Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@@H:25]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@@H:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@@H]3CCNC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (D) in the portion of Example 18 which is concerned with the preparation of starting materials tert-Butyl (3R)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate was reacted with 4N HCl in dioxane. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.52 (m, 2H), 0.66 (m, 2H), 1.79 (m, 1H), 2.04 (m, 1H), 2.14 (s, 3H), 2.84 (m, 4H), 3.07 (m, 1H), 5.00 (m, 1 if), 7.48 (m, 3H), 7.71 (d, 1H), 7.82 (s, 1H), 7.89 (d, 1 if), 8.18 (s, 1H), 8.42 (s, 1 if); Mass Spectrum: M+H+ 405.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH2:17][C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH3:7])[CH:10]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
2 ml of pyridine is added to 30 ml of a solution of 3-methoxyaniline (4.92 g, 40 mmol) in dichloromethane and the mixture is stirred for 5 minutes, while maintaining the temperature inside vessel at lower than 0° C., and thereto 20 ml of a solution of chloroacetyl chloride (6.78 g, 60 mmol) in dichloromethane is drop-added slowly. A reaction is carried out at room temperature for 12 hours after completion of drop-addition, and then terminated. The reaction solution is washed with 5% of HCl (30 ml×3), 5% of NaOH (30 ml×3), water (30 ml×3), and saturated saline (30 ml) successively, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to remove the solvent to obtain 6.43 g of 2-chloro-N-(3-methoxyphenyl)acetamide, with a yield of 80.7%.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CN(C)C1CCNCC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N(C)C)CC3)c(F)c21
Yield: 36.6 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g), 4-dimethylaminopiperidine (2.1 g), and pyridine (3 ml) was refluxed for 6 hours. The mixture was evaporated to dryness. The residue was treated with water and extracted with dichloromethane. The organic layer was washed with water, dried, and evaporated. The solid was recrystallized from ethyl acetate and gave 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-dimethylamino-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid (0.22 g), mp 210°-211° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:45])([F:44])[CH2:40][CH2:41][CH2:42]Br>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:42][CH2:41][CH2:40][C:39]([F:45])([F:44])[F:38])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: FC(F)(F)CCCBr
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCC(F)(F)F)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 5 ml of acetonitrile is mixed with 101 mg (0.73 mmol) of potassium carbonate and 139 mg (0.73 mmol) of 4,4,4-trifluoro-1-bromobutane and stirred under reflux for 12 h. After conversion is complete, the salts are filtered off and the mother liquor evaporated. 253 mg (0.49 mmol, 100% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:4]2[N:3]=1.Cl.[CH3:19][C:20]1([CH3:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([N:23]3[CH2:24][CH2:25][C:20]([CH3:26])([CH3:19])[CH2:21][CH2:22]3)[N:4]2[N:3]=1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Reactant: CC1(C)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Temperature: 60 °C

