Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]2>ClCCCl.C(O)(C)(C)C>[C:26]1([S:23]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=5)[N:8]=[CH:7][N:6]=4)=[CH:22][CH:21]=3)[CH:17]=[CH:18]2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Yield: 74.8 %

Procedure:
6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling the solids were filtered and rinsed with CH2Cl2 and placed under high vacuum to remove any excess solvent. Quinazoline 14 (3.23 g, 75%) was obtained as a yellow solid. 1H NMR (DMSO d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz, 0.6 Hz).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12](Cl)[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].CCOCC.[CH3:23][C:24]([CH3:28])([OH:27])[CH2:25][CH3:26]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:27][C:24]([CH3:28])([CH3:23])[CH2:25][CH3:26])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1Cl
Reactant: CCC(C)(C)O
Solvent: CCOCC
Product: CCC(C)(C)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 43 %

Procedure:
A solution of 2-chloro-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (14g, 0.05 mole) in 1,1-dimethylpropanol (50 ml) was boiled under reflux for 41/2 hours. After cooling, the solution was taken into ether (250 ml), washed with dilute aqueous sodium hydroxide solution (twice) and with water (twice) and dried over sodium sulphate. The solvent was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(1,1-dimethylpropoxy)benzofuran-5-yl methanesulphonate (7g, 43% yield) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@H:22]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:23]1)[CH:2]=[CH2:3].CN(C=[O:65])C>[Pd](Cl)Cl.[Cu](Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=2)=[CH:8][C:7]([C@H:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)=[C:6]([CH:11]=1)[CH2:5][O:4][CH2:1][C:2](=[O:65])[CH3:3]
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CN(C)C=O
Agent: Cl[Cu]Cl
Agent: Cl[Pd]Cl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCC(C)=O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
A mixture of palladium chloride (159 mg, 0.053 mmol) and copper chloride (267 mg, 0.27 mmol) in DMF (3 mL) was stirred for 2.5 h at room temperature. (2S,3S,4R,5R,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (intermediate O-1) (300 mg, 0.36 mmol) was added to the mixture and stirred overnight under oxygen. The reaction mixture was filtered, the filtrate was poured into water and extracted with ethyl acetate (20 mL×3). The combined extracts were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative TLC, which afforded 1-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)propan-2-one (intermediate T-1) (178 mg, 0.33 mmol, yield 58.2%). 1H-NMR (DMSO-d6, 300 MHz) δ 1.062 (t, J=8.1 Hz, 3H), 1.988 (s, 3H), 2.452 (dd, J=8.1 Hz, 2H), 3.603 (m, 6H), 3.793 (m, 2H), 3.997 (s, 2H), 4.125 (s, 2H), 4.491 (11, 7H), 4.744 (m, 4H), 6.789 (m, 2H), 7.015 (m, 4H), 7.169 (m, 5H), 7.288 (m, 13H), 7.457 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH3:7].O.[CH2:9]1[CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[C:11]2[CH:10]=[CH:13][CH:9]=[CH:10][C:11]=2[NH:7][CH2:9][CH2:13]1
Reactant: N
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: c1ccc2c(c1)NCCO2
Yield: 91 %

Procedure:
2H-1,4-benzoxazin-3-(4M-one (4.5 g, 30 mmol) was added portionwise to a stirred suspension of lithium aluminium hydride (4.7 g, 120 mmol) in THF (100 ml) and heated at reflux for 3 h. The mixture was cooled in an ice/water bath and ammonia solution (8 ml) and water (40 ml) were added while stirring. The mixture was filtered through Celite and reduced. Chromatography (50% EtOAc/50% 60-80 petroleum ether) afforded benzomorpholine (3.7 g, 91%) as a pale brown oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(O)cc(C(F)(F)F)nc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in 450 mL 8:1 CH2Cl2:DMF. POCl3 (50 mL) is added dropwise and the reaction is allowed to stir overnight. The reaction is then poured into 500 mL ice/H2O and the aqueous is extracted 2× with CH2Cl2. The organic portions are combined, washed 1× with brine, dried over MgSO4, and evaporated. The resulting oil crystallizes upon standing. The solid is recrystallized from 95% EtOH. A second crop of crystals could be obtained by concentrating down the EtOH filtrate. The total yield of product is 15.36 g.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1Cl>C(Cl)Cl.C1CCCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1cc(Cl)c(N)c2Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 20 g (0.061 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 45, 7-amino-6,8-dichloro-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 105° (methylene chloride/cyclohexane).
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=O.O>O1CCCC1>[CH:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:34][CH2:33]1)=[CH2:2]
Reactant: COC(=O)C1CCC(C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1CCC(C(=O)OC)CC1
Reaction time: 0.5 h

