Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13].[F:30][C:31]([F:37])([F:36])[C:32]([OH:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:35][C:32]([CH3:34])([CH3:33])[C:31]([F:37])([F:36])[F:30])=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of (2-fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (compound 2.3) (20 mg), 2-trifluoromethyl-2-propanol (0.053 mL), potassium carbonate or cesium carbonate (3 equivalents) in dimethylacetamide was heated at 150° C. for 30 min and then at 180° C. for 1 h in a microwave oven. After such time the reaction mixture was concentrated and purified by column chromatography (SiO2) to yield the title compound as a light yellow solid (4.9 mg). MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: C1(C2OC=C(C3C=CC(N)=CC=3)N=2)C=CC=CC=1.[Cl:19][C:20]1[CH:45]=[C:44](Cl)[CH:43]=[CH:42][C:21]=1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][CH:35]=2)=[CH:27][CH:26]=1)=[O:23].ClC1C=CC=CC=1C(Cl)=O>>[Cl:19][C:20]1[CH:45]=[CH:44][CH:43]=[CH:42][C:21]=1[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][CH:35]=2)=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(Nc1ccc(-c2coc(-c3ccccc3)n2)cc1)c1ccc(Cl)cc1Cl
Agent: Nc1ccc(-c2coc(-c3ccccc3)n2)cc1
Agent: O=C(Cl)c1ccccc1Cl
Product: O=C(Nc1ccc(-c2coc(-c3ccccc3)n2)cc1)c1ccccc1Cl

Procedure:
compound 36 was prepared from 35b in a similar fashion to compound 35 following Method F, except that 2-chlorobenzoyl chloride was used in place of 2,4-dichlorobenzoyl chloride. ESI+ m/z=375.1 [MH]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:16]=1)=[O:23])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CCl)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(CN2CCOCC2)c1

Procedure:
Morpholine (2.3 ml) was added to a solution of (3-chloromethyl-benzyl)-carbamic acid tert-butyl ester (Intermediate 5, 1.7 g) in THF (20 ml) and the mixture heated at reflux under nitrogen for 6 hours. Concentration of the reaction under vacuum gave N-tert-butyloxycarbonyl-3-(4-morpholinylmethyl)benzylamine (1.94 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.Cl.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1.O.N>P(Cl)(Cl)(Cl)=O>[CH3:15][N:2]([CH3:1])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:25][C:24]1[C:19]([NH2:18])=[N:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=1)=[O:7]
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(N)c(N)n1
Agent: Cl
Agent: N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N(C)C)c(N)n1

Procedure:
An amount of 1.05 gm of 2-dimethylamino-4-nitro-benzoic acid is suspended in 35 ml of phosphorus oxychloride, and 1.05 gm of 2,3-diamino-6-methoxy-pyridine dihydrochloride are added thereto. The mixture is refluxed for 5 minutes, left to cool for 15 minutes with stirring, and finally decomposed with water. The solution obtained is cooled and poured onto a mixture of ice and concentrated ammonia. The product is then precipitated. It is subjected to suction filtration, washed with water, and dried in a circulating air drier at 50° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (0.5 g, 3.07 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (0.77 g, 3.22 mmol) in EtOH (15 mL) was added Et3N (0.62 g, 6.13 mmol) and the mixture was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the product as colourless oil (0.23 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2(O)[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][C:9]1([C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1
Reactant: COc1nccnc1C1(O)CN2CCC1CC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.4 g of (8) (0.010 mol) in 100 ml of CH2Cl2 was cooled to 0° C. as 2 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred for 1.5 h, then heated to reflux for 45 min. Upon cooling to ambient temperature, ice-water was added to the reaction, followed by enough saturated aqueous K2CO3 to make the reaction basic. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 to give 1.74 g of (12). Recrystallization from hexane gave colorless crystals, mp 59°-60° C. NMR ppm (CDCl3) 1.5 (1H, bs), 1.65 (2H, m), 2.35 (1H, m), 2.7 (2H, m) 2.97 (1H, m), 3.15 (2H, m), 3.65 (1H, m), 4.03 (1H, bm), 4.07 (3H, s), 8.1 (2H, m). Anal. C12H16ClN3O requires C: 56.81; H: 6.36; N: 16.56%. Found C: 56.63; H: 6.41; N: 16.48%. Further elution with 5% ethanol-0.5%NH4OH-CHC13 gave 0.13 g of (11), identical to the material produced previously.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CO[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[CH3:26].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=2[CH3:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
A mixture of (3,4-dichlorophenyl)acetonitrile (0.149 mol) in DMF (100 ml) was stirred at 0° C. under N2 flow. Sodium hydride (0.223 mol) was added portionwise. The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of, 2-methoxy-1,3-dimethyl-5-nitrobenzene (0.149 mol) in DMF (100 ml) was added dropwise at 0° C. under N2 flow. The mixture was stirred at RT for 6 hours, then cooled, hydrolized with H2O and with HCl 3N and extracted with EtOAc. The organic layer was separated, washed several times with H2O, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 43.4 g (87%) of (±)-α-(3,4-dichlorophenyl)-2,6-dimethyl-4-nitrobenzeneacetonitrile (interm. 48).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>[OH-].[Na+].O.O1CCCC1>[C:9]([OH:23])(=[O:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCC(=O)O
Yield: 23.7 %

