Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:22]2[CH2:23][CH2:24][CH:19]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:20][CH2:21]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.7 %

Procedure:
To 5-fluoro-2-nitrophenyl methyl ether (26.0 g, 152 mmol), 1,4′-bipiperidine (25.5 g, 152 mmol) and K2CO3 (22.9 g, 166 mmol) was added DMSO (260 mL). The mixture was stirred at room temperature for 3 days. The mixture was poured into H2O (1000 mL) and the H2O washed with EtOAc (2×500 mL). The EtOAc washes were combined and washed with H2O (2×500 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (47.9 g, 150 mmol, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=9.5 Hz, 1H), 6.40 (dd, J=9.5 and 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 3.99-3.93 (m, 2H), 3.93 (s, 3H), 2.98-2.89 (m, 2H), 2.58-2.48 (m, 5H), 1.99-1.90 (m, 2H), 1.70-1.55 (m, 8H), 1.48-1.40 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[NH:39]1[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:39]4[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]4)[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: O=C(O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(C(=O)O)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added isonipecotic acid (60 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 561 (M+H).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>C1COCC1.O>[CH3:15][O:14][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:13]
Reactant: COC(=O)Cl
Reactant: NC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC1(C(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A suspension of 39.9 g (279 mmol) of 1-aminocyclohexane-1-carboxylic acid in a mixture of 75 ml of THF and 75 ml of water was treated dropwise with 23.8 ml of methyl chloroformate, dissolved in 40 ml of THF, such that the temperature of the suspension did not rise above 50° C. In the course of this, the pH of the solution was kept between 8.5 and 9.5 by addition of 25% strength sodium hydroxide solution. After stirring at pH 8 for 30 minutes, the mixture was diluted with water, the THF was removed in vacuo and the aqueous phase was washed twice with methyl tert-butyl ether. The aqueous phase was adjusted to pH 2 using 6 N hydrochloric acid and extracted successively with methyl tert-butyl ether and dichloromethane. The combined organic phases were concentrated in vacuo. The residue was triturated with diethyl ether and the product was filtered off. 47.85 g (85%) of 1-methoxycarbonylaminocyclohexane-1-carboxylic acid were obtained.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1([C:37]2[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=2)[CH:40]=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:40][C:39]4[CH:42]=[CH:43][N:44]=[C:37]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:38]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(N5CCCC5)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-pyrrolidin-1-ylisonicotinaldehyde (14 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[C:32]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=[N:34][CH:35]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(Cl)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.130 mmol) and 2,6-Dichloropyrazine (0.0311 g, 0.209 mmol) were combined then added dry N,N-Dimethylformamide (0.911 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=8.8, 2H), 7.90 (s, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.69 (d, J=16.4, 2H), 3.86 (t, J=5.1, 2H), 3.79-3.69 (m, 4 H), 3.49 (d, J=4.3, 4H), 3.18-3.06 (m, 2H), 2.80 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])=[CH:9][C:8]=1[F:22].[Si:23]([O:30][CH:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:23]([O:30][CH:31]([CH2:35][CH2:34][OH:33])[C:32]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])=[CH:9][C:8]=1[F:22])=[O:36])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCO)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.1 ml of n-butyl lithium (2.66 M hexane solution) was dropwise added to a tetrahydrofuran (100 ml) solution of 1.1 g of N-(4-bromo-3-fluorophenyl)pyridine-2-carboxamide at −78° C., and the reaction liquid was stirred at the same temperature for 15 minutes. 1.21 g of 3-((t-butyl(dimethyl)silyl)oxy)dihydrofuran-2 (3H)-one was added to the reaction liquid, and the reaction liquid was stirred at the same temperature for 1 hour. Aqueous saturated sodium bicarbonate solution was added to the reaction liquid at the same temperature, then heated up to room temperature and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=100/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.C(C(O)=O)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[O:7])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: COc1ccc(CCBr)cc1
