Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: C=CCOC(=O)Cl
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Product: C=CCOC(=O)Nc1ccc(CC(CC(=O)c2cc(OC)c(OC)c(OC)c2)NC(=O)[C@@H]2CCCN2)cc1
Yield: 74.5 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol) with allyl chloroformate (0.036 mL, 0.34 mmol) provided 90 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-carboalloxy)aminophenyl)ethylamide as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O.Cl.[Cl:23][C:24]([Cl:29])=[CH:25][CH2:26][O:27][NH2:28].Cl>N1C=CC=CC=1>[Cl:23][C:24]([Cl:29])=[CH:25][CH2:26][O:27][N:28]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:14][C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])=[CH:12][C:11]=1[Cl:21]
Reactant: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NOCC=C(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: ClC(Cl)=CCON=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
To a mixture of 0.37 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal and 10 ml of pyridine was added 0.20 g of O-(3,3-dichloro-2-propenyl)hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.23 g (yield, 48%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal O-(3,3-dichloro-2-propenyl)oxime, nD25.2 1.5559.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24](Cl)=[O:25])[CH:19]=[C:20]([F:22])[CH:21]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Product: CC(C)(C)c1c(NC(=O)Cc2cc(F)cc(F)c2)nn2cccnc12

Procedure:
The product from Example 105B and 3,5-difluorophenylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.70 (s, 2H), 6.98-7.16 (m, 4H), 8.49 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=6.8, 1.7 Hz, 1H), 10.01 (s, 1H); MS (DCI) m/z 345 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH:16][C:11]([NH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[S:12]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 49%).
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52](Br)=[CH:53][CH:54]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([C:31]2[CH:32]=[CH:33][C:28]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:21])([F:22])[F:20])[C:15]([F:17])([F:16])[F:18])=[C:8]([CH3:27])[CH:7]=3)[CH2:1][CH3:2])=[CH:29][C:30]=2[CH3:43])=[CH:53][CH:54]=1)[CH3:45]
Reactant: CCOC(=O)Cc1ccc(Br)nc1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 58.2 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 50 mg, 0.082 mmol), (6-bromo-pyridin-3-yl)acetic acid ethyl ester (Example 74-(1); 40 mg, 0.165 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1, then dichloromethane/methanol=20/1) to give the title compound (31 mg, 58%).
Reaction SMILES: [N:1]1([S:6]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:9]([S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])[C:10](=[O:12])[CH3:11])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)CS(=O)(=O)N1CCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)S(=O)(=O)N1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Alternatively, the Bignelli reaction was carried out in two steps with higher yields. To 1-(pyrrolidin-1-ylsulfonyl)propan-2-one in THF was added an equivalent amount of 3,4-dichlorobenzaldehyde and a catalytic amount of titanium tetraisopropoxide. The reaction was stirred at 80° C. overnight. Solvent was removed and the residue was purified by silica flash chromatography (0% to 15% ethyl acetate-hexanes) to provide 4-(3,4-dichlorophenyl)-3-(pyrrolidin-1-ylsulfonyl)but-3-en-2-one. The product obtained was dissolved in 1,4-dioxane and one equivalent of 3-methyl-1H-pyrazol-5-amine was added. The reaction was stirred at 80° C. for 24-48 hrs. Solvent was removed and product was obtained after flash chromatography (silica gel, 0% to 40% ethyl acetate-hexanes).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH:18]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH:19]([CH3:21])[CH3:20])=[CH:12][C:11]=2[CH3:31])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:46])[CH:42]([OH:45])[CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:46])[CH:42]([OH:45])[CH2:43][NH:44][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)=[C:11]([CH3:31])[CH:12]=2)[CH:19]([CH3:21])[CH3:20])=[CH:23][CH:24]=1
Reactant: Cc1cc(OC(c2ccc(C(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(C)C)cc1
Reactant: COC(=O)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(O)CNC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(4′-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoic acid (150 mg, 0.36 mmol) in methylene chloride (4 mL) is added triethyl amine (0.15 mL, 1.08 mmol), DMAP (5.0 mg), 3-Amino-2-hydroxy-propionic acid methyl ester (83 mg, 0.54 mmol) and EDCI (208 mg, 1.08 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31]>>[NH2:22][C:20]1[S:21][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:24]3[C:25]([S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:7][C:2]=2[F:1])=[N:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3nnc(N)s3)c(F)c2)OC1(C)C
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2nnc(N)s2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-thiadiazol-2-amine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C17H17FN4O3S2, 408.07; m/z found, 409.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.15-8.12 (m, 2H), 7.68 (m, 1H), 7.61 (m, 1H), 7.44-7.38 (m, 3H), 3.42-3.38 (m, 1H), 3.30-3.25 (m, 1H), 3.22-3.18 (m, 1H), 1.02 (d, J=6.6, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:24][C:11]3=[N:12][C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([C:16]([CH3:18])=[CH2:17])[CH:15]=[C:10]3[C:9]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.I[CH2:30][C@@H:31]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:32]=[CH2:33].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:35]([O:34][C@@H:31]([CH:32]=[CH2:33])[CH2:30][N:19]([C:13]1[N:12]=[C:11]2[O:24][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:25]([NH:27][CH3:28])=[O:26])[C:10]2=[CH:15][C:14]=1[C:16]([CH3:18])=[CH2:17])[S:20]([CH3:23])(=[O:21])=[O:22])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=C[C@@H](CI)OCc1ccccc1
Reactant: C=C(C)c1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=C[C@@H](CN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1C(=C)C)S(C)(=O)=O)OCc1ccccc1
Yield: 57.4 %

