Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([Cl:38])=[C:30]([Cl:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)c(Cl)c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: C([S@@]([NH:7][C@@H:8]([C:10]1[S:14][C:13]([C:15]([O-:17])=[O:16])=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.[ClH:18]>>[ClH:18].[NH2:7][C@@H:8]([C:10]1[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH:11]=1)[CH3:9]
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)[O-])s1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)s1
Temperature: 60 °C

Procedure:
To a vial containing 5-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]thiophene-2-carboxylate (0.050 g, 0.15 mmol) was added hydrochloric acid (3 mL, 12.0 mmol, 4.0 M of in 1,4-dioxane). This mixture was capped and heated at 60° C. for 2 h, after which it was evaporated to dryness to afford (R)-5-(1-aminoethyl)thiophene-2-carboxylic acid hydrochloride as a white solid. LC-MS: (FA) ES+ 172.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:38][CH3:39])[C:26]([NH:35][C:36]#[N:37])=[N:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.O>[CH2:28]([N:27]=[C:26]([NH:35][C:36]#[N:37])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:40])=[O:3])[CH:7]=1)[CH2:38][CH3:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccccc2)NC#N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=NCc1ccccc1)NC#N

Procedure:
[2′-(N′-Benzyl-N″-cyano-N-ethyl-guanidinomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.055 g, 0.1 mmol) in TIFF (2 mL) and H2O (0.5 mL) was treated with lithium hydroxide (0.02 g, 0.5 mmol), and the reaction was monitored by analytical LCMS. Once no starting material was seen, the mixture was diluted with EtOAc and H2O. Citric acid was added to neutralize the solution to pH 3, and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated twice from CH2Cl2 to give the title compound. M+H is 525.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1)(=O)C>CO.Cl>[CH3:1][O:4][CH:5]1[C@@H:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)Nc1cccc2ccccc12
Agent: Cl
Solvent: CO
Product: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
In methanol (20 ml) was suspended (2S,3S)-2-acetoxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]tetrahydrofuran (0.1 g) and following addition of concentrated hydrochloric acid (5 drops), the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give (3S)-2-methoxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]-tetrahydrofuran (chemical structure below) (0.08 g, 87%). As recrystallized from dichloromethane-isopropyl ether, colorless crystals, m.p. 184°-185° C., optical rotation [α]D +13.0° (C=0.27, CHCl3).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][S:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=O.CC(C[AlH]CC(C)C)C.O>C(Cl)Cl>[CH:10]([C:9]1[S:8][CH:7]=[N:6][C:5]=1[CH:3]=[O:2])([CH3:12])[CH3:11]
Reactant: COC(=O)c1ncsc1C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)c1scnc1C=O
Reaction time: 0.75 h

Procedure:
A solution of 6.8 g (37 mmol) of 5-isopropyl-thiazole-4-carboxylic acid methyl ester (J. Chem. Soc., Perkin Trans. 1, 1982:159-164) in CH2Cl2 (120 mL) was cooled to −78° C. under nitrogen and treated dropwise with DIBAL (37 mL of 1.0 M in CH2Cl2; 37 mmol). The mixture was stirred at low temperature for 45 minutes and then treated with another 20 mL of DIBAL. The solution was stirred for 1 hour at −78° C. H2O was added, and the mixture was extracted with EtOAc (3×150 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. Chromatography of the residue over silica gel, eluting with 2:1 hexane:EtOAc, gave the title compound.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[F:48][C:46]1[CH:45]=[CH:44][C:43]2[N:39]([CH:36]3[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:38][CH2:37]3)[CH:40]=[N:41][C:42]=2[CH:47]=1
Reactant: Fc1ccc2c(c1)ncn2C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5cc(F)ccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 73.3 %

Procedure:
The title compound was prepared from 40 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 40 mg 1-piperidin-4-yl-5-fluoro-1-H-benzoimidazole (from Step C ) and 60 mg of sodium triacetoxyborohydride in 4 mL of THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 43 mg of the title compound as an oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][SH:10])=[CH:4][CH:3]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: SCCc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(SCCc2ccncc2)cc1

