Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][C@H:24]([CH2:26][OH:27])[CH3:25]>>[OH:27][CH2:26][C@@H:24]([NH:23][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH3:25]
Reactant: C[C@H](N)CO
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)N[C@@H](C)CO)s1
Yield: 71 %

Procedure:
As described for example 53, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (100 mg, 0.31 mmol) was converted, using L-alaninol instead of 2-amino-1,3-propandiol, to the title compound (80 mg, 71%) which was obtained as an off white oil. MS: m/e=366.3 [M+H]+.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=1.[OH-].[K+].Br[C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37]>C1(C)C=CC=CC=1>[Br:37][C:36]([F:39])([F:38])[C:35]([F:41])([F:40])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:25]3[CH:26]=[CH:27][C:28]([O:31][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[Br:37])=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:11]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)Oc1ccc(C2(c3ccc(OC(F)(F)C(F)(F)Br)cc3)c3ccccc3-c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Into a 2 liter 5-necked round bottom flask fitted with a mechanical stirrer, Dean-Stark trap topped with a nitrogen padded reflux condenser and a thermocouple attached to a temperature controller, are placed DMSO (650 ml) and toluene (200 ml). While the stirred solution is purged with nitrogen, 9,9-bis(4'-hydroxyphenyl)fluorene (200.0 g, 0.57 mole) is added to the flask. While purging with nitrogen continues, potassium hydroxide (85% pellets, 77.5 g, 1.17 mole) is added all at once, and the mixture is heated to 100° C. with constant stirring. After two hours, the temperature is increased until the solution begins to reflux (130° C.). Water is removed by azeotropic distillation for 24 hours. The Dean-Stark trap is replaced by a Soxhlet extractor containing anhydrous sodium sulfate, and the toluene is refluxed through the Soxhlet for 5 hours. A small amount of toluene (60 ml) is then removed by simple distillation. Then the reactor is cooled to 35° C. Addition of 1,2-dibromotetrafluoroethane (315 g, 1.21 mole) via dropping addition funnel is then maintained at a rate that keeps the reaction temperature at 35°-38° C. When the addition is complete, the mixture is heated at 50° C. for 8 hours, then cooled to room temperature with constant stirring. The mixture is filtered, and the precipitate is washed twice with acetone. The filtrates are combined and evaporated thoroughly. The residue from the evaporation is washed with water to remove residual potassium bromide (KBr). After the residue is air dried for 24 hours, it is purified by column chromatography (on neutral alumina, using hexane eluent) to provide as product, 9,9-bis(4'-[2"-bromotetrafluoroethoxy]phenyl)fluorene (331.4 g, 0.468 mole, 82% yield), melting point 157°-158° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)(=O)=O.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[N:8][CH:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: O=S(=O)(Oc1ccc(Cl)cn1)C(F)(F)F
Product: C[Sn](C)(C)c1ccc(Cl)cn1

Procedure:
5-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 5-chloro-2-(trimethylstannyl)pyridine. The crude material (˜4 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (0-50% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.48 (25% ethyl acetate/hexanes); MS (Q1) 427 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:10]([C:19](=[O:21])[CH3:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (18.7 g, 72.4 mmol) in toluene (300 mL) at room temperature was added acetic anhydride (8.2 mL, 86.9 mmol). Boron trifluoride diethyletherate (10.1 mL, 79.6 mmol) was then added dropwise and the resulting solution was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The reaction was extracted with ethyl acetate, and the ethyl acetate phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (14.2 g, 65%) as reddish needles.1H NMR (CDCl3): δ 8.37 (dd, 1H), 7.49 (dd, 2H), 7.39 (dd, 1H), 7.10 (dd, 1H), 6.98 (dd, 2H), 3.84 (s, 3H), 2.13 (s, 3H); MS m/z 301 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:21][CH3:22])=[O:5])C.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[C:24]=[O:25]>>[CH2:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[C:24]1=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNc1c(C(=O)OCC)cnc2c(OC)cccc12
Reactant: Cc1cccc(N=C=O)c1
Product: CCCCn1c(=O)n(-c2cccc(C)c2)c(=O)c2cnc3c(OC)cccc3c21
Yield: 43.7 %

Procedure:
1-Butyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-butylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 390 [M+1]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([C:29]6[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=6)=[CH:41][CH:40]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, off-white solid (54 mg, 53%), MS (ISP) m/z=510.5 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyridin-3-yl-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O.[OH-].[Na+]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:13]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cnc1CSCCNc1ncccc1C(=O)O

