Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:40])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:21]([N:23]([CH:37]([CH3:39])[CH3:38])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[O:22])[C:18]([CH3:20])=[CH:19][C:5]=2[O:4]1.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>O1CCCC1>[CH2:41]([NH:43][C:44]([O:1][CH2:2][C:3]1([CH3:40])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:21]([N:23]([CH:37]([CH3:38])[CH3:39])[C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:25]3)=[O:22])[C:18]([CH3:20])=[CH:19][C:5]=2[O:4]1)=[O:45])[CH3:42]
Reactant: CCN=C=O
Reactant: COCCCCN1C(=O)C(C)(CO)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Solvent: C1CCOC1
Product: CCNC(=O)OCC1(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCCCOC)C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (66 mg) in tetrahydrofuran (1 ml) was added ethyl isocyanate (83 mg), and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (65 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:6][C:7](O)=O)[C:3](O)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:7][N:11]([CH2:12][CH2:13][OH:14])[CH2:3]1
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: NCCO
Product: CC1(C)CCN(CCO)C1

Procedure:
The title compound was synthesized as described in Intermediate 21 using 2,2-dimethylsuccinic acid and 2-aminoethanol as starting materials. 1H NMR (CDCl3): δ 3.55 (t, 2H), 3.35 (br s, 1H), 2.60 (m, 4H), 2.33 (s, 2H), 1.55 (t, 2H), 1.43 (s, 6H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:31]=[CH:30][C:29]4[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=4[CH:23]=3)[N:17]=2)[CH2:12][CH2:11]1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>C1COCC1>[CH3:32][C:28]1([CH3:33])[CH2:27][CH2:26][C:25]([CH3:34])([CH3:35])[C:24]2[CH:23]=[C:22]([C:18]3[N:17]=[C:16]([N:13]4[CH2:12][CH2:11][N:10]([CH2:9][CH:7]5[CH2:8][CH:6]5[CH2:4][OH:3])[CH2:15][CH2:14]4)[CH:21]=[CH:20][CH:19]=3)[CH:31]=[CH:30][C:29]1=2
Reactant: CCOC(=O)C1CC1CN1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCN(CC5CC5CO)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.21 mmol) of 2-{4-[6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl]piperazin-1-ylmethyl}cyclopropanecarboxylic acid ethyl ester is dissolved in 4 ml of THF, and 1.05 ml (1.05 mmol) of diisobutylaluminium hydride (1.0 M in THF) are added. The reaction mixture is stirred at room temperature under nitrogen atmosphere for 18 h. Water is added to the reaction mixture, which is then briefly stirred, ethyl acetate is added, and the mixture is filtered through Celite. The filter cake is washed with ethyl acetate and methanol, and the mother liquor is evaporated. The residue is purified by column chromatography on silica gel.
Reaction SMILES: NC1C=CC(NC(=O)C)=CC=1.B1([O-])OO1.O.O.O.O.[Na+].B(O)(O)O.C([NH:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[N:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43]C(=O)C)=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)(=O)C>C(O)(=O)C>[NH2:43][C:40]1[CH:39]=[CH:38][C:37]([N:36]=[N:35][C:32]2[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=2)=[CH:42][CH:41]=1
Reactant: CC(=O)Nc1ccc(N=Nc2ccc(NC(C)=O)cc2)cc1
Agent: CC(=O)Nc1ccc(N)cc1
Agent: OB(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
4,4′-diaminoazobenzene (DAAB, III) is synthesized via a two-step route shown in FIG. 1. Glacial acetic acid (500 mL), 4′-aminoacetanilide (I) (29.0 g, 0.19 mol), sodium perborate tetrahydrate (40 g, 0.26 mol) and boric acid (10 g, 0.16 mol) are added to a 1 L three-necked round-bottomed flask equipped with a magnetic stir bar, a condenser, and a thermometer. The mixture is heated with stirring to 50-60° C. and held at this temperature for 6 hours. After the mixture is allowed to cool to room temperature, the yellow product is collected on a Büchner funnel and washed with water until the washings are neutral as indicated by pH paper. The product is then dried in a vacuum oven at 110° C. to afford 16.7 g. (58%) of 4,4′-bis(acetamido)azobenzene (II), m.p. 289.4-290.0° C. (dec.). 1H-NMR (DMSO-d6, δ in ppm): 2.08 (s, 6H, CH3), 7.76-7.83 (m, 8H, Ar—H), 10.25 (s, 2H, NH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Br:11][C:12]1[CH:13]=[C:14]([OH:22])[C:15](=[CH:20][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(#N)C>[CH2:9]([O:22][C:14]1[CH:13]=[C:12]([Br:11])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH:8]=[CH2:7]
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C=CCOc1cc(Br)ccc1C(=O)OC

