Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH2:6])[CH2:4][CH2:3]1.[CH2:7](N(CC)CC)[CH3:8].[C:14]([N:21]1[CH:25]=[CH:24]N=C1)(N1C=CN=C1)=[O:15]>C(Cl)(Cl)Cl>[CH:2]1([CH2:5][NH:6][C:14]([NH:21][CH2:25][CH:24]2[CH2:8][CH2:7]2)=[O:15])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: NCC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CC1)NCC1CC1
Yield: 59.1 %

Procedure:
Cyclopropanemethylamine hydrochloride (Aldrich, 1.00 g, 9.30 mmol) and triethylamine (0.95 g, 9.39 mmol) were dissolved in chloroform (10 mL). 1,1'-Carbonyldiimidazole (Aldrich, 0.754 g, 4.65 mmol) was added and the resulting solution maintained at ~55° C. for 22 h. The chloroform solution was extracted with 1N hydrochloric acid (2×50 mL) and then with water (50 mL) and dried. Evaporation of the chloroform gave crude product (650 mg) which was recrystallized from toluene to give 1,3-bis(cyclopropylmethyl)urea as white crystals (462 mg, 59%), m.p. 127°-130° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:11])[CH3:10])=[CH:5][C:4]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1ccc(C(C)C)cc1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1CN1CCNCC1
Yield: 126.8 %

Procedure:
A solution of the product from step (a) (1.98 g) in TFA (4 ml) and dichloromethane (2 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue azeotroped with toluene. Aq. potassium carbonate was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4) and evaporated in vacuo to give the sub-title compound (1.79 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[N+:24]([C:23]1[C:15]2[N:14]=[C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[O:7][C:17](=[O:18])[C:16]=2[CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: O
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.1 %

Procedure:
3-(trifluoromethyl)benzoyl chloride 2 (4.5 mL, 30.2 mmol) was added to a suspension of 2-amino-3-nitrobenzoic acid 1 (5.0 g, 27.5 mmol) in pyridine (65 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O (300 mL). The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 3 (5 g, 51% yield) as a yellow solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=3[F:30])[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C([Sn](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:28][C:27]1[CH:26]=[C:25]([F:29])[CH:24]=[C:23]([F:30])[C:22]=1[CH2:21][N:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=2)=[C:16]2[C:11]([C:12]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:14]=[CH:15]2)=[N:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(Br)c2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1

Procedure:
A solution of 3-(3-bromophenyl)-2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazole (2.0 g, 4.1 mmol) and trimethylsilyl-acetylene-tributyltin in 30 mL of toluene was degassed. Palladium-tetrakis-triphenylphosphine (0.046 g, 0.4 mmol) was added and the mixture heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 60, hexane-ethyl acetate, 9:1) to give the title compound (1.8 g) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8][Si](C)(C)C)=[CH2:7])(=O)[CH3:2].[C:13](OCC)(=O)[CH:14]=[CH2:15].P(OC(C)C)(OC(C)C)[O:21]C(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]=[C:14]1[CH2:15][CH2:8][CH:6]([C:5]([O:4][CH2:1][CH3:2])=[O:21])[CH2:7]1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C=C1CCC(C(=O)OCC)C1
Temperature: 100 °C
Yield: 132.6 %