Procedure:
An intimate mixture of powdered 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.71 g; 0.010 moles) and 2-chloropyridine-3-carboxylic acid (1.73 g; 0.011 moles) was heated to 150° for 6 hours. The resulting cooled glass was dissolved in a little water and neutralised by slow addition of 2N sodium hydroxide solution. At pH6, solid precipitated out of solution. This was filtered off, and recrystallised from water to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino pyridine 3-carboxylic acid as small, colourless crystals (1.04 g) which sublimed at 98°.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(O)CO.C(OCC)(=O)C>[CH2:18]([NH:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (10 g) in dry ethylene glycol (50 ml) at room temperature and under nitrogen was added n-butylamine (16 ml) in one go. The reaction was heated at 120° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (150 ml) and washed with water (2×50 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. This afforded the title compound as a viscous green oil (10.2 g) that was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:16]=[CH:15][C:6](/[CH:7]=[N:8]/[S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[C:5]([F:17])[CH:4]=1.[CH3:19][Mg]Br>C(Cl)Cl>[F:18][CH:2]([F:1])[C:3]1[CH:16]=[CH:15][C:6]([C@@H:7]([NH:8][S@@:9]([C:11]([CH3:13])([CH3:14])[CH3:12])=[O:10])[CH3:19])=[C:5]([F:17])[CH:4]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)F)cc1F
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(F)F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (266 mg, 0.959 mmol) in DCM (9.6 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 30 min at 0° C., gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. The mixture was cooled to 0° C., and carefully quenched with saturated aqueous NH4Cl solution (3 mL). The separated aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate], providing (R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (160.5 mg) as a white solid. LCMS m/z 294.5 (M+H)+, Rt 0.85 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]=[CH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[N:23][CH:24]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 16 h