Procedure:
139 g of ground potassium carbonate, 470 ml of acetonitrile, 16 g of benzyltributylammonium chloride and 136 g of allyl bromide were introduced into a 3-liter round-bottomed flask and 236 g of ground methyl 4-bromosalicylate were added in small amounts. The contents were heated under reflux with vigorous stirring, for 5 hours and then a part of the acetonitrile was distilled off under slight vacuum and the residue was taken up with water. A precipitate of methyl 2-allyloxy-4-bromobenzoate was obtained, which was drained, washed with water and air-dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH-].[K+].Br[CH2:13][CH2:14][Cl:15]>CCO>[Cl:15][CH2:14][CH2:13][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCBr
Reactant: CC1(C)NC(=O)NC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)NC(=O)N(CCCl)C1=O
Temperature: 25 °C

Procedure:
5,5-Dimethylhydantoin (5 g, 39 mmol, 1 eq.) was added to a solution of potassium hydroxide (2.18 g, 39 mmol, 1 eq.) in EtOH (100 mL). 1-bromo-2-chloroethane (11.2 g, 78 mmol, 2 eq.) was added in one portion. The resulting mixture was refluxed overnight. Reaction was cooled to room temperature and concentrated in vacuo. Crude residue was re-suspended in ethyl acetate (150 mL), and washed with H2O (100 mL), saturated aqueous sodium bicarbonate (100 mL) then brine (100 mL). Organic layer was dried (Na2SO4) and concentrated in vacuo to yield the crude product, which was directly used in the next step. Yield: 5.4 g (73%). LCMS—[M+H] m/z 191.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:24]([O:26]CCCC)=[CH2:25].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:23])[NH:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:26])[CH3:25]
Reactant: COC(=O)c1cc(Br)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)cc(C(=O)NC(C)c2ccc(F)cc2)c1
Temperature: 122 °C
Yield: 65.3 %

Procedure:
A mixture of methyl 3-bromo-5-((1-(4-fluorophenyl)ethyl)-carbamoyl)benzoate (880 mg, 2.32 mmol), 1-(vinyloxy)butane (464.7 mg, 0.6 mL, 4.64 mmol), palladium acetate (16.0 mg, 0.070 mmol), DPPP (63.1 mg, 0.0153 mmol) and potassium carbonate (382 mg, 2.78 mmol) in DMF (2.5 mL) and H2O (0.3 mL) in a Smith process vial was heated at 122° C. in microwave for 3 h. The reaction mixture was cooled down to RT and hydrolyzed by addition of 5% HCl slowly. The reaction mixture was worked up by extraction with ethyl acetate and concentration under vacuum. The crude mixture was purified by reverse phase prep HPLC to give the title compound (520 mg, 65.4% yield): HPLC retention time: 1.88 min (method A). MS (ESI) (M+H)+ 343.00.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[CH2:12]1[NH:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: C1CN1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCN)o1
Reaction time: 18 h
Yield: 2.5 %

Procedure:
To a solution of 5-(dimethylamino)methyl-2-furanmethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulphonic acid (11.6 g) in tetrahydrofuran (40 ml). The solution was evaporated and the oily residue heated at 98°-100° for 10 mins. After 18 hr, 5 N sodium hydroxide (60 ml) was added and the solution evaporated to dryness. Anhydrous sodium sulphate and ethyl acetate (150 ml) were added and after 2 hr the suspension was filtered, treated with decolourising charcoal and evaporated. The resulting oil was chromatographed on silica, firstly with methanol-ammonia 0.88 79:1, and the eluate discarded, and secondly with methanol-ammonia 0.88 19:1. This eluate was evaporated to give an oil from which the bisoxalate salt of 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine (from ethanol) 0.2 g, m.p. 125°-128°, was obtained. Route (ii)
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])[CH2:21][CH2:20]1
Reactant: C=CC(=O)OCCCCCCCCCCCC
Reactant: CN1CCNCC1
Product: CCCCCCCCCCCCOC(=O)CCN1CCN(C)CC1
Temperature: 85 °C

