Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=O)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1oc(COc2ccccc2C=O)nc1-c1ccccc1
Product: COC(=O)C=Cc1ccccc1OCc1nc(-c2ccccc2)c(C)o1

Procedure:
According to the method described for Reference Example 22, 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 2-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--chloroform-ether gave colorless prisms, m.p.128°-129° C.
Reaction SMILES: C(OC([N:8]1[CH2:44][CH2:43][C:11]2([O:15][C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[C:30]([Cl:42])[CH:29]=3)=[N:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:14]4[O:15][C:11]5([CH2:43][CH2:44][NH:8][CH2:9][CH2:10]5)[CH2:12][N:13]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN=C(Nc1ccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ncnc3ccc(NC4=NCC5(CCNCC5)O4)cc23)ccc1OCc1ccccn1

Procedure:
N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1-oxa-3,8-diaza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS ESI (+) m/z 516, 518 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CDCl3) δ 8.61 (s, 1H), 8.58 (d, 1H), 8.22 (bs, 1H), 7.97 (d, 1H), 7.70 (m, 2H), 7.67 (d, 1H), 7.64 (dd, 1H), 7.35 (d, 1H), 7.26 (m, 1H), 7.02 (d, 1H), 5.31 (s, 2H), 3.73 (s, 2H), 3.05 (m, 2H), 2.96 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.[CH:8]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1.[CH3:18][C@H:19]1[C:23](=O)[O:22]C(=O)[N:20]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(O)(=O)C>C1COCC1.O>[CH2:29]([O:28][C:26]([NH:20][C@@H:19]([CH3:18])[C:23]([C:8]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1)=[O:22])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
A solution of diisopropylamine (0.740 mL) in THF (25 mL) was cooled to −78° C., n-butyllithium-hexane solution (3.26 mL, 1.6 mol/L) was added dropwise and, after the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of tert-butyl cyclopropanecarboxylate (0.800 g) in THF (5 mL) was added dropwise, and the mixture was further stirred at −78° C. for 30 min. A solution of benzyl(4S)-4-methyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate (1.00 g) in THF (10 mL) was added dropwise at −78° C. over 10 min, and the mixture was further stirred at −78° C. for 30 min. Acetic acid (2.0 mL) was added to the reaction mixture and, after warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/1) to give the title compound as a colorless oil (yield: 401 mg, 29%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Cl)=[C:4]([NH:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])=[O:21])[C:3]1=[O:35].C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]([NH:19][C:20]([NH:22][C:23]2[C:28]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])=[O:21])[C:3]1=[O:35]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1c(-c2ccccc2Cl)c2cccnc2n(C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1c(-c2ccccc2)c2cccnc2n(C)c1=O
Yield: 76.1 %