Procedure:
2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide (87 mg, 0.216 mmol), (S)-((1-iodobut-3-en-2-yloxy)methyl)benzene (62.1 mg, 0.216 mmol) and cesium carbonate (70.3 mg, 0.216 mmol) are heated under microwave irradiation for 30 min at 120° C. HPLC affords (S)-6-(N-(2-(benzyloxy)but-3-enyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide (70 mg, 0.124 mmol, 57.6% yield)
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22]CC)=O)([O-])=O>C(O)C.O.[Fe]>[O:22]=[C:20]1[CH2:19][C:7]2[C:6](=[C:11]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)Cc1cccc(Sc2ccccc2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C1Cc2cccc(Sc3ccccc3)c2N1

Procedure:
A suspension of iron powder (1.5 g.) and ammonium chloride (0.15 g.) in a mixture of ethanol (7 ml.) and water (7ml.) was refluxed with stirring. Ethyl 2-(2-nitro-3-phenylthiophenyl)acetate (1.6 g.) was added to the suspension, and the mixture was refluxed for 7 hours and filtered. The filtrate was evaporated to dryness under reduced pressure, and residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was dissolved in ethanol (10 ml.) and heated with conc. hydrochloric acid (0.1 ml.). The precipitating crystals were collected by filtration and dried to give the captioned compound (0.9 g.). mp 160° to 161° C.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15](=[O:17])[NH2:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O>CO.[Pd]>[C:15]([C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)N1
Yield: 96.2 %

Procedure:
53 mg (163 umol) of cis-1-benzyl-4-carbamoylazetidine-2-carboxylic acid benzyl ester (II) in 10 ml of methanol are hydrogenated in a Parr shaker over 18 mg of 10% Pd/C under a hydrogen pressure of 3.3 atm for 3 hours. 10 ml of water is added, the mixture filtered through a fluted filter, and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo (0.1 torr, 4 hours) affords 22.6 mg (96%) of a colorless glass. 1H NMR (D2O): δ 5.00 (t, 1H, J=9), 4.75 (t, 1H, J=9), 3.14 (dt, 1H, J=10 (t), 12 (d)), 2.52 (dt, 1H, J=8(t), 12 (d)). IR (nujol): 3399, 3141, 3141, 3019, 2537, 2409, 1688, 1615, 1563, 1391, 1294, 1217, 1165, 1115, 1048, 968, 887, 810, 762, 696, 637 cm-1. Mass Spectra: El: m/z 142(M-2H, 40%), 100 (100), 91 (14), 82 (27), 68 (28), 54 (50), 44 (95); CI (isobutane): m/z 145 (M+ H, 100%), 126 (7), 100 (24), 99 (15), 84 (15), 72 (22).
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](=[O:11])[C:5](=[O:12])[CH:4]=1.Cl.[Cl:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C>ClCCl>[Cl:14][CH2:15][CH2:16][NH:17][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](=[O:11])[C:5](=[O:12])[CH:4]=1
Reactant: COC1=CC(=O)C(=O)C=C1OC
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CC(=O)C(=O)C=C1NCCCl
Yield: 31.8 %