Procedure:
A mixture of 2-(pyridin-4-yl)ethanethiol hydrochloride (3.84 g, 21.8 mmol, 4-fluoro-1-nitrobenzene (6.12 g, 43.3 mmol), and K2CO3 (9.0 g, 65.1 mmol) in acetonitrile (150 mL) was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/1) to afford 2.0 g of 4-(2-((4-nitrophenyl)thio)ethyl)pyridine as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, 2H), 8.14 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 3.30 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:27]([NH:37][C@@H:38]([C:41](O)=[O:42])[CH2:39][OH:40])([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CO.C(Cl)Cl.O>[OH:42][CH2:41][C@@H:38]([NH:37][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:40]
Reactant: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(N[C@H](CO)C(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine 249(a) (521 mg, 1.5 mmol), N-CBZ-D-Serine (359 mg, 1.5 mmol), and DIEA (0.653 mL, 3.75 mol) in DMA (4 mL) was added HATU (855 mg, 2.25 mmol) and the solution was stirred at room temperature for 0.5 hour. Excess H2O was added to the reaction mixture. The precipitate was collected and were redissolved in CH2Cl2, washed with NaHCO3 (aq) (2×), brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography. (1% MeOH/DCM as eluent) to afford (R)-benzyl 3-hydroxy-1-(4-(2-(4-morpholino-phenylamino)pyrimidin-4-yl)phenylamino)-1-oxopropan-2-ylcarbamate 365(a) (668 mg, 78% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Br:9])[NH2:5].Cl.Cl[CH2:12][CH:13]([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:12][CH:13]([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[Br:9]
Reactant: CC(CCl)CN(C)C
Reactant: Nc1ccc(Br)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CNc1ccc(Br)c(Br)c1)CN(C)C

Procedure:
In the manner given in Example 5, 3,4-dibromoaniline, 3-chloro-2-methyl-1-dimethylaminopropane hydrochloride and sodium carbonate are heated in toluene to give N'-(3,4-dibromophenyl)-N,N,2-trimethylpropane-1,3-diamine.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C[O:17][C:18]([NH:20][NH2:21])=[S:19]>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][CH:3]2[CH2:2][S:19][C:18](=[O:17])[NH:20][NH:21]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CCl
Reactant: COC(=S)NN
Solvent: CC#N
Product: O=C1NNC(C=Cc2ccc([N+](=O)[O-])cc2)CS1

Procedure:
A solution containing 11.2 g of 1-chloro-4-(4-nitrophenyl)-2-oxo-3-butene (J. Org. Chem. 28, 2446, 1963) and 6.8 g of hydrazinecarbothioic acid O-methylester in 200 ml of acetonitrile was refluxed for 3 h. The crystals were filtered and washed with acetonitrile and ether. Yield 7.7 g (59%), mp. 231°-240° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:19]([O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32](O)=[O:33])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:33])[CH3:20]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Product: CCOc1ccc2ccccc2c1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing 2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoxaline (Intermediate 35) and 2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI): mass calculated for C27H26N4O2, 438.53; m/z found 439.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.32 (d, J=16.4, 1H), 7.95-7.55 (m, 6H), 7.52-7.17 (m, 4H), 4.34-2.94 (m, 12H), 1.49-1.19 (m, 3H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([NH:16][C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[ClH:26].O>CO.[Pd]>[ClH:26].[NH2:11][C@@H:12]([C:14]([NH:16][C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH3:13]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)N