Procedure:
The following reaction was performed in a 15 mL sealed tube, behind a safety shield. To 2-((trimethylsilyl)methyl)allyl acetate (2.227 mL, 10.73 mmol) in toluene (2 mL) was sequentially added ethyl acrylate (2.92 mL, 26.8 mmol), triisopropyl phosphite (1.474 mL, 6.44 mmol) and palladium(II)acetate (0.241 g, 1.073 mmol). The contents were purged with nitrogen gas for 5 min. and heated at 100° C. for 45 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The liquid was transferred to a 50 mL round bottom flask and distilled using a high vacuum pump. Fractions distilling at 50° C. were collected and concentrated to yield 1.317 g (80%) of ethyl 3-methylenecyclopentanecarboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 4.90-4.85 (m, 2 H), 4.14 (q, 2 H, J=7.0 Hz), 2.87-2.78 (m, 1 H), 2.61-2.53 (m, 2 H), 2.51-2.23 (m, 2 H), 2.09-1.82 (m, 2 H), 1.29-1.23 (t, 3 H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: O=C(Oc1ccccc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of 6-chloronicotinic acid (68.0 g, 0.431 mol), phenol (40.6 g, 0.431 mol), DCC (93.6 g, 0.453 mol), and DMAP (1.60 g, 0.0129 mol) in ether (1 L) was stirred at room temperature overnight. The solvent was evaporated and the residue was stirred in CH2Cl2. The solid was filtered and the filtrate was purified by flash chromatography eluted with CH2Cl2 to give 88.0 g (88%) of the desired product. MS (DCI/NH3) m/z: 234.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=8.14 Hz, 2H) 7.31 (t, J=7.29 Hz, 1H) 7.47 (dd, J=17.12, 7.97 Hz, 3H) 8.40 (m, 1H) 9.17 (d, J=1.70 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15].[Br:18]Br.CO>CN(C)C=O>[Br:18][CH2:1][C:2]1[N+:11]([O-:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N+:4]([O-:13])[C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reaction time: 1.5 h