Procedure:
Hydroquinone (55 g) was dissolved in a solution of sodium hydroxide (20 g) in water (300 ml) and to the resulting solution was added dropwise a solution of tetradecanoyl chloride (123 g) in tetrahydrofuran (150 ml) with cooling. The precipitate formed was filtered off and the filtrate was extracted with ethyl acetate. The extract was thoroughly washed with water to remove unreacted hydroquinone and the solvent was removed. The residue was recrystallized from n-hexane to give hydroquinone monomyristate (20 g). m.p. 75°-78° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([N:25]([CH:22]([CH3:24])[CH3:23])[NH:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:20])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)/C=C/c1cn(Cc2ccccc2)c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-benzyl-1H-indol-3-yl)acrylic acid (30 mg, 0.14 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (28.92 mg, 0.16 mmol, 1.5 equivalent) and HATU (61.6 mg, 0.16 mmol, 1.5 equivalent) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.03 ml, 0.16 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=1:1) and dried so that white solid form of (E)-N′-(3-(1-benzyl-1H-indol-3-yl)acryloyl)-N-isopropylbenzohydrazide was obtained (40.6 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][S:9]([CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])(=[O:11])=[O:10])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.C(O[Cl:23])(C)(C)C>CO>[Cl:23][N:3]1[C:2]([CH2:8][S:9]([CH2:12][CH2:13][S:14]([OH:17])(=[O:16])=[O:15])(=[O:10])=[O:11])([CH3:1])[CH2:6][O:5][C:4]1=[O:7]
Reactant: CC(C)(C)OCl
Reactant: CC1(CS(=O)(=O)CCS(=O)(=O)O)COC(=O)N1
Solvent: CO
Product: CC1(CS(=O)(=O)CCS(=O)(=O)O)COC(=O)N1Cl
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of 2-((4-methyl-2-oxooxazolidin-4-yl)methylsulfonyl)ethanesulfonic acid (950 mg, 3.31 mmol) in MeOH (5 ml) was added, dropwise, tert-butylhypochlorite (500 ul, 4.2 mmol). The solution was stirred for 1 h, concentrated in vacuo, and purified by preparatory HPLC (H2O/MeOH) to afford the title compound as a clear oil (430.0 mg, 1.336 mmol, 40%). 1H NMR (D2O, 400 MHz) δ 1.60 (s, 3H), 3.3-3.4 (m, 2H), 3.6-3.7 (m, 2H), 3.80 (d, J=14.8 Hz, 1H), 3.96 (d, J=14.8 Hz, 1H), 4.47 (d, J=9.4 Hz, 1H), 5.05 (d, J=9.4 Hz, 1H). ESI/APCI expected for C7H12ClNO7S2: 320.97. Found: 320 (M−H+).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(N)(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[C@@H:33]1[O:50][CH2:49][C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]1[O:35][C:36](=[O:38])[CH3:37])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:1][C:2]1[N:3]([C@@H:49]2[O:50][CH2:33][C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:44]2[O:45][C:46](=[O:48])[CH3:47])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Agent: CC(N)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Bromo-5,6-dichlorobenzimidazole (4.0 g, 15 mmol), N,O-bis(trimethylsiyl) acetamide (Aldrich, 3.7 mL, 15 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 75 mL) were combined and refluxed under nitrogen for 0.5 h. The solution was cooled to room temperature and trimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol) was added. Immediately, 4.8 g (15 mmol) solid 1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose 1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution was stirred under nitrogen at reflux for 0.5 h, then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layers was dried with magnesium sulfate (anhyd.), filtered, and evaporated. The crude residue was purified on a silica gel column (5×20 cm, 230-400 mesh) with CH2Cl2 to give 2-bromo-5,6-dichloro-1-(2,3,4tri-O-acetyl-β-D-ribopyranosyl)-1H-benzimidazole which was fractionated in two parts based on elution. The faster product fraction was impure (1.9 g) and purified by a second column to give 1.4 g (2.7 mmol); the slower product fraction was (3.0 g, 5.7 mmol) for a total yield of 56%; m.p. 100-110° C.; 1H NMR (DMSO-d6) δ 8.39 (s, 1H), 7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz), 5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95 (overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.Cl>[Pd].CO>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(O)cc1N
Reaction time: 12 h