Procedure:
A solution of 7 g. of Nα -benzyloxycarbonyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol and 22 ml. of 0.95 l N hydrogen chloride in methanol is stirred with 500 mg. of 20% palladium on carbon catalyst under hydrogen at one inch water pressure until thin layer chromatography of a sample shows complete conversion (three to six hours). The solution is filtered to remove the catalyst and is evaporated to a foam. Solution in chloroform, 50 ml., and precipitation by ethyl ether affords an oil which is collected and dried at 45° C. and 1 mm. pressure. The oil is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[S:10]2(=[O:34])=[O:33])[CH:5]=[CH:6][C:7]=1[F:8].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[S:10]2(=[O:33])=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S1(=O)N(CCN2CCNCC2)c2ccccc2N1c1ccc(F)c(F)c1
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-{2-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.34 g, 0.69 mmol) in dichloromethane (5 mL) was treated with hydrogen chloride (2.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(3,4-difluorophenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2 g, 74%) as a white solid:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][N:13]([CH3:15])[C@H:10]1[CH2:9][C@@H:8]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(dimethylamino)cyclohexyl)acetamide (40 mg, 0.14 mmol) in isopropanol (6 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.17 mmol) and triethylamine (0.02 mL, 0.14 mmol). The mixture was stirred at RT for 16 h and concentrated in vacuo to a crude oil, which was purified by semi-preparative reverse phase HPLC (gradient elution, water/methanol/TFA) to give the title compound (70 mg, 71% yield). LC/MS found [M+H]+=479. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.87 (s, 1H), 8.72 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 5.49 (m, 1H), 4.23 (m, 1H), 4.2 (m, 1H), 4.12 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 2.82 (s, 6H), 2.51 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 2.14-1.86 (m, 5H), 1.84 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)Cl.C1(C)C=CC=CC=1.CCO>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:41]3[CH:40]=[C:39]([Br:42])[CH:38]=[CH:37][C:36]=3[O:35][CH3:34])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(Br)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (6.80 g, 11.39 mmol), 2-methoxy-5-bromo-phenyl boronic acid (3.00 g, 12.99 mmol), and sodium carbonate (2.65 g, 25.0 mmol) in 200 ml of 1:2:4 mixture of water:EtOH:toluene was stirred at room temperature for 30 min. Catalytic amount of tetrakis(triphenylphosphine) palladium (0.66 g, 5% mol) was added. The mixture was stirred under reflux for 24 h. TLC (CH2Cl2:hexane/1:1) showed no starting material. The solvents were removed. Water (100 ml) was added. The mixture was extracted with methylene chloride (3×100 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 7.88 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (t, J=7 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.31-7.34 (m, 1H), 6.90-6.93 (m, 1H), 5.63 (d, J=8 Hz, 0.5H), 5.25 (d, J=8 Hz, 0.5H), 4.98 (d, J=15.5 Hz, 0.5H), 4.88 (d, J=16 Hz, 0.5H), 4.12 (d, J=15.5 Hz, 0.5H), 3.88 (d, J=16.5 Hz, 0.5H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (m, 1H), 0.59 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:38][CH2:37][CH2:36][C@@H:33]1[CH:34]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:34][CH:33]1[CH2:36][CH2:37][CH2:38][N:32]1[C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of triphenylphosphine (31.7 g, 120.8 mmol) and carbon tetrabromide (20.0 g, 60.3 mmol) in methylene chloride (450 mL) at 0° C. was added dropwise a solution of N-(tert-Butoxycarbonyl)-D-prolinal (6.0 g, 30.1 mmol) in methylene chloride (50 mL). Upon complete addition of the aldehyde, the cooling bath was removed and mixing continued for an additional 30 minutes at ambient temperature. The mixture was poured into saturated sodium bicarbonate solution (600 mL) and the organic layer was extracted, dried over sodium sulfate anhydrous, concentrated in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-butyl 2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=300. 1H NMR (CDCl3, 400 Mhz) 6.37 ppm (s, 1H), 4.36 (s, 1H), 3.5-3.4 (m, 2H), 2.2-2.1 (m, 1H), 1.88-1.82 (m, 2H), 1.77-1.71 (m, 1H), 1.56 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([C:24]=2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1.Cl.[N:39]1([CH2:44][CH2:45]Cl)[CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:18]3[C:23]([C:24]=2[CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCN(c2ccccc2Cl)CC1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: O=C(c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN1CCCC1)N1CCN(c2ccccc2Cl)CC1
Yield: 53.8 %

Procedure:
Substantially the same procedure as in Example 89 was repeated using Compound 88 (0.95 g, 1.88 mmol) obtained in Example 88 and 2-pyrrolidinylethylchloride hydrochloride (335 mg, 1.97 mmol) to give 0.61 g (yield: 54%) of the title compound.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[NH:21][CH2:22][CH2:23][CH2:24][N:25]=1.[O:26]1C2C3OC(CNCCCNC4NCCCN=4)CCC=3C=CC=2OCC1>>[O:1]1[CH:2]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[NH:21][CH2:22][CH2:23][CH2:24][N:25]=2)[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]3[CH2:11][CH2:12][CH2:13][O:26][C:7]=3[C:6]1=2
Reactant: c1cc2c(c3c1CCC3)OC(CNCCCNC1=NCCCN1)CC2
Reactant: c1cc2c(c3c1CCC(CNCCCNC1=NCCCN1)O3)OCCO2
Product: c1cc2c(c3c1CCCO3)OC(CNCCCNC1=NCCCN1)CC2

Procedure:
N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[(2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (202 mg, 0.53 mmole), phenylboronic acid (130 mg, 1.07 mmole), cesium carbonate (522 mg, 1.60 mmole) and tetrakis(triphenylphosphine)palladium (62 mg, 0.05 mmole) in dioxane (2.8 ml) was refluxed for 16 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow oil (93 mg). MS: (+) m/z 377.27 (M+H+)