Procedure:
4,5-Dimethoxy-1,2-benzoquinone (672.4 mg, 4 mmol) was dissolved in dichloromethane (40 ml) and stirred in a round-bottomed flask equipped with a cylindrical funnel from which a solution of chloroethylamine hydrochloride (1.2 g, 4.4 mmol) and triethylamine (2.4 ml, 16.8 mmol) in dichloromethane (50 ml) was added dropwise into the solution over the course of one hour. The reaction mixture was maintained with stirring at room temperature for 21 hours. After filtration, the remaining solution was washed with 10% hydrochloric acid, distilled water and then distilled water saturated with sodium chloride, and then dried over magnesium sulfate. Evaporation of the solvent gave the black red crude product. Column chromatography with chloroform: methanol (4:0.5, (v/v)) elution gave 4-chloroethylamino-5-methoxy-1,2-benzoquinone 274.3 mg, 31.8% yield) which was recrystallized from ethanol as red needles: mp 150°-152° C.; Found: C,50.17; H,4.77; N,6.44; Cl,16.39. Anal. Calcd. for C9H10ClNO3 : C,50.13; H,4.67; N,6.49; Cl,16.44%. I.R. υmax 3400, 2940, 1660, 1640, 1620, 1580, 1510, 1250, 1180, 810 cm-1. U.V. λmax (95% EtOH) 210 nm (log ε4.35), 304 (4.23), 464 (3.51), 1HNMR (CDCl3) δ, 3.6 (m, 4H, NCH2CH2), 3.9 (S, 3H, O CH3), 5.4 (S, 1H, 6-H), 5.7 (s, 1H, 3-H), 6.2 (br,s, 1H, NH).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][CH2:7][C:8](Br)=[O:9].[Cl:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(Cl)Cl>[Br:6][CH2:7][C:8]([N:19]1[CH2:18][CH2:17][CH:16]([O:15][C:14]2[CH:22]=[CH:23][CH:24]=[C:12]([Cl:11])[CH:13]=2)[CH2:21][CH2:20]1)=[O:9]
Reactant: Clc1cccc(OC2CCNCC2)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CCC(Oc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of sodium bicarbonate (34 g, 0.040 mol), 400 ml of methylene chloride and bromoacetyl bromide (15.7 ml, 36.5 g, 0.176 mol) cooled by an ice/salt bath was added dropwise a solution of 4-m-chlorophenoxypiperidine (34.9 g, 0.165 mol) in 400 ml of methylene chloride. The reaction mixture was stirred 1 hour at 0° and 3 hours at room temperature. The reaction mixture was poured into water, extracted with methylene chloride, and the extract was washed with water, 3N HCl, saturated sodium bicarbonate and saturated sodium chloride. Evaporation of the solvent provided N-(2-bromoacetyl)-4-(m-chlorophenoxy)piperidine.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[N:13]=[CH:12][N:11]=1.C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[Cl:9])=[O:4]
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: C#CCNC(=O)CCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and 4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 mL; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22+mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (˜20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1× saturated NH4Cl, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1:1 Hexanes/EtOAc and collecting fractions with an Rf=0.25. 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide was obtained as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCl3) δ 4.12 (2H, s), 4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=1.6 Hz), 9.03 (1H, s). Irms (M+): 294.0, 296.0, 298.1.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[CH3:8][NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[S:3][C:4]([N:9]([CH3:8])[CH:10]2[CH2:11][C:12]([CH3:18])([CH3:19])[NH:13][C:14]([CH3:17])([CH3:16])[CH2:15]2)=[N:5][N:6]=1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: Brc1nnc(Br)s1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (2.975 g, 12.2 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (2.493 g, 14.64 mmol) in dioxane (40 mL) was added DIPEA (10.65 mL, 61 mmol) and the resulting mixture refluxed at 120° C. for 16 hours. The reaction mixture was cooled to room temperature then filtered under vacuum, rinsed with dioxane, and the filtrate concentrated in vacuo to afford the crude product as a pink/red oil. The crude material was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pink/red solid (2.924 g, 72% yield). LC-MS: Rt 0.70 min; MS m/z 335.2 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13-4.03 (m, 1H), 2.92 (s, 3H), 1.57 (dd, J=12.13, 3.54 Hz, 2H), 1.39 (t, J=12.13 Hz, 2H), 1.26 (br. s., 1H), 1.16 (s, 6H), 1.06 (s, 6H). LC-MS: Rt 1.12 min; MS m/z 335.2 [M+H]+ [Method B].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 85 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 37 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([N:6]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[CH2:5].C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]([CH:4]1[N:6]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]([C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:5]1)=[O:34]
Reactant: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(C(=O)c2ccccc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Yield: 92 %

Procedure:
The procedure of Example 35 was followed using the product from Example 34 (500 mg, 1.04 mmol) and sodium bicarbonate (114 mg, 1.35 mmoml) in methanol (5 ml) to give 460 mg (92%) of the product.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CI.[CH3:38]COCC>CS(C)=O>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][O:19][CH3:38])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CS(C)=O
Product: COCC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A solution of 0.025 g (0.057 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine, 0.013 g (0.23 mmol) of KOH and 0.028 mL (0.46 mmol) of methyl iodide in 2 mL of DMSO was stirred at rt for 1.2 h. The reaction mixture was poured into ether and washed with sat'd NaHCO3 and NaCl solutions, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. Mass Spectrum (ESI) m/e=461 (M+1).