Reactant: O=C(c1csc2ccccc12)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C(=O)c3csc4ccccc34)CC2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Mix (benzo[b]thiophene-3-yl)(4-piperidinyl)methanone.CF3CO2H (2.0 g, 5.56 mmol), 2-(4-methoxyphenyl)ethyl bromide (1.27 g, 5.93 mmol), potassium carbonate (1.95 g, 1.41 mmol) and anhydrous dimethylformamide (20 mL). Warm to approximately 90° C. and stir overnight. Allow to cool to room temperature and partition between a 2:1 mixture of ethyl acetate:toluene and water. Separate the aqueous phase and wash the organic phase with water and saturated sodium chloride. Dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (40% ethyl acetate/hexane) and recrystallize (cyclohexane) to give the title compound as pale yellow plates; mp 114°-116° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[CH2:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25].CCCCC>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([CH:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]C(C)(C)C
Reactant: C=C(C(=O)OC)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)C(CC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]prop-2-enoate (42c) (114 mg, 0.35 mmol) in anhydrous tetrahydrofuran (5 mL) was cooled to −78° C. tert-Butyllithium 1.6M in pentane (0.24 mL, 0.38 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 20 minutes before being quenched with brine (3 mL). The mixture was extracted with dichloromethane (2×6 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to provide the desired product (42d) (102 mg, 0.26 mmol, 76%) as a light yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][OH:36])=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:58][C:59]1[CH:68]=[C:67](O)[CH:66]=[CH:65][C:60]=1[C:61]([O:63][CH3:64])=[O:62].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:64][O:63][C:61](=[O:62])[C:60]1[CH:65]=[CH:66][C:67]([O:36][CH2:35][CH2:34][O:33][C:20]2[C:19]([Br:37])=[CH:18][C:17]([C:16](=[O:38])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:22][C:21]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:68][C:59]=1[OH:58]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.687 g, 1.16 mmol, 1 eq) in THF (10 mL) was added triphenylphosphine (0.680 g, 2.59 mmol, 2.23 eq) and methyl 2,4 dihydroxybenzoate (0.388 g, 2.30 mmol, 2.0 eq). The reaction was cooled to 0° C. and diethyl azodicarboxylate (0.220 mL, 1.40 mmol, 1.2 eq) was added. The cold bath was removed and the reaction was stirred overnight at rt. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc:hexane) to afford 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester 1H NMR (CDCl3) δ 11.90 (s, 1H); 7.97 (d, 1H); 7.84-7.50 (m, 6H); 7.28-7.12 (m, 5H); 6.40 (m, 1H); 6.24 (m, 1H); 6.10 (bt, 1H); 4.12 (dd, 2H); 4.00 (m, 2H); 3.92 (s, 3H); 3.45 (dd, 2H); 2.59 (t, 2H); 1.60 (m, 4H); 1.33 (m, 8H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[CH:4]=1.[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][CH:24]([CH2:2][C:3]2[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=2)[CH2:9][Cl:10])[CH2:23][CH2:22]1)[CH3:11]
Reactant: ClCc1cccc(CCl)c1
Reactant: CC(C)Oc1ccccc1N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1ccccc1N1CCC(Cc2cccc(CCl)c2)CC1
Yield: 25.5 %

Procedure:
A biphasic solution of α,α'-dichloro-m-xylene (2.40 g, 0.0137 mol), N-[2-(1-methylethoxy)phenyl]piperidine (3.00 g, 0.0137 mol), sodium carbonate (2.19 g, 0.020 mol), ethyl acetate (20 mL), and H2O (20 mL) was refluxed for 3 h. The organic layer was separated, dried (MgSO4), filtered, and evaporated to an oil. The residue was chromatographed on silica gel using chloroform as eluant to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperidinyl]methyl]benzyl chloride (1.25 g, 25%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=O)[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[S:40])[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.700 g, 1.66 mmol) in toluene (15 mL) and DME (15 mL) was added Lawesson's reagent (1.058 g, 2.66 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.540 g, 74%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.8 Hz, 1H), 6.67 (br, 1H), 6.39 (m, 1H), 6.36 (m, 1H), 4.88 (d, J=15.2 Hz, 2H), 4.74 (m, 1H), 4.27 (m, 2H), 4.19 (m, 2H), 3.97 (m, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47]Cl)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C>CC#N>[C:31]([O:35][C:36]([N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][N:11]([CH2:10][CH2:9][CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(CCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21)C(=O)OC(C)(C)C