Procedure:
Methyl 3-methyl-2-quinoxalinecarboxylate-1,4-dioxide (1.2 moles) were suspended in 475 ml of dimethylformamide and 64 ml of bromine was added dropwise with stirring over 1.5 hours while the temperature rose to 42° C. After additional stirring for 48 hours 1.5 liters of methanol were added and stirred for about 1/2 hour. The precipitated product was removed by filtration, washed with water and dried. Yield, 251 grams (68%); m.p. 113°-16° C.
Reaction SMILES: [Na].CN([CH:5]=[C:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)C.Cl.[CH3:15][NH:16][C:17]([NH2:19])=[NH:18]>C(O)C>[CH3:15][NH:16][C:17]1[N:19]=[CH:5][C:6]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[N:18]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CNC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CNc1ncc2c(n1)CCCC2=O
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To anhydrous ethanol (15 mL) was added sodium metal (0.45 g, 19.5 mmol). After complete dissolution of sodium metal in ethanol, 2-((dimethylamino)methylene)cyclohexane-1,3-dione (1 g, 5.5 mmol) and N-methylguanidine hydrochloride (1 g, 9.0 mmol) were added and the reaction was refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ice-cooled water (50 mL) was then added to the residue and the aqueous solution extracted with EtOAc (3×40 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.6 g, 57%) as a solid. The crude product was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 8.90 and 8.80 (2s, 1H), 5.98 and 5.82 (2s, 1H), 3.11 and 3.09 (2s, 3H), 2.96-2.88 (m, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.10 (quintet, J=6.0 Hz, 2H). LCMS [M+H]: 178.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][C:4]=1[F:12].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[ClH:13].[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:5][C:4]=1[F:12]
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Fc1cc2c(cc1Br)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4cc(F)c(Br)cc43)ncnc2c1
Yield: 74 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 (with conversion to the HCl salt as outlined for Example 2), this product was prepared in 74% yield from 6-bromo-5-fluoro-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 252°-252° C.; LC-MS: 374, 376 (MH+); anal. RP18-HPLC RT: 5.26 min.).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=O)=[O:17])[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:42][CH:43]([CH:50]([CH3:52])[CH3:51])[CH:44]([OH:49])[C:45]([F:48])([F:47])[F:46]>C(#N)C.CN(C)C=O>[F:46][C:45]([F:47])([F:48])[CH:44]([OH:49])[CH:43]([NH:42][C:20](=[O:22])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16](=[O:17])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH:50]([CH3:51])[CH3:52]
Reactant: CC(C)C(N)C(O)C(F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(O)C(F)(F)F
Temperature: -20 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of Boc-L-alanyl-L-alanyl-L-proline (1.0 g, 2.80 mmol) in dry acetonitrile (25 ml) was added N-methylmorpholine (0.34 ml, 3.06 mmol). The solution was cooled to -20° C. and isobutylchloroformate (0.37 ml, 2.88 mmol) was added dropwise. To this solution, a pre-cooled (-20° C.) mixture of 3-amino-1,1,1-trifluoro-4-methyl-2-pentanol hydrochloride (0.61 g, 2.91 mmol), N,N-dimethylformamide (4 ml) and N-methylmorpholine (0.34, 3.06 mmol) was added. The reaction mixture was stirred at -20° C. for 4 hr, allowed to warm to room temperature and stirred overnight. Removal of the solvents in vacuo produced a pale yellow residue, which was purified by flash chromatography using ethyl acetate as an eluent to give 1,1,1-Trifluoro-3-[(N-tert-butyloxycarbonylalanyl)alanylprolylamino]-4-methylpentane-2-ol (1.09 g, 2.1 mmol) in 76% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[C:4]([Cl:12])[CH:3]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[C:4]([Cl:12])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Clc1cc(Br)ccc1OC1CC1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(OC2CC2)c(Cl)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-2-chloro-1-cyclopropoxy-benzene (610 mg, 2.46 mmol, 1.00 eq.) in dioxane (20 mL), bis(tri-t-butylphosphine)palladium (0) (193 mg, 0.37 mmol, 0.15 eq.) and 2-tert-butoxy-2-oxoethylzinc chloride (0.5M in diethyl ether) (8.9 mL, 4.44 mmol, 1.80 eq.) were added in sequence. The resulting mixture was stirred at r.t. for 18 hours and further at 60° C. for 4 hours. The mixture was allowed to cool down to r.t. and filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane to Heptane+5% AcOEt) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH:25]=[C:26]([CH3:29])[CH:27]=O.COC1C=C(C=C(OC)C=1OC)C(O)=O.C[N:46](CCCN=C=NCC)C>C(Cl)Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:46][CH2:27][C:26]([CH3:29])=[CH:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[F:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC(=O)O
Reactant: CC(C=O)=Cc1ccc(F)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=Cc1ccc(F)cc1F)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Experimental condition analogous to Example 2 were used with 2-(S)-{[3-(2,4-difluoro-phenyl)-2-methyl-allylaminmo]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester were used with 2-(S)-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-(2,4-difluoro-phenyl)-2-methyl-propenal described in scheme 15) 0.4 g (1 mmol), 3,4,5-trimethoxy benzoic acid 0.27 g (1.3 mmol), triethylamine 0.1 ml, 1-(dimethylaminopropyl)-3-ethylcarbodiimide 0.31 g (1.63 mmol), and 1-hydroxybenzotriazole 0.014 g (0.1 mmol) in 10 ml DCM. The reaction yielded 0.49 g of 2-(S)-{[3-(2,4-difluoro-phenyl)-2-methyl-allylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. The compound was transformed to the HCl salt, yielding 45 mg of a white solid. Yield: 14%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20](Br)[CH:21]=1)[C:17]#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)[C:17]#[N:18]
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
p-Methoxybenzyl alcohol (2.6 mL) was dissolved in anhydrous DMF (50 mL) and NaH (808 mg, 60% dispersion in oil) was added in several portions. After gas evolution ceased, 3,5-dibromobenzonitrile (5.0 g) was added and the reaction mixture was stirred at 70° C. After 2 h additional amount of NaH (147 mg) was added and heating was continued for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 3.1 g of the title compound (51% yield). HRMS calcd for C15H12O2BrN M+ 371.0051, observed 371.0048.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([O:23]C)[CH:17]=[C:16]([O:25]C)[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[C:18]([OH:23])[CH:17]=[C:16]([OH:25])[C:15]=2[C@@H:27]1[CH2:31][CH2:30][N:29]([CH3:32])[C@H:28]1[CH2:33][OH:34]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(NC(C)C)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)Nc1cccc(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1Cl

