Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[N:27]1([CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: C1CNCCN1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN4CCNCC4)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with piperazine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](F)[CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCC1
Reactant: Fc1cncc(Br)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1cncc(NC2CCC2)c1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-5-fluoropyridine (Frontier Scientific, Logan, USA, 5.63 mmol) and cyclobutylamine (Fluka, Buchs, Switzerland, 12.38 mmol) in NMP (8 ml) was heated under microwave irradiation for 1 h at 190° C. and for 5.5 h at 200° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, with brine (3×), dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as an off-white solid. (HPLC: tR 2.31 min (Method A); M+H=227, 229 MS-ES)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:16]=[CH:15][C:14]2[C:17]3[C:6]=1[CH2:7][CH2:8][C:9](=[CH:18][C:19]#[N:20])[C:10]=3[CH:11]=[CH:12][CH:13]=2>CO.Cl[Pd]Cl>[CH3:3][O:4][C:5]1[CH:16]=[CH:15][C:14]2[C:17]3[C:6]=1[CH2:7][CH2:8][CH:9]([CH2:18][C:19]#[N:20])[C:10]=3[CH:11]=[CH:12][CH:13]=2
Reactant: COc1ccc2cccc3c2c1CCC3=CC#N
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cccc3c2c1CCC3CC#N
Reaction time: 0.25 h

Procedure:
The catalyst is prepared starting from 55 mg of PdCl2 in 5 ml of methanol treated with 25 mg of sodium borohydride. After 15 minutes' stirring, the compound obtained in Step A (1 g, 4.25.10−3 mol), diluted with methanol (15 ml), is incorporated. The mixture is purged with argon and placed under hydrogen. The reaction is monitored by GPC analysis. After 2 hours 30 minutes' hydrogenation, the reaction mixture is filtered over Celite, rinsed and then evaporated under reduced pressure. The title product is isolated in the form of a colourless oil.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:19][O:20][C:21](=[O:37])[CH:22]([O:34][CH2:35][CH3:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>C(#N)C>[CH3:19][O:20][C:21](=[O:37])[CH:22]([O:34][CH2:35][CH3:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: CCOC(Cc1ccc(O)cc1[N+](=O)[O-])C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1[N+](=O)[O-])C(=O)OC
Yield: 81.5 %

Procedure:
2-(4-Methanesulfonyloxyphenyl)ethylmethanesulfonate (1.14 g; 3.87 mmole), 2-ethoxy-3-(4-hydroxy-2-nitrophenyl)propanoic acid methyl ester (1.04 g; 3.86 mmole) and potassium carbonate (1.07 g; 7.75 mmole) were mixed in acetonitrile (approx. 100 ml). The reaction mixture was heated to reflux for 6 hours and according to TLC the reaction was not complete. Another portion of 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (0.2 g; 0.68 mmole) was added. The reaction mixture was heated to reflux over night, and then evaporated to dryness. Ethyl acetate and water were added into the residue. The phases were separated and the organic phase was washed with brine, dried with magnesium sulfate and evaporated. Chromatography of the crude product on silica gel with a gradient of ethyl acetate/heptane as eluant gave 1.47 g (81% yield) of 2-ethoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)-2-nitrophenyl]propanoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:27][CH2:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: COc1ccc(CCN)cc1
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2Br)cc1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-(4-methoxyphenyl)ethylamine in dioxane. ES-MS m/e (%): 391 (M{81Br}+H+, 100), 389 (M{79Br}+H+, 99).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C@H:37]12[CH2:43][C@H:40]([NH:41][CH2:42]1)[CH2:39][N:38]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>ClCCl>[C:34]([C:18]1[S:17][C:16]([N:15]2[C:9]3[CH:8]=[C:7]([CH2:6][N:41]4[CH2:42][C@@H:37]5[CH2:43][C@H:40]4[CH2:39][N:38]5[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:12]=[CH:11][C:10]=3[N:13]=[CH:14]2)=[CH:20][C:19]=1[O:21][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:32])([F:33])[F:31])[CH3:23])(=[O:36])[NH2:35]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CN4C[C@@H]5C[C@H]4CN5C(=O)OC(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate are dissolved in 2.5 ml dichloromethane. Under N2 atmosphere tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (198 mg) is added. The reaction mixture is stirred at 40° C. for 1 hour and then concentrated to dryness under vacuum. The residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain tert-butyl (1S,4S)-5-{[1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16]([NH2:18])=[NH:17].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CC(C)=O>[CH:26]1([C:32]([NH:17][C:16]([NH:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)=[NH:18])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: N=C(N)NCc1ccccn1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N=C(NCc1ccccn1)NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8.00 g of 50% aqueous NaOH, 19.92 g of 2-pyridylmethyl guanidine sulfate, and 100 ml of acetone is stirred overnight at RT. Anhydrous sodium sulfate (8 g) is added to the mixture and stirring continued for 5 hr. A solution of 7.33 g of cyclohexyl carbonyl chloride in 100 ml of acetone is added dropwise to the stirred mixture and the reaction mixture allowed to stand over the weekend. The solvent is evaporated in vacuo and the residue partitioned between methylene chloride and H2O. The aqueous phase is separated and extracted with methylene chloride. The combined organic extract is dried over sodium sulfate, filtered and the filtrate evaporated in vacuo, yielding the guanidine as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=O)[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:11]4[CH2:20][CH2:19][CH2:18][CH:12]4[C:13](=[S:30])[NH:14][C:15]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Product: S=C1Nc2cc(N3CCOCC3)ccc2C2CCCC12
Yield: 84.3 %