Procedure:
297.4 g of methoxymethyltriphenylphosphonium bromide was dispersed in 900 mL of tetrahydrofuran (THF) and 95.6 g potassium t-butoxide was added at −8° C. in 3 minutes. After stirring for 30 minutes, all of methyl 4-formylcyclohexanecarboxylate was dissolved in 270 mL of THF and the resulting solution was added dropwise at −6 to 4° C. over 50 minutes. After stirring at 0 to 4° C. for 30 minutes, 15 mL of water was added. The solvent of the reaction mixture was distilled off under reduced pressure and 500 mL of hexane was added, followed by stirring at room temperature for 30 minutes. The precipitate was filtered and the precipitate was suspended and washed again with 500 mL of hexane. After combining with the hexane filtrate, the mixture was washed in turn with a mixed solution of methanol and water (1:1), water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 81.2 g of an oily substance. The oily substance was distilled under reduced pressure to obtain 57.3 g of methyl 4-vinylclohexanecarboxylate. A boiling point was 122 to 127° C./48 hPa. The gas chromatography analysis revealed that, the resulting substance is a mixture of a cis isomer and a trans isomer in a mixing ratio of 26:74.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.CS(C)=O>[O:17]1[CH2:4][CH:8]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[S+](C)C
Reactant: O=CCCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(CCC2CO2)cc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulphoxide (100 ml) was added over 5 minutes to sodium hydride (6.76 g of a 55% oil dispersion, 0.155 mol) under a nitrogen atmosphere. The mixture was stirred vigorously for 10 minutes, then diluted with anhydrous tetrahydrofuran (80 ml). The mixture was cooled to 5° C. and a solution of trimethylsulphonium iodide (31.63 g, 0.155 mol) in dimethyl sulphoxide (80 ml) was added slowly keeping the temperature of the reaction mixture at 5° C. After addition the reaction mixture was stirred at 5° C. for 2 minutes then a solution of hydrocinnamaldehyde (20.0 g, 0.149 mol) in anhydrous tetrahydrofuran (20 ml) was added over 1 minute. After 15 minutes at 5° C. the cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (200 ml), then extracted with ethyl acetate (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (200 ml), dried (potassium carbonate) then evaporated to give an orange oil which was purified by distillation under vacuum. (±)-(3,4-Epoxybutyl)-benzene was obtained as a colourless oil (5.2 g, 23%), bp 80°-85° C. (4 mbar).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].C[O-].[Na+].Cl.[CH:21]([NH2:23])=[NH:22]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: N=CN
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A solution of 2-(4-chlorophenyl)-malonic acid dimethyl ester (18.90 g) in methanol (200 ml) was added dropwise at 0° C. to a solution sodium methylate (14.60 g) in methanol (150 ml). The mixture was stirred for 1 h at 0° C. before formamidine hydrochloride (7.66 g) was added. The suspension was stirred at rt for 20 h. The solvent was removed and the residue was suspended in 2 N aq. HCl (200 ml). The pH of the suspension was carefully adjusted to 4–5 by adding 10 M NaOH (20 ml), stirring was continued for 30 min. The white precipitate was collected, washed with water and diethyl ether and dried to give 5-(4-chlorophenyl)-pyrimidine-4,6-diol (16.44 g) as a white powder. LC-MS: tR=2.75 min, [M+H]+=222.96, [M−H]−=220.92.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([O:19]CC)=[O:18])[CH2:8][C:7]2=1.[OH-].[Li+]>O1CCCC1.CO>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([C:17]([OH:19])=[O:18])[CH2:8][C:7]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A stirred solution of ethyl 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate of Step 1 (1.8 g, 5.5 mmol) in tetrahydrofuran (20 mL) and methanol (3 mL) was treated with 1N lithium hydroxide (11 mL) and heated under nitrogen in an oil bath kept at 40° C. for 2 hours. The organic solvents were evaporated, the residue was diluted with water, cooled in an ice bath and acidified with 2N hydrochloric acid (10 mL). The suspension was extracted with ethyl acetate, and the extracts were washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a colorless foam that was dried in vacuo to yield the title compound (1.6 g). MS [(+)ES, m/z]: 300.1 [M+H]+. MS [(−)ES, m/z]: 298.0 [M−H]−. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 254 nm; Rt 2.0 min.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[Cl:19])[C:6]([NH2:10])=[N:7][C:8]=1[NH2:9])=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[Cl:19])[C:6]([NH2:10])=[N:7][C:8]=1[NH2:9]
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-Formyl-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.198 g, 6.24×10−4 mole) in ethanol (100 ml) was added sodium borohydride (0.0359, 9.35×10−4 mole) at room temperature. The reaction was stirred at room temperature under nitrogen for 1 hr, water (1 ml) was added and the solution evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml), washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The product was purified by ‘flash chromatography’ using 11-40% ethyl acetate in cyclohexane as the eluent. Yield 0.104 g (52%), M.p. 185-186° C. N.m.r. (D6DMSO) δ: 4.32 (2H, d), 4.98 (1H, t), 5.56 (2H, s), 5.85 (2H, s), 7.30 (1H, d), 7.76 (1H, d).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>CO.O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:7]=[C:6]([CH2:4][OH:3])[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid ethyl ester (60 mg, 0.2 mmol) in MeOH/tetrahydrofuran (1:1 v/v, 1 mL) was added at 0° C. over 5 min sodium borohydride (75 mg, 2.0 mmol). The mixture was stirred at 0° C. for 1 h and then poured into ice-cold 3 N HCl (3 mL). The mixture was extracted with AcOEt and the organic layer was washed with H2O, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed on silica gel using AcOEt/cyclohexane (1:2 v/v) as eluent to give [5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (45 mg, 87%). Pale yellow solid. MS (ISN) 258.1 [(M−H)−]; mp 185-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH:11]=[CH:10]1.[CH3:29][NH2:30]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(F)ccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: CN
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1ccn2-c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(970 mg, 2.4 mmol) was dissolved in aqueous solution of methylamine(40%, 10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the solvent by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 810 mg of desired compound as solid in 85% of yield.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][CH2:17][CH:18](OS(C)(=O)=O)[CH2:19][N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22]OS(C)(=O)=O>C(O)C>[CH2:1]([N:8]1[CH2:22][CH2:21][N:20]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH:18]1[CH2:17][F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCN(Cc1ccccc1)CC(CF)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
4.82 g (0.045 mole) of benzylamine and 9.09 g (0.09 mole) of triethylamine were added to a solution of N-(3-fluoro-2-methylsulfonyloxypropyl)-N-(2-methylsulfonyloxyethyl)benzylamine [prepared as described in step (b) above] dissolved in 200 ml of ethanol. The mixture was heated under reflux for 2 hours and then concentrated by evaporation under reduced pressure. 100 ml of ethanol and 40 ml of a 2N aqueous solution of sodium hydroxide were added to the residue, and the mixture was concentrated by evaporation under reduced pressure. The residue was mixed with ethyl acetate, and insoluble materials were removed by filtration. The filtrate was freed from the solvent by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 3.60 g of 1,4-dibenzyl-2-fluoromethylpiperazine as a yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH:16]=[CH2:17]>CC(C)=O>[CH2:17]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
94 g phenol (1 mol), 155 g anhydrous potassium carbonate (1.2 mol) and 300 mL acetone were added to a three-necked bottle, and stirred at 50° C. for 10 minutes. 107 g 3-bromopropylene (0.9 mol) was added dropwise, then the mixture was refluxed for 2 hours. After acetone was evaporated under reduced pressure, water was added to the residual solution and a solid was isolated. After sucked filtration, 108 g solid was obtained. Yield: 90.1%. MS: 135 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.[C:9](=O)([O:15]C1C=CC=CC=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([O:10][C:9](=[O:15])[NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Reactant: NC1CCC(N)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reaction time: 2.5 h