Procedure:
To a solution of 4-amino-3-nitrophenol (25.0 g, 162 mmol) and methanol (300 mL) was added 10% Pd/C (300 mg). The reaction was placed under hydrogen and shaken for 12 hours. Afterward, 4N HCl (50 mL) was added. The mixture was then filtered through celite. The filtrate was concentrated to give 3,4-diaminophenol.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[CH3:7])C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCCC>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:4]([OH:23])=[CH:5][C:6]([CH3:7])=[N:8]2)=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(O)c2ccc(OCc3ccccc3)cc2n1
Temperature: 250 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
3.67 g (11.8 mmol) of 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester were added dropwise within 20 minutes to 5.5 ml of Dowtherm A heated at 250° C. (metal bath temperature). The solution was stirred further 10 minutes at 250° C. (bath temperature), cooled to RT and then treated with 20 ml of heptane. The brown viscous oil that had formed was isolated and triturated with 45 ml of AcOEt. The brown solid obtained was filtered off by suction, washed with AcOEt and dried in a high vacuum to give 1.19 g (35%) of 7-benzyloxy-2-methyl-quinolin-4-ol. ISP mass spectrum, m/e: 266.3 (M+1 calculated for C17H15NO2: 266).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl benzoate.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])=[N:10][C:9]=2[C:8]([CH2:26][CH2:27][CH3:28])=[N:7]1.[Br:29][CH2:30][C:31](Cl)=[O:32].O>ClCCl>[Br:29][CH2:30][C:31]([C:20]1[CH:19]=[CH:18][C:17]([O:22][CH2:23][CH2:24][CH3:25])=[C:16]([C:11]2[NH:12][C:13](=[O:15])[C:14]3[N:6]([CH3:5])[N:7]=[C:8]([CH2:26][CH2:27][CH3:28])[C:9]=3[N:10]=2)[CH:21]=1)=[O:32]
Reactant: O=C(Cl)CBr
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Aluminium trichloride (6.0 g, 0.045 mol) was added portionwise to a stirred solution of 1-methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (5.0 g, 0.0153 mol) and 2-bromoacetyl chloride (2.5 ml, 0.0303 mol) in dichloromethane (100 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours, heated under reflux for 3 hours and then added cautiously to ice and water (100 g). The resulting mixture was stirred for 1 hour and extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with brine (2×50 ml), dried (Na2SO4), then evaporated under vacuum to give an off-white solid, which was triturated with ether to give the title compound as a white solid (4.1 g, 60%). A small sample was crystallised from ethyl acetate-hexane to give the pure product, m.p. 136°-137° C. Found: C,53.82; H,5.24; N,12.57. C20H23BrN4O3 requires C,53.70; H,5.18; N,12.52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: Clc1ccccn1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCNc2ccccn2)CC1
Yield: 13.4 %

Procedure:
The product of Example 27 (3.9 g, 16 mmol) and 2-chloropyridine (1.82 g, 16 mmol) were heated at 160° C. in a sealed vessel for 6 h. After cooling, the residue was taken up into CH2Cl2 (50 ml) washed with aqueous NaOH (3×50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography [alumina; ethyl acetate-toluene (1:4)] to give the product (0.7 g) as a brown oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.C(=O)(O)[O-:27].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH2:3][OH:27])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCCCO)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 22 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 24, 765 mg, 2.07 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was treated with a 1.0M borane solution in tetrahydrofuran (4.14 mL, 4.14 mmol). The reaction was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and treated with ethanol (15 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (45 mL) and hydrogen peroxide (15 mL). The resulting mixture was allowed to warm from 0° C. to 25° C. over 1 h. The reaction was then slowly quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (3×30 mL). The organics were washed with a saturated aqueous solution of sodium chloride (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-(3-hydroxy-propyl)-urea (173 mg, 22%) as a white foam: [α]23589=37.3° (e=0.075, chloroform); EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1154.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]=[O:34].[OH-].[Na+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:32])=[C:13]([C:15]2([CH2:33][OH:34])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:16]2=[O:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(c2cc(OCc3ccccc3)ccc2O)c2ccccc2N1Cc1ccc(Cl)s1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(CO)c1cc(OCc2ccccc2)ccc1O
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a mixture of 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one (2.80 g, 6.07 mmol), para-formaldehyde (0.73 g, 24.3 mmol) in tetrahydrofuran (10.0 mL) was added an aqueous solution of sodium hydroxide (0.97 g, 24.3 mmol) in water (10.0 mL) at 0° C. The reaction solution was stirred for 2 h, then quenched by the addition of 10% aqueous hydrochloric acid solution (30.0 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with diethyl ether, filtered and dried to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (2.71 g, 91%) as a colourless solid: MS (ES+) m/z 494.2 (M+1), 492.3 (M+1).