Procedure:
Analogously to Example 4, 7-(4-morpholinyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.37 mmol) is reacted with Lawesson's reagent (164 mg, 0.41 mmol) to form 90 mg (84%) of product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:11]=3[CH:20]=2)[CH2:6][CH2:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(N3CCN(Cc4ccccc4)CC3)ccc2o1
Reaction time: 2 h

Procedure:
A solution of 1 g of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate in 50 ml of dichloromethane is treated with 1 g of benzyl chloride and stirred for 2 hours. After customary working up, ethyl 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxylate, m.p. 219°-222°, is obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: CC(C)Nc1ccc2c(c1)OCC2
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 12.2 g. of N-isopropyl-2,3-dihydro-6-benzofuranamine in 250 ml. of glacial acetic acid, cooled to 15°±5°C. is added 24.0 g. of sodium isocyanate. The mixture is stirred at room temperature for 18 hours and then concentrated in vacuo. The residue is treated with 200 ml. of 2N sodium hydroxide solution and then extracted twice with chloroform. The combined chloroform extracts are dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain an oil of 1-isopropyl-1-(2,3-dihydro-6-benzofuranyl)urea.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:17]2[C@@:13]([CH3:29])([C@@H:14]([C@@:18]3([CH3:28])[O:22][CH2:21][C@@H:20]([CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])[CH2:19]3)[CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][C@@H:20]1[CH2:21][O:22][C@@:18]([C@@H:14]2[C@:13]3([CH3:29])[C@H:17]([C@@H:9]([OH:8])[CH2:10][CH2:11][CH2:12]3)[CH2:16][CH2:15]2)([CH3:28])[CH2:19]1
Reactant: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]32C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O)CCC[C@@]32C)C1
Yield: 92.5 %

Procedure:
A solution of 13 (330 mg, 0.78 mmol) in dry THF (4 mL) was treated with nBu4NF (1.02 g, 3.25 mmol). The mixture was heated at reflux for 90 h. H2O (20 mL) and EtOAc (20 mL) were added. The aqueous layer was extracted with EtOAc (4×20 mL) and the combined organic layer was dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 2×5.5 cm, 30% EtOAc-hexanes) to give 13a (224 mg, 93%, white solid, mp: 98° C.).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCO
Temperature: -20 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 85.0 g (0.904 mole) of 1,5-pentanediol and 30.3 g (0.30 mole) of triethylamine in 350 mL of dry CH2Cl2 at -20° C. was added dropwise a solution of 28.5 g (0.25 mole) of methanesulfonylchloride in 100 mL of CH2Cl2 over 2 hours under nitrogen atmosphere. The solution was stirred at 2 hours at -20° C. and then at -4° C. for 18 hours. The reaction mixture was washed with H2O, 1N HCl, H2O, then dried and evaporated. The residual oil was chromatographed on a silica gel column, eluting with EtOAc-CH2Cl2 (2:8). After combining the appropriate fractions there was obtained 25.7 g (56.5%) of 5-hydroxypentylmethylsulfonate as a colorless oil.
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([CH2:5]3)[CH2:3]1)[CH2:9]2.[BrH:18]>C(O)(=O)C.O>[Br:18][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Br
Reactant: OC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Solvent: CC(=O)O
Solvent: O
Product: BrC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Yield: 68 %

Procedure:
Stir 0.03 mol of 3-phenyl adamantanol (II) with 100 ml of 40% HBr in glacial acetic acid for 20 min at 60° C. and 30 min at room temperature. Subsequently, dilute the reaction mixture with water and extract with ether. Wash the combined organic extracts with sodium chloride solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 68%).
Reaction SMILES: [OH-].[K+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[C:13]([CH2:15][C:16]([O:18]CC)=[O:17])[N:14]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[C:13]([CH2:15][C:16]([O-:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1.[K+:2]
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.5 %

Procedure:
A solution of 0.4 g of potassium hydroxide in 30 ml of methanol is added to 1.0 g of ethyl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate at 5° to 10° C. The mixture is stirred at room temperature for 10 hours. Then, the precipitates are collected by filtration, washed with ether and then dried. 0.85 g of potassium 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate is obtained. Yield: 80.2%
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[CH2:15][CH3:16].N1CCCCC1>CO>[CH3:16][C:15]1[CH:14]=[N:1][C:2]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC=O
Reactant: COC(=O)c1cccc(C=O)c1N
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1cccc2cc(C)cnc12
Yield: 66 %

