p. 181°-183° C.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:11]1[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH2:4][CH2:3][CH2:2][N:1]3[C:37]=1[CH2:38][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2cccc3c2n1CCC3)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
To a solution of the above crude aldehyde (180 mg, 0.97 mmol) and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (372 mg, 1.06 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (410 mg, 1.93 mmol). The reaction mixture was stirred at room temperature for 3 days. Then the solvent was removed under reduced pressure to afford a yellow oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (135 mg, 27%). 1H NMR (CDCl3) δ 1.42-1.47 (m, 2H), 1.56-1.63 (m, 2H), 1.93-1.96 (m, 2H), 2.06-2.07 (m, 2H), 2.22 (t, 2H, J=6.0 Hz), 2.60-2.67 (m, 3H), 2.70 (m, 1H), 2.95 (t, 2H, J=6.0 Hz), 3.56 (t, 2H, J=6.0 Hz), 4.01 (t, 1H, J=6.0 Hz), 4.16 (ABq, 2H, J=42.0, 15.0 Hz), 4.29-4.35 (m, 1H), 4.51 (br s, 1H), 4.58-4.66 (m, 1H), 6.94 (d, 1H, J=7.2 Hz), 7.01-7.06 (m, 1H), 7.09 (t, 1H, J=8.1 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.68-7.70 (m, 2H), 7.78-7.81 (m, 2H), 8.41 (d, 1H, J=3.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14](I)[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]2)=[CH:5][N:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([F:34])[CH:27]=1>C1COCC1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]([OH:31])[C:14]2[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[CH:16]([CH3:18])[CH3:17])=[C:28]([F:34])[CH:27]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1I
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
To a solution of ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.4, 1.15 g, 2.55 mmol) in 14 ml THF, a solution of 1M isopropylmagnesium chloride lithium chloride complex (2.68 ml, 2.68 mmol) was added at 0° C. and the mixture was stirred for 15 min. Then the solution was cooled down to −78° C. and a solution of 4-chloro-2-fluorobenzaldehyde (405 mg, 2.55 mmol) in 3 ml THF was added. The reaction mixture was stirred for 30 min at temperatures between −78° C. to −20° C. The solution was quenched with 10 ml of 1M NH4Cl solution, washed with brine and extracted 3 times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by chromatography (Silicagel, heptane, heptane/EtOAc 1:4) to give 977 mg (1.901 mmol, 74.5% yield) of the title compound as a white foam. LCMS: (M+H)=479; tR=1.18 min (LC-MS 4). HPLC: tR=5.48 min (HPLC 7). TLC: Rf=0.35 (Heptane/EtOAc 1:2).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[C:7]=1[C:15]#[N:16])=[O:4].S(=O)(=O)(O)[OH:18].[OH-].[NH4+]>O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[C:7]=1[C:15](=[O:18])[NH2:16])=[O:4]
Reactant: CCCOc1nsc(NC(=O)NC)c1C#N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCOc1nsc(NC(=O)NC)c1C(N)=O

Procedure:
A mixture of 8.5 g of 1-methyl-3-(4-cyano-3-propoxy-5-isothiazolyl)urea with 20 ml of concentrated sulfuric acid was heated to 50° during 1 hour. Analysis by thin-layer chromatography at this time indicated the reaction to be complete. The reaction mixture was poured with stirring into 200 ml of water. The resulting solution was neutralized with ammonium hydroxide solution and the precipitate was collected by filtration. The dried solid was recrystallized from ethanol to give 6.3 g of 1-methyl-3-(4-carbamoyl-3-propoxy-5-isothiazolyl)urea, m.p. 195°-198°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH3:22].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:7])[NH:22][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: O=C(O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-bromo-4-phenylisocoumarin-3-carboxylic acid (15 g) in methanol (100 ml) was added 12% ammonia-methanol solution (60 ml) and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated, and 1N hydrochloric acid was added to the obtained residue. The mixture was extracted with ethyl acetate. The organic layer was dried and concentrated and 4N hydrochloric acid ethyl acetate solution (30 ml) was added to the obtained oily substance. The mixture was stirred at room temperature for 2 hrs. and the reaction mixture was concentrated. The obtained crystal was washed with water and dried under reduced pressure to give 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid as colorless crystals.