Procedure:
To a solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.33 g, 4.18 mmol, 1 equiv) in DMF (14 mL) was added 4,4-dimethylpiperidine hydrochloride (0.75 g, 5.01 mmol, 1.2 equiv) and DIPEA (1.75 mL, 10.02 mmol, 2.4 equiv). The reaction was then heated in an oil bath at 60° C. Upon completion, the reaction was removed from heating, diluted with water, and extracted with EtOAc (×2). The combined EtOAc extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-100% EtOAc/hexane) to provide methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate as an off white solid (1.50 g, 91%). 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 3.41 (br. s., 4H), 2.51 (s, H), 1.54 (t, J=5.6 Hz, 4H), 1.09 (s, 6H); LCMS (ESI, M+1): 395.25.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH:12]=[O:13])[CH:4]=[CH:5][N:6]=1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=2)[CH2:12][OH:13])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 5-(2-methylimidazol-1-yl)-2-nitrobenzaldehyde (349 mg) and methanol (5.0 ml) was added slowly sodium borohydride (114 mg) at 0° C. and the mixture was stirred at room temperature for 4 hours. Methanol was distilled at reduced pressure to give a residue. Water was added to the residue and the mixture was stirred at room temperature for 30 minutes, filtered and dried to give 360 mg (100%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:19][C:20]([OH:22])=[O:21])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
The mixture of 4-hydroxyquinoline (290 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 8 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 3, and then extracted three times with ethyl acetate (20 ml each). Water layer was placed in cold room, and solid came out. The crystals were filtered with suction and washed with water, and then dried to give 120 mg quinoline-4-oxyacetic acid as gray crystals, mp 274-276° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:41])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 127.9 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-(phenylacetylamino)pyrazine (c-16) (539 mg, 1.32 mmol) was suspended in anhydrous toluene (50 mL) and to this was added Lawesson's reagent (320 mg, 790 μmol) while stirring at room temperature, and then heated to reflux for 17 h. After refluxing, it was cooled to room temperature, and concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (55 g, n-hexane/ethyl acetate=3/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-(phenylthioacetylamino)pyrazine (c-17) as a yellow amorphous powder (430 mg, 76.6%). Rf=0.33 (n-hexane/ethyl acetate=7/3). Mp. 45-47° C. UV (MeOH) λmax (log ε) 334 (4.23), 295 (4.16), 272 (4.25). UV (pH 7.4 PB) λmax(log ε) 360.5 (4.22), 283.5 (4.16). 1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.92 (s, 2H), 4.14 (s, 2H), 7.01 (d, J=6.8 Hz, 2H), 7.04-7.10 (AA′BB′, 2H), 7.12-7.24 (m, 3H), 7.29 (t, J=7.3 Hz, 1H), 7.37 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.1 Hz, 2H), 8.05-8.10 (AA′BB′, 2H), 8.99 (s, 1H), 12.20 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 39.3, 51.6, 55.3, 114.5 (2C), 126.3, 127.0, 127.6, 128.2 (2C), 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0 (2C), 136.9, 137.9, 138.0, 145.0, 149.6, 152.1, 160.9, 204.6. IR (KBr, cm−1) 700, 835, 1028, 1115, 1175, 1252, 1292, 1319, 1369, 1422, 1437, 1493, 1516, 1607, 2961, 3395. HRMS (FAB+) m/z 426.1646 (M+H, C26H24N3OS requires 426.1640).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=1.[CH:19]1([C:22]#[N:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1>O>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)[CH:13]=1
Reactant: N#CC1CC1
Reactant: Fc1cc(Br)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
LiHMDS (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) is added dropwise to a cold (−5° C.) mixture of 4-bromo-2-fluoro-pyridine [Marsais, F. et al, Journal of Organic Chemistry, (1992), 57, 565-573] (1 g, 5.7 mmol), cyclopropanecarbonitrile (1.25 mL, 17 mmol, 3 eq), 4 Å molecular sieves and toluene (20 mL). The reaction mixture is allowed to warm to rt, stirred for 16 h, poured into H2O and filtered. The filtrate is diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/EtOAc, 9:1), to afford 620 mg of the title compound as a white solid: ESI-MS: 223.1/225.1 [M+H]+; tR=4.22 min (System 1); TLC: Rf=0.25 (Hex/EtOAc, 9:1).
Reaction SMILES: C([O:8][C:9](=[O:72])[C@H:10]([CH2:68][CH:69]([CH3:71])[CH3:70])[NH:11][C:12](=[O:67])[C@H:13]([C:63]([CH3:66])([CH3:65])[CH3:64])[NH:14][C:15](=[O:62])[C@H:16]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])[NH:17][C:18](=[O:53])[C@H:19]([CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[NH:20][C:21](=[O:43])[C@H:22]([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C1C=CC=CC=1>CN(C)C=O.[Pd]>[C:30]([O:29][C:27]([CH2:26][CH2:25][C:24]([NH:23][C@H:22]([C:21]([NH:20][C@H:19]([C:18]([NH:17][C@H:16]([C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:72])=[O:8])[CH2:68][CH:69]([CH3:70])[CH3:71])=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH3:61])=[O:53])[CH2:44][CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:43])[CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)(C)C
Yield: 96.8 %

Procedure:
A solution of 6.8 g (6.75 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 200 ml of dimethylformamide was hydrogenated over 600 mg of 10% palladium/carbon for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to give 15 g of crude product which was chromatographed on silica gel using 10-15% methanol in dichloromethane for the elution to give 6 g of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine as a white solid of melting point 235°-236° C.; MS: m/e 918.4 [M+H]+, m/e 940.3 [M+Na]+.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(O)(C)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CSC(=C(C#N)C#N)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
With the exclusion of air, 7.22 g (42.4 mmol) of 3,3-bis(methylsulfanyl)-2-cyano-acrylonitrile (Maybridge), 7.90 g (42.4 mmol) of piperazine-N-carboxylic acid tert-butyl ester (Aldrich; Milwaukee/USA) and 0.24 g (3 mmol) of pyridine are heated to boiling in 75 ml of isopropanol for 4 hours. Cooling, concentration by evaporation and drying under a high vacuum yield 3-(4-tert-butoxycarbonyl-piperazin-1-yl)-3-methylsulfanyl-2-cyano-acrylonitrile; C14H20N4SO2: calc. C54.52%, H 6.54%, N 18.17%, S 10.40%; found C54.37%, H 6.50%, N 17.85%, S 10.25%.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH:28]1([C:31]([N:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=2[C:7]2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:27])[CH:6]=2)[CH2:25][CH3:26])=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-33) was prepared by following the procedures of Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=[CH:19][C:20](=[O:22])[CH3:21].[OH-].[K+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:18]([C:14]2[S:13][CH:17]=[CH:16][N:15]=2)[CH2:19][C:20](=[O:22])[CH:21]=1
Reactant: CC(=O)C=Cc1nccs1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)CC(c2nccs2)C1
Temperature: 70 °C