Procedure:
To a 3 L 3-neck RB flask equipped with a mechanical stirrer, condenser with N2 inlet and temperature probe is added 1,4-diaminocylcohexane P1 (152.2 g, 1332.9 mmol), EtOH (1 L) and t-butyl phenyl carbonate (250 mL, 1351.5 mmol). The reaction mixture is wrapped with Al foil and heated using a heating mantle (JKem temperature controller >2 L setting, Tset=100° C.). A brown solution is obtained and an internal temperature of 73.8° C. is recorded after 2.5 h. After heating for 18 h the now heterogeneous reaction mixture is allowed too cool. The mixture is filtered to remove bis-Boc protected amine, which precipitated as a white solid. The filtrate is concentrated in vacuo to a thick peach colored syrup. The mixture is transferred to an Erlenmeyer flask and the transfer is completed with CH2Cl2 (50 mL). To the mixture H2O (100 mL) is added (pH=9) followed by concentrated HCl (180 mL to pH=2) resulting in the precipitation of the (4-aminocyclohexyl)carbamic acid tert-butyl ester as a hydrochloride salt. The mixture is swirled vigorously until a thick slurry is obtained. Additional CH2Cl2 is added to maximize the amount of precipitate and the slurry is filtered (additional product is obtained from this filtrate #1, as described below). The solid is washed with Et2O (1.4 L). To free-base the HCl salt H2O (500 mL) is added followed by NaOH (2.5N, to pH=12). The mixture is extracted with CH2Cl2 (3×). The combined organic extracts are washed with H2O (3×400 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give (4-aminocyclohexyl)carbamic acid tert-butyl ester P2a (92.89 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:34]([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:40]3[CH:39]=[N:38][N:37]([CH:34]([CH3:36])[CH3:35])[CH:41]=3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1c(Cc2ccc(-c3cnn(C(C)C)c3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and 1-isopropyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O>[Si:24]([O:23][CH2:22][CH2:21][N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:12])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate (0.85 g, 3.33 mmol) in anhydrous N,N-dimethylformamide (8 mL) under nitrogen atmosphere was added in one portion sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h, and then (2-bromoethoxy)(tert-butyl)dimethylsilane (0.86 mL, 4.01 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 h, and then partitioned between ethyl acetate (100 mL), water (35 mL) and brine (35 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-30% ethyl acetate in hexanes to afford the title compound as a colorless solid in 79% yield (1.09 g): 1H NMR (300 MHz, CDCl3) δ 6.13 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.85-3.69 (m, 6H), 3.41 (t, J=5.2 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); MS (ES+) m/z 413.4 (M+1).