Procedure:
In a 40-mL scintillation vial, 12.0 g (0.05 moles) of lauryl acrylate is charged followed by the slow addition of 5.0 g (0.05 moles) of 1-methyl piperazine. The mixture is agitated using a magnetic stirrer bar and heated to 85° C. for at least 16 hours using a heating block. The final product is a light brown liquid at ambient temperature. Complete conversion is apparent from the lack of olefin protons in the 1H-NMR spectra. 1H-NMR (300 MHz, CDCl3): δ 3.83 (t, 6.6 Hz, 2H), 2.45 (t, 7.3 Hz, 2H), 2.24 (m, 10H), 2.02 (s, 3H), 1.38 (t, 6.8 Hz, 2H), 1.03 (m, 18H), 0.65 (t, 7.1 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.78, 63.92, 54.64, 53.12, 52.39, 45.53, 31.93, 31.45, 29.19, 21.17, 29.12, 29.08, 28.89, 28.80, 28.20, 25.47, 22.20, 13.63.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C1COCC1>[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[O:16][N:15]=1
Reactant: Cc1cc(C)on1
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCBr)on1
Temperature: -70 °C

Procedure:
To a solution of diisopropylamine (8.4 ml, 0.06 mol) in THF, was added, at -5° C., and under nitrogen, n-butyllithium (1.6M in Hexane, 37.5 ml, 0.06 mole). After the addition was complete, the solution was cooled to -70° C. and 3,5-dimethylisoxazole (5.82 g, 0.06 mol) in THF (20 ml) was added dropwise. The mixture was stirred for an additional hour at -70° C., then added, via nitrogen purge, to a solution of 1,6-dibromohexane (58.56 g, 0.24 mol) in THF (40 ml), and chilled to -70° C. with stirring. The mixture was allowed to gradually warm to room temperature and then stirred overnight. After quenching with saturated solution of ammonium chloride (30 ml), the mixture was extracted with isopropylacetate (250 ml) and the extract was washed with distilled water and dried. Removal of the solvent and excess 1,6-dibromohexane gave an oil which was purified by c.c. (EtAcO/Hexane; 1:4).
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1C=C[CH:31]=[CH:30][C:29]1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][CH:30]=[CH:29][N+:28]=1[CH3:27])[CH3:10]
Reactant: Cn1ccccc1=O
Reactant: CCOCC
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: ClCC1CO1
Product: CCOc1cccc[n+]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium tetrafluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 4.36 g (0.040 mole) of 1-methyl-2-pyridone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight (about 16 hours). The solvent is evaporated at room temperature, in vacuo and the quaternary salt obtained is recrystallized from methanol-ether (1:1) to give 8.0 g (71%) of 2-ethoxy-1-methylpyridinium fluoroborate, m.p. 58°-60° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl.C1CCCCC1.CCOCC>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1)=[O:21]
Reactant: Nc1cccc(I)c1
Reactant: O=C(Cl)CCCBr
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: O=C(CCCBr)Nc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 3-iodoaniline (1.5 g, 6.85 mmol) and triethylamine (1.34 mL, 9.59 mmol) in dichloromethane (28 mL) at 0° C. was added dropwise 4-bromobutyryl chloride (0.99 mL, 8.56 mmol). The reaction mixture was then stirred at room temperature overnight. The organic extract was washed with an aqueous 1M HCl solution, aqueous 1M NaOH solution and brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-15%) in cyclohexane to yield a sticky solid. Trituration in a mixture of cyclohexane and ether and then filtration give the title compound as a solid (1.61 g, 64%).
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[I:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:16]2[CH:17]=[C:12]([I:11])[CH:13]=[N:14][C:15]2=[O:18])=[CH:5][CH:6]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: O=c1ncc(I)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(I)cn1COc1ccc(Cl)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 6, by adding a solution of 1-chloromethoxy-4-chlorobenzene (see Preparation 3) (10 mmol) in dichloromethane (10 ml) to a solution of 5-iodopyrimidin-2-one (10 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml), and heating the resultant mixture under reflux for 3 h. The product, 2.05 g (56%), consisted of the N- and O-isomers in the ratio 4:1. The O-isomer was removed from the product by extraction with acetone and the remaining N-isomer was recrystallized from EtOAc; m.p. 216° C. (Found C36.64; H2.24 Calc. for C11H8ClIN2O2 : C36 44; H2.23) 1H NMR (DMSO-d6 /CDCl3): δ 5.85 (CH2), 6.9-7.5 (Ph), 8.68 and 8.82 (H-4 and H-6, respectively, J 3 Hz). IR (KBr) 1650 cm-1 (CO). MS (70 eV, m/z (% rel. int.)): 362 (37,M) 235 (100), 222 (6), 108 (22).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N+:17]([O-])=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1.S(=O)(=O)(O)O>O>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=1[N:13]1[N:17]=[C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]2=[N:14]1
Reactant: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 82.9 %