Procedure:
A mixture of example 64 (0.900 g, 1.98 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].C1(P([C:52]2[CH:57]=[CH:56]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:58]([N:60](CC)[CH2:61][CH3:62])[CH3:59].C(#N)C>[Cu]I.[C].[Pd].CN(C=O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:52]#[C:57][CH2:56][N:60]([CH2:61][CH3:62])[CH2:58][CH3:59])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(Br)c2)c2cccnc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: [Pd]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCN(CC)CC)c2)c2cccnc21

Procedure:
A mixture of N-[1-butyl-4-(3-bromophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (4.6 g, 8 mmol), 3-diethylamino-3-propyne (2.67 g, 24 mmol), copper (I) iodide (122 mg, 0.64 mmol), triphenylphosphine (335 mg, 1.28 mmol), 10% palladium-carbon (336 mg), triethylamine (30 ml), acetonitrile (30 ml), and DMF (30 ml) was heated under reflux for six hours. After allowed to stand for cooling, the mixture was filtered through a cerite pad. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (500 ml). The mixture was washed with water, washed with a 0.5N aqueous hydrochloric acid solution, washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-4% methanol in chloroform) to give the title compound (3.05g, 5.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8]C)[CH:7]=1.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cc(O)cc(Cl)c1
Temperature: 220 °C
Yield: 48.4 %

Procedure:
A mixture of 1-(3-chloro-5-methoxy-phenyl)-ethanone (14.3 g, 0.08 mol.) and pyridine hydrochloride (44.8 g, 0.39 mol.) was heated at 220° C. for 2 hrs. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with water (40 mL), brine (40 mL) and concentrated to give an oil. Flash Chromatography on Silica Get eluting with ethyl acetate/hexanes (1:1) gave 6.6 g solid. MS (m/e): 170/172 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:39])[CH2:10][N:11]([CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH2:29][C:30](=[CH:34][C:35]([O:37]C)=[O:36])[CH:31]=[CH:32][CH:33]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[Cl:23].ClC1C=CC=CC=1C(C)CN(CCCOC1CC(=CC(O)=O)C=CC=1)CC1C=CC=C(C(F)(F)F)C=1Cl>>[ClH:23].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:39])[CH2:10][N:11]([CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH2:29][C:30](=[CH:34][C:35]([OH:37])=[O:36])[CH:31]=[CH:32][CH:33]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=1[Cl:23]
Reactant: COC(=O)C=C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(C)c2ccccc2OC)C1
Agent: CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: COc1ccccc1C(C)CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl
Product: Cl
Yield: 62 %

Procedure:
The titled compound was prepared from N-(2-[2-methoxyphenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxymethylenephenoxy)propylamine in 62% yield in the same manner as the preparation of N-(2-[2-Chlorophenyl]-propyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine in Example 184g. MS (ESI) 550 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([S:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][S:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCSc1cccc2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSc2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(1-naphthylthio)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(1-naphthylthio)pentyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1)=[O:23]>C(Cl)Cl>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:22](=[O:23])[O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)O[C@H]2CCOC2)C1
Temperature: 25 °C

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg, 2.6 mmol) in 5 mL CH2Cl2 was added triethylamine (0.73 mL, 5.2 mmol), and the reaction was cooled to −20° C. (S)-tetrahydrofuran-3-yl chloroformate (525 mg, 3.48 mmol) was added in portions over a period of 10 minutes to the above reaction mixture. After allowing the reaction to warm to room temperature, it was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford (S)-tetrahydrofuran-3-yl (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave (S)-tetrahydrofuran-3-yl (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 63%). LC/MS: m/z 301.3 (M+H)+ at 2.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).