Procedure:
Diethyl malonate (1.16 g) was added to a solution of sodium (158 mg) in dry absolute ethanol (10 ml) and the mixture was heated to reflux. 1-(2-Thiazolyl)but-1-en-3-one (1.0 g) in dry absolute ethanol (5 ml) was added dropwise to the solution. After refluxing for 2.5 hr, an aqueous potassium hydroxide solution (862 mg in 12 ml) was added and the mixture was extracted with diethyl ether. The aqueous layer was heated to 70° C. and neutralised with dilute hydrochloric acid and the water was then evaporated under reduced pressure. The residue was extracted with dry dimethylformamide. Evaporation of the solvent gave 3-hydroxy-5-(2-thiazolyl)cyclohex-2-en-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: NCc1cccc(Cl)c1
Reactant: CCCC=O
Product: CCCCNCc1cccc(Cl)c1
Yield: 31.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (3-chlorophenyl)methanamine (750 mg, 5.30 mmol) and butyraldehyde (480 μL, 5.30 mmol) were converted to the title compound (331 mg, 32%). 1H NMR (CDCl3) δ 7.64-7.55 (m, 2H), 7.44-7.33 (m, 2H), 4.02 (s, 2H), 2.84-2.72 (m, 2H), 1.84 (td, J=7.8, 15.8 Hz, 2H), 1.38 (sxt, J=7.5 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 198.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1([OH:27])[CH2:7][N:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:9])[CH2:5]1)[CH3:3].[CH2:28]=O.[BH4-].[Na+]>CO.C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:8]([N:6]2[CH2:7][C:4]([C@@H:2]([NH:1][CH3:28])[CH3:3])([OH:27])[CH2:5]2)=[O:9])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: C[C@H](N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN[C@@H](C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using similar procedures to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). 1H NMR (400 MHz, CD3OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C19H19F3IN3O2: 506 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](O)=[N:8][C:7]([CH:12]([CH3:14])[CH3:13])=[N:6][C:5]=2[C:4]([CH3:15])=[N:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>P(Cl)(Cl)(Cl)=O>[Cl:17][C:9]1[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=2[N:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nn(C)c2c(O)nc(C(C)C)nc12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2c(Cl)nc(C(C)C)nc12
Yield: 97.4 %

Procedure:
A mixture of 10 g (0.048 mol) of 1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol and 10.2 g (0.049 mol) of phosphorus pentachloride in 70 ml of phosphorus oxychloride is stirred under reflux five hours and evaporated in vacuo. The residue is dissolved in 150 ml of methylene dichloride and stirred with 100 ml of a saturated solution of sodium bicarbonate. The organic layer is separated, dried over MgSO4, and evaporated in vacuo to to give 10.5 g of 7-chloro-1,3-dimethyl-5-isopropyl-1H-pyrazolo[4,3-d]pyrimidine, mp 87°-89° C. from pet ether.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH2:27]([O:29][C:30](=[O:53])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][C:37]([Cl:41])=[CH:38][CH:39]=2)[CH:34]([C:42]2[C:43]([OH:51])=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)[C:33]1=[O:52])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:53])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][C:37]([Cl:41])=[CH:38][CH:39]=2)[C:34]([C:42]2[C:43]([OH:51])=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)([CH2:5][OH:16])[C:33]1=[O:52])[CH3:28]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl[5-chloro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%): MS (ES+) m/z 418.7 (M+1).
Reaction SMILES: N#N.OS(O)(=O)=O.[Br:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:15]=2[C:16]([OH:18])=O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]([O:13][C:14]3[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:15]=3[C:16]2=[O:18])=[CH:26][CH:27]=1
Reactant: COc1cc(C(=O)O)c(Oc2ccc(Br)cc2)cc1F
Agent: N#N
Agent: O=S(=O)(O)O
Product: COc1cc2c(=O)c3cc(Br)ccc3oc2cc1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 3 neck 22 L RBF equipped with a mechanical stirrer, temperature probe and N2 inlet was charged with concentrated H2SO4 (2.7 L) and heated to 60° C. To this mixture was added 2-(4-bromophenoxy)-4-fluoro-5-methoxybenzoic acid (1.3 kg, 3.81 mol) in portions such that the internal temp remained below 70° C. The resulting mixture was stirred at 60° C. for 1 hour at which point the reaction mixture was cooled to 0° C. and slowly poured onto ice water. The resulting solids were removed by filtration, washed with water and triturated with EtOAc (3 L). The solid was then washed with EtOAc, hexane and dried under vacuum at 30° C. to afford 7-bromo-3-fluoro-2-methoxy-9H-xanthen-9-one as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=O)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[S:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCN(NC2CCN(c3ccncc3)CC2)C(=S)C1
Temperature: 100 °C
Reaction time: 5 h
Yield: 37.7 %

Procedure:
A solution of 4-(6-chloronaphthalene-2-sulfonyl)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-piperazinone (200 mg) in pyridine (10 ml) was combined with phosphorus pentasulfide (80 mg) and stirred at 100° C. for 5 hours. The supernatant of the reaction mixture was concentrated and the residue was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (35 mg) as a colorless solid.