Procedure:
Under nitrogen atmosphere, to a solution of methyl 2-amino-3-formylbenzoate (3.00 g) in methanol (80 ml) were added propanal (1.50 mL) and piperidine (800 μL), and the mixture was heated under reflux. To the mixture were further added propanal (700 μL) and piperidine (400 μL), and the mixture was further heated under reflux for total 4 hours. The solvent in the reaction solution was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed twice with water, and washed with a saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified twice by silica gel column (hexane/ethyl acetate=3/1→2/1→1/1) and silica gel column (hexane/ethyl acetate=3/1→2/1) to give 3-methyl-8-methoxycarbonylquinoline (2.21 g, 66%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36]>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:37][CH2:33][CH2:34][CH2:35][CH3:36])[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CCCCNCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Yield: 38.2 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.348 g, 0.736 mmol) and n-butylamine (1.0 mL, 10 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5-10% methanol in chloroform. After drying in vacuo at 55° C. for 40 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-butyl-amine as a light beige semi-solid (0.105 g, 38.2%) was obtained. This was dissolved in chloroform, and ethereal hydrochloride was added. The resulting solid was filtered and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a white solid (0.0813 g): MP: 271-3° C. dec; Mass Spectrum (+EI, [M+H]+) m/z 374. 1HNMR (300 MHz, DMSO-d6): δ14.27-14.35 (br, 1H), 8.98-9.00 (br, 2H), 8.03-8.06 (m, 2H), 7.62-7.76 (m, 4H), 7.46 (d, 1H, J=2.19 Hz) 7.25 (dd, 1H, J=9.15 Hz and 2.29 Hz), 4.38-4.41 (m, 2H), 3.41-3.44 (m, 2H), 3.03 (t, 2H, J=7.87 Hz), 1.62-1.72 (m, 2H), 1.33-1.45 (m, 2H), 0.94 ppm (t, 3H, J=7.32 Hz). Elemental Analysis for C19H23N3O3S.1.00 mol HCl.0.05 mol H2O: Calcd: C, 55.55; H, 5.91; N, 10.23; Found: C, 55.23; H, 5.87; N, 10.09.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14](NC(C)(C)C)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22]>O1CCOCC1.O>[C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:15])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)NC(=O)c1occc1C(=O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccoc1C(=O)O
Temperature: 120 °C

Procedure:
To slurry of 3-benzoyl-N-tert-butylfuran-2-carboxamide (0.863 g, 3.18 mmol) in 4 mL dioxane and 3 mL water was added sulfuric acid (1.02 ml, 19.1 mmol). The mixture was sealed and heated to 120° C. for a total of 48 h. Additional 3.0 equiv H2SO4 was added, and the reaction was heated for 8 h. The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (4×), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-benzoylfuran-2-carboxylic acid as a brown semi-solid. This material was carried on without further purification. MS m/z=217 [M+H]+. Calc'd for C12H8O4: 216.2.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([NH:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=3[F:22])=[N:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCCl
Temperature: 40 °C
Yield: 78.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.6 g, 11.3 mmol), (prepared as described for the starting material in Example 4), 1 bromo-4-chlorobutane (1.95 ml, 16.9 mmol) and potassium carbonate (4.66 g, 33.8 mmol) in DMF (75 ml) was heated at 40° C. for 4 hours. The mixture was allowed to cool and was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (1/1). The purified solid product was triturated with pentane, collected by filtration and dried under vacuum to give 7-(4-chlorobutoxy)-4(4chloro-2-fluoroanilino)-6-methoxyquinazoline (3.64 g, 79%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:41]I>C1COCC1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1([O:29][CH3:41])[CH2:26][CH2:27][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C2(O)CCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutanol (17.3 mg, 0.031 mmol) in THF (0.2 mL) at 0° C. was added sodium hydride (5 mg, 0.1 mmol). The mixture was stirred at room temperature for 30 minutes and methyl iodide (20 μL, 0.3 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexane) to afford the title compound (11.1 mg, 63%). 1H NMR (400 MHz, CDCl3) δ ppm 1.64-1.76 (m, 1H) 1.98-2.10 (m, 1H) 2.33-2.43 (m, 2H) 2.43-2.53 (m, 2H) 2.85 (s, 3H) 4.17-4.21 (m, 3H) 4.75 (s 2H) 4.86 (s, 2H) 7.41-7.46 (m, 2H) 7.50 (d, J=8.30 Hz, 1H) 7.73 (s, 2H) 7.76 (s, 1H). MS (ES+) Calc 567.2, Found: 568.4 (M+1) According to the procedure described in example 31 and using the corresponding ketone reagent, example 32 was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Ni].CO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of the product of Example 13A (6.3 g, 18.7 mmol) and Raney nickel (2.0 g) in 300 mL methanol was stirred under hydrogen at ambient temperature for 5 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with a gradient of 2/1 to 1/1 petroleum/ethyl acetate to give the title compound.