Procedure:
In order to conduct the reaction of Process (c), the system was heated, and was stirred at 66° to 68° C. (boiling point) for 5 hours. As this result, the N-oxide disappeared, thus Process (c) being completed. Thereafter, water 50 ml was added to the reaction liquor, and the resultant reaction liquor was neutralized with 62% sulfuric acid 10 g to precipitate a crystal. The precipitated crystal was separated by filtration, and the separated crystal was fully washed with hot water of 60° to 70° C. and further with a small amount of methanol. The washed crystal was then dried, thus obtaining 8.7 g of 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole having a melting point of 138° to 140° C. at the yield of 82.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Sc2cccs2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenylthio)thiophene (9.8 g) in dry tetrahydrofuran (75 ml) at -30° C. under nitrogen, was added dropwise, n-butyllithium (17.4 ml, 2.5M) and the solution left to stir at -30° C. for 2 hours. Dry dimethylformamide (5.1 ml) was then added and the solution allowed to stir at -30° C. for a further hour, warmed to room termperature and stirred overnight. The reaction mixture was poured onto 2N hydrochloric acid (75 ml), extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 25% ether-hexane to give an orange oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])C.[NH4+:14].[OH-]>>[CH3:12][S:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:14])=[O:3])(=[O:11])=[O:10]
Reactant: [NH4+]
Reactant: CCOC(=O)CCCNS(C)(=O)=O
Agent: [OH-]
Product: CS(=O)(=O)NCCCC(N)=O

Procedure:
A solution of 4-methanesulfonylamino-butyric acid ethyl ester (7.08 g, 33.8 mmol) in concentrated NH4OH (200 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated to afford the title compound of Step B as a white solid (6.16 g). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.30 (s, 3H), 3.05-3.09 (m, 2H), 2.91 (s, 3H), 2.24-2.30 (m, 2H), 1.80-1.85 (m, 2H); MS 181 (M++1).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=2[Cl:23])=[CH:10][CH:9]=1>>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:12][C:11]1[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To cooled chlorosulfonic acid (2.0 mL) at 0° C. was added 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (700 mg, 2.2 mmol) in several portions. The resulting mixture was stirred at 0° C. for 5 min, then at RT for 2.5 h. The solution was added dropwise to ice water (40 mL) and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried and concentrated to yield the title compound of Step A (920 mg) as a crude product which was used in the next step without purification. MS (APCl−) Calc.: 410.9. Found: 392.1 (M−1−Cl+OH, sulfonic acid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>CCO>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(CCCBr)cc1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Solvent: CCO
Product: CC(=O)c1ccc(CCCOc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)cc1
Yield: 76.6 %

Procedure:
Alkylation of 4-benzyloxy-7-hydroxycoumarin (2.68; 0.01 mole) with 1-(4-acetylphenyl)-3-bromopropane (2.41 g; 0.01 mole) as described in example 45 gave 3.28 g (77%) of title compound of m.p. (EtOH) 117° νmax (mull) 1725, 1682, 1620 cm-1 ; τ(DMSO) 7.92 (2H, m); 7.48(3H, s); 7.18 (2H, m); 5.94(2H, t, J 6.4 Hz); 6.69(2H,s); 6.16 (1H,s); 3.17-2.00(12H,m). (Found; C, 75.14; H, 5.52; C21H24O5 requires; C, 75.68; H, 5.65%)
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30]>C(Cl)Cl>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1ccncc1
Reactant: NCc1cccs1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1csc(CNCCCSc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
In 200 ml of methylene chloride were dissolved 10.34 g (61.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 10.2 ml (73.3 mmol) of triethylamine, methanesulfonyl chloride [5.7 ml (73.3 mmol)] was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried. Then the solvent was distilled off. To 8.05 g of the residue was added 3.3 ml (32.5 mmol) of 2-thiophenemethylamine. The mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.5 g of the desired compound (yield: 29.1%, yellow oil).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[C:23](=O)([O-])[OH:24].[Na+]>CN(C=O)C>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]([CH:23]=[O:24])=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1H-Indol-6-yl)(morpholino)methanone (36.0 g, 156.5 mmol) in DMF (540 mL) was added drop wise at 0° C. to a solution of phosphoryl chloride (43.9 mL, 469 mmol) in DMF (884 mL) and the mixture was stirred at room temperature for 4 h. The reaction mixture was then neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate and evaporated. The residue was finally purified by column chromatography [100-200 mesh silica; dichloromethane with 10% methanol]. White solid. Yield: 36 g (89% of theory)