Procedure:
To a solution of N-[1-methyl-4-(2-chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (350 mg, 0.72 mmol) in methanol (20 ml) were added ammonium formate (135 mg, 2.15 mmol) and 10% palladium-carbon (100 mg), and the mixture was refluxed for 4 hours. After allowed to stand for cooling, the mixture was filtered through a cerite pad, and the filtrate was concentrated under reduced pressure. To the residue was added dilute aqueous ammonia, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give the title compound (249 mg, mmol) as a colorless powder.
Reaction SMILES: [S:1]1[C:5]([NH:6][CH:7]=[C:8]2[C:13](=[O:14])OC(C)(C)OC2=O)=[CH:4][C:3]2[CH2:18][CH2:19][CH2:20][C:2]1=2.ClCCl.CO>O(C1C=CC=CC=1)C1C=CC=CC=1>[C:4]12[C:13]([OH:14])=[CH:8][CH:7]=[N:6][C:5]=1[S:1][C:2]1[CH2:20][CH2:19][CH2:18][C:3]2=1
Reactant: CC1(C)OC(=O)C(=CNc2cc3c(s2)CCC3)C(=O)O1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2sc3c(c12)CCC3
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 5-[([4H,5H,6H-cyclopenta[b]thiophen-2-yl]amino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (540 mg, 1.84 mmol, 1.00 equiv) in phenoxybenzene (5 mL) was heated at 220° C. for 30 min under nitrogen. After cooling to room temperature, the residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give the desired 7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-ol (0.28 g, 80%) as a brown solid. MS (ES): m/z 192 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].[N+](=[CH2:64])=[N-].B(F)(F)F>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:64])[CH:46]([O:51][Si:52]([C:55]([CH3:57])([CH3:56])[CH3:58])([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O[Si](C)(C)C(C)(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=[N+]=[N-]
Agent: FB(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O[Si](C)(C)C(C)(C)C)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
An ethereal solution of 17-ethyl-1-hydroxy-12-[2'-(3"-t-butyldimethylsilyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone is treated with diazomethane and BF3 etherate as in Example 67 to yield 17-ethyl-1-hydroxy-12-[2'-(3"-t-butyldimethylsilyloxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:25]=1
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
Methyl bromoacetate (2.1 g) was added to a stirred mixture of N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)propylamine (3.87 g) and anhydrous potassium carbonate (5.73 g) in dry acetone (180 ml). The mixture was stirred and boiled under reflux for 7 hours, then left to stand at ambient temperature for 18 hours then hot filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica using ethyl acetate/triethylamine, 9 to 1 as the mobile phase. The product was obtained as an oil which was dissolved in ether, and extracted into 5M hydrochloric acid. The acid extracts were basified with 5M sodium hydroxide solution and the product extracted into ether to give methyl N-[2-(4-chlorophenoxy)ethyl]-N-[3-(imidazol-1-yl)propyl]glycinate as an oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CS(O)(=O)=O.[CH:41]1[CH:46]=[CH:45][C:44]([CH2:47][O:48][C:49](Cl)=[O:50])=[CH:43][CH:42]=1.C(O[K])(C)=O>O.C(O)C.C(COC)OC>[NH2:3][CH2:2][CH2:1][NH:4][C:49](=[O:50])[O:48][CH2:47][C:44]1[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Yield: 50.9 %

Procedure:
Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL) containing bromocresol green as an indicator. Methane sulfonic acid (2.8 g, 31 mmol) in water (3.0 mL) is added until a blue to pale yellow color transition is just achieved. The solution is diluted with ethanol (8.0 mL) and vigorously stirred. To the mixture was added the solution of Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/v aqueous AcOK (10 mL) at 20° C. simultaneously to maintain the pale yellow-green color of the indicator. After the additions are complete the mixture was stirred (RT, 1 h) and concentrated at low temperature under vacuum to removed the volatiles. The residue was shaken with water (20 mL) and filtered. The filtrate was then washed with toluene (3×50 mL), basified with excess 40% aqueous NaOH and extracted with toluene (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and evaporated to give benzyl 2-aminoethylcarbamate as an oil (1.65 g, 51%). Mass calculated for C10H14N2O2=194.23; found: [M−H]+=193.3.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N2CCC(N)CC2)nc1
Yield: 110 %

Procedure:
A solution of tert-butyl 1-(5-ethylpyrimidin-2-yl)piperidin-4-ylcarbamate (3.2 g, 10 mmol) in 50% TFA/CH2Cl2 (30 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated sodium carbonate (200 mL) then brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (1-(5-ethylpyrimidin-2-yl)piperidin-4-amine (2.2 g, 11 mmol, 100%). Mass spectrum (apci) m/z=207.1 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29][C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])[CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.[OH-:40].[Ca+2].[OH-:42]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])(=[O:42])=[O:40])[CH:25]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccccc1Sc1ccc2nc(-c3ccc(F)cc3)ccc2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2nc(-c3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Chloroperoxybenzoic acid (77%; 597 mg, 2.67 mmol) was added to a solution of methyl 2-{[2-(4-fluorophenyl)quinolin-6-yl]thio}benzoate (346 mg, 0.89 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature under nitrogen for 1 hour 20 minutes. Calcium hydroxide (308 mg, 4.16 mmol) was added and the resulting slurry stirred for 1 hour 15 minutes. The mixture was filtered and the filter cake washed thoroughly with dichloromethane. The filtrate was evaporated and the residue given a preliminary purification by elution from a silica pad with dichloromethane then 2.5% ethyl acetate/dichloromethane to afford an oil. Crystallisation from diethyl ether gave the title compound, in two crops, as pale yellow crystals (301 mg, 80%). 1H NMR (500 MHz, CDCl3) δ 8.57 (1H, d, J 1.7 Hz), 8.36 (1H, d, J 8.7 Hz), 8.25-8.15 (5H, m), 7.95 (1H, d, J 8.6 Hz), 7.67-7.65 (2H, m), 7.61 (1H, m), 7.22 (2H, t, J 8.6 Hz), 3.95 (3H, s); m/z (ES+) 422 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH3:14][C:15]([O-:18])(C)C.[K+].C(OC(=O)C)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][C:15](=[O:18])[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O)c(OC(C)=O)c1
Reaction time: 0.17 h