Procedure:
A solution containing 1-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (500 mg, 2.34 mmol), 2-amino-N-(5-chloropyridin-2-yl)benzamide (580 mg, 0.23 mmol), and pyridinium p-toluenesulfonate (58 mg, 0.23 mmol) in benzene (250 mL) was heated at reflux with azeotropic removal of water. After 16 h, the mixture was concentrated and the residue partitioned between EtOAc (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL), brine (150 mL); then dried with MgSO4, filtered and concentrated to afford, after purification by column chromatography (SiO2: 0 to 10% EtOAc:methylene chloride), 750 mg (72%) of the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH3:23])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N+:18]([O-:39])=[C:17]([CH3:23])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added a solution of mCPBA (114 mg, 77%, 0.51 mmol) in DCM (2 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour before quenched with NaHCO3 solution. The mixture was extracted with DCM (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (104 mg, 94%). LCMS-ESI+ (m/z): 442.2, 444.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:26]=3)[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)OC(C)(C)[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
7-Methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3-chromene (25 g) was dissolved in acetic acid (250 ml) at 60° C. Palladium on carbon (2.5 g, 10%, 50% wet) was added and the mixture hydrogenated at 1 atmosphere hydrogen pressure at 60° C. for 24 hours. The catalyst was filtered off and the filtrate evaporated to en oil. The oil was dissolved in toluene (100 ml) and washed with sodium hydroxide solution (4M) until alkaline. The aqueous phase was separated and extracted with another portion of toluene (20 ml). The combined organic phases was washed with water (2×50 ml) and evaporated to an oil. The oil was dissolved in methanol (100 ml) and crystallized by adding water (200 ml). The product was filtered off and dried.
Reaction SMILES: C[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39]O)[CH2:33][CH2:32]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][CH2:39][O:10][C:8]2[CH:9]=[CH:2][C:3]([CH:4]=[O:5])=[CH:6][CH:7]=2)[CH2:33][CH2:32]1
Reactant: Cc1cc(O)ccc1C=O
Reactant: CN1CCC(CCCO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(CCCOc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To an ice-cooled solution of 2-methyl-4-hydroxybenzaldehyde (722 mg, 5.3 mmol), PPh3 polymer resin (3 mmol/g, 2.2 g, 6.4 mmol), and 3-(1-methyl-piperidin-4-yl)-propan-1-ol (833 mg, 5.3 mmol, 1.0 equiv) in THF (25 mL) was added di-tert-butyl-azodicarboxylate (1.47 g, 6.4 mmol). The reaction mixture was allowed to warm to rt and was stirred for 16 h. The mixture was filtered through diatomaceous earth, diluted with water, and extracted three times with EtOAc. The combined extracts were dried (Na2SO4) and concentrated. Purification by Method 1 afforded 578 mg (40%) of the desired aldehyde. MS (ESI): mass calcd for C16H23NO2, 261.17; m/z found, 262.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.85 (s, 1H), 7.80 (d, J=8.6, 2H), 6.97 (d, J=8.6, 2H), 4.01 (t, J=6.4, 2H), 2.84-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.78 (m, 4H), 1.71-1.69 (m, 2H), 1.41-1.37 (m, 2H), 1.29-1.26 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([S:23]([CH3:26])(=[O:25])=[O:24])[C:3]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:9][C:4]=1[C:5]([O:7]C)=O.[H-].[Na+].CO>CN(C=O)C>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:9][C:4]=2[C:5](=[O:7])[CH2:26][S:23]1(=[O:25])=[O:24]
Reactant: COC(=O)c1cc(C#CCOC2CCCCO2)ccc1N(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of methyl 2-(methyl(methylsulfonyl)amino)-5-(3-(tetrahydro-2H-pyran -2-yloxy)-1-propynyl)benzoate (Preparation 51, 0.93 g) in DMF (15 mL) at 0° C. is added NaH (0.20 g; 60% dispersion in mineral oil) portionwise. The reaction mixture is warmed to ambient temperature stirring for 1 h upon which methanol (4 mL) is added and the organic portion is washed with a saturated solution of citric acid (50 mL). The aqueous layer is extracted with Et2O (2×50 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude orange liquid is purified by silica gel column chromatography (2/1, hexanes/EtOAc) to afford 0.59g (69%) of the title compound as a white solid. Physical characteristics: m.p. 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 8.21, 7.71, 7.10, 4.87, 4.48, 4.33, 3.88, 3.55, 3.44, 1.79, 1.62; IR (diffuse reflectance) 2962, 2908, 1684, 1493, 1339, 1211, 1204, 1156, 1135, 1130, 1123, 1030, 899, 886, 838 cm−1; MS (ESI−) 348 (M−H−). Anal. Found: C, 58.37; H, 5.58; N, 3.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12]1(I)[CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH:8][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: IC1CCCC1
Reactant: COc1cccc(CCN)c1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(CCNC2CCCC2)c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
3-Methoxyphenethylamine (4.5 mL, 30 mmol), and cyclopentyl iodide (1.15 mL, 10 mmol) in CH3CN (15 mL) were irradiated for 10 min in a microwave at 110° C. After cooling to room temperature the mixture was diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane as eluent and the product N-(3-methoxyphenethyl)cyclopentanamine (1.45 g, 66%) was obtained as a colorless liquid which solidified upon standing. 1H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 7.20 (t, 1H, J=8.0 Hz), 6.79-6.73 (overlapping doublets and singlet, 3H), 3.74 (s, 3H), 3.44-3.39 (m, 1H), 3.38-3.11 (m, 4H), 1.84-1.83 (m, 2H), 1.82-1.81 (m, 4H), 1.66-1.56 (m, 2H). LC-MS (ESI) Calcd for: C14H21NO [M+H]+: 220.16. Found: 220.00.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:23])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][C:19]([N:30]=[C:31]=[O:32])=[C:18]([F:33])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][C:19]([N:30]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:31]2=[O:32])=[C:18]([F:33])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1cc(OCc2ccccc2)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 312 mg (7.82 mmol) of sodium hydride (60% oil dispersion) in 10 mL of N,N-dimethylformamide was added 1.43 g (7.82 mmol) of ethyl-3-amino-4,4,4-trifluorocrotonate in 7 mL of toluene over a period of 30 min at -5° C. The resulting mixture was stirred for an additional 30 min before it was cooled to -70° C. Then a solution of 2.17 g (7.82 mmol) of 4-chloro-2-fluoro-5-(phenylmethoxy)phenyl isocyanate in 7 mL of toluene was added dropwise at a rate that maintained the reaction temperature below -60° C. After the addition, the thick reaction mixture was maintained at -60° C. for an additional 1 h before the cooling bath was removed. The mixture was gradually warmed to room temperature and stirring was continued for 1.5 h. Then the mixture was poured into a solution of 10 mL of concentrated HCl in 200 mL of water. The toluene layer was separated and the aqueous layer was further extracted twice with 200 mL of ether, dried (MgSO4), concentrated in vacuo to give yellow oil which was flash chromatographed over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 1.85 g of the title compound as a pale yellow foam: 1 -NMR (CDCl3, 200 MHz): ppm 7.40 (m, 6H), 6.85 (d, 1H), 6.2 (s, 1H), 5.05 (s, 2H).