Yield: 76.5 %

Procedure:
Using the General Procedure for N-alkylation: A solution of (2S)-2-(tert-butoxycarbonylamino)-5-(5,6,7,8-tetrahydroquinolin-8-ylamino)-pentanoic acid tert-butyl ester (0.700 g, 1.67 mmol), 1-(tert-butoxycarbonyl)-2-(chloromethyl)-benzimidazole (0.690 g, 2.59 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) in CH3CN (16 mL) was heated at 60° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (50:1 CH2Cl2—MeOH) provided 0.830 g (77%) of 2-{[(4-tert-butoxycarbonyl-4-tert-butoxycarbonylamino-butyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a tan foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)([CH3:25])[CH3:24]>>[C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:19](=[O:21])[C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=2)[N:30]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: CC(C)(C)c1nc(CN)cs1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1
Product: CC(C)(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC3CC3)cn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid (example H) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.1491 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=CC(CN)=CC=1.[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35]([NH:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:36])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCCCc1ccccc1
Agent: NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCCCc1ccccc1)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 72 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with 3-phenylpropan-1-amine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(3-phenylpropyl)-isonicotinamide was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.82-8.78 (m, 1H), 8.56-8.50 (m, 2H), 8.05-8.03 (m, 2H), 7.64-7.50 (m, 4H), 7.32-7.16 (m, 5H), 3.31-3.27 (m, 2H), 2.67-2.62 (m, 2H), 1.90-1.80 (m, 2H); MS (ES+) m/z 360.5 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[S:25][C:24]([CH3:26])=[N:23][C:22]=4[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[Na+].[I-:34]>CC(C)=O.C(Cl)Cl>[I:34][CH2:12][C:13]12[CH2:20][CH2:19][C:16]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:17][CH2:18]1)[O:15][CH2:14]2
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4sc(C)nc4-c4ccccc4)(CC2)OC3)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Temperature: 85 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of (1-(2-Methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate (125 mg, 0.266 mmol) and NaI (120 mg, 0.799 mmol) in acetone (5 mL) was stirred in a seal tube at 85° C. for 18 h. The reaction was cooled to rt, diluted with DCM (5 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0-30% EtOAc:hexanes) to afford the title compound (100 mg, 88% yield) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.45-7.34 (m, 5H), 3.79 (s, 2H), 2.96 (s, 2H), 2.66 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.78 (m, 2H), 1.71-1.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([OH:18])=[O:17].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:8][CH2:9][CH2:10]1)[CH2:6][CH:5]2[CH2:15][C:16]([OH:18])=[O:17]
Reactant: [H][H]
Reactant: O=C(O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC1CC2(CCC2)Oc2ccc(Cl)cc21
Yield: 97.3 %

Procedure:
To a stirred solution of (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetic acid (2.5 g, 9.444 mmol) in ethyl acetate (25 ml) was added 10% Pd/C (50 mg) at room temperature. The reaction mixture was stirred for 12 h at 40 psi hydrogen pressure in Paar hydrogenation apparatus. The reaction mixture was filtered through a celite bed, the filtrate was dried (Na2SO4) and concentrated to give 2.45 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.68-1.78 (m, 5H), 1.86-1.96 (m, 1H), 2.09-2.21 (m, 2H), 2.29-2.38 (m, 1H), 2.99 (d, J=13.2 Hz, 1H), 3.44 (br s, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H).