Procedure:
3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolved in DMF (5 ml), potassium tert-butylate (210 mg, 2.87 mmol) was added and the mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) was added and stirring continued for 10 min. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, the combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:14])[CH2:8][C:9](OCC)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:21][NH2:22].CC(O)C.O>CCCCC>[C:1]([O:5][O:6][C:7]([O:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:14])[CH2:8][C:9]([NH:21][NH2:22])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CC(C)(OOC(C)(C)C)OOC(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CC(C)O
Product: CC(C)(C)OOC(C)(CC(=O)NN)OOC(C)(C)C
Temperature: 0 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
3,3-Di-(t-butylperoxy)butanohydrazide was prepared by reacting ethyl 3,3-di-(t-butylperoxy)butanoate with 9 molar excess of 54% aqueous hydrazine. A 3-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 100 mL of IPA, 14.6 g (0.05 mole) of 100% ethyl 3,3-di-(t-butylperoxy)butanoate and 30 g (about 0.50 mole) of 54% aqueous hydrazine at 25° C. The solution was stirred for about 20 hours at 20°-22° C., then the reaction mass was poured into 1000 mL of water and extracted twice with 200 mL portions of methylene chloride. After drying over 10% by weight of anhydrous magnesium sulfate and separation of the spent desiccant by filtration, the methylene chloride was removed in vacuo leaving 14.3 g (>100% of theory, uncorrected) of a liquid product. 75 mL of pentane was added, the solution cooled to 0° C. and a solid precipitated. The solid was separated by filtration and air dried, leaving 4.8 g (35% of theory, uncorrected) of a white solid, mp, 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=3)[N:21]=2)[CH2:10][CH2:9]1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4c(Cl)cncc4Cl)CC3)nn12

Procedure:
A mixture of 1-(3,5-dichloropyridin-4-yl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[Si](C(C)C)(C(C)C)C(C)C)=[CH:10][CH:9]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(C3CNCCN3C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCNCC1c1ccc2cc[nH]c2c1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 6-(N-methylpiperazinyl)-1-triisopropylsilyl indole (237 mg, 0.64 mmol) in 1 ml of THF, 1M TBAF (0.64 ml, 0.64 mmol) was added dropwise at room temperature. After 30 mins, the mixture was diluted with dichloromethane and washed 3 times with water to give the title product (100.6 mg, 73% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[O:16][CH3:17].NC1C=CN=CC=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: Brc1ccccc1
Agent: Nc1ccncc1
Product: COc1cc(Cl)ccc1Nc1ccccc1

Procedure:
The title compound was prepared by substituting bromobenzene and 2-amino-5-chloroanisole for Example 189A and 4-aminopyridine, respectively, in Example 191. MS (ESI) m/e 234 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].O>C(O)(=O)C.[Pt]=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH2:17][NH:16][CH2:15][CH2:14]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Nc1ccc2cnccc2c1)c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Nc1ccc2c(c1)CCNC2)c1ccccc1
Yield: 76.2 %

Procedure:
A solution of 6-phenylsulphonamidoisoquinoline (2.11 g, 0.0074M) in acetic acid (50 ml) was hydrogenated over a platinum oxide catayst (0.5 g) at approximately 345 kilopascals pressure and room temperature for 3 hours (the theoretical uptake of hydrogen was observed). A small volume of H2O was added to dissolve the product and the catalyst was then filtered off. The filtrate was evaporated to dryness to yield an oil which crystallised under ether to yield 6-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline (1.63 g, 76%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 20 °C
Reaction time: 56 h
Yield: 97 %

Procedure:
To a stirred solution of 4-hydroxyphenyl benzoate (10 g, 47 mmol) in acetic acid (250 mL) was added, dropwise with external ice-bath cooling, nitric acid (d=1.42, 2.9 mL) (T=10° C.). The mixture was warmed to 20° C. and stirred for a further 56 h. The solution was evaporated in vacuo and water added to the residue. The resulting yellow solid was collected by filtration, washed with water and dried in vacuo to give the title compound (11.8 g, 97%).