Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7][OH:8])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].[CH2:20](Cl)Cl>B(F)(F)F.CCOCC>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][O:8][CH3:20])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: ClCCl
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Agent: FB(F)F
Solvent: CCOCC
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1COC

Procedure:
To (±)-cis-3-Ethyl-4-hydroxymethyl-N-toluensulfonyl-2-azetidinone (18 mg) in CH2Cl2 at 0° to 5° C. was added boron trifluoride etherate solution (1 drop) and then diazomethane-ether solution dropwise (4 ml). The reaction mixture was purified by preparative TLC on a silica gel plate (1500μ) and developed with CH2Cl2 to afford the titled compound. NMR(CDCl3): δ1.04(3H, t), 1.54-1.92(2H, m) 2.45(3H, s), 3.16(1H, m), 3.26(3H, s), 3.70(2H, m ), 4.18(1H, m), 7.34(2H, d), 7.88(2H, d).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].Cl>CO.[Zn]>[F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2F)c1F
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(-c2ccccc2F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,2′-difluoro-3-nitro-biphenyl (100 mg, 0.36 mmol) in methanol (5 mL) were added a 3N aqueous HCl solution (7.23 mL, 21.7 mmol) and Zn powder (426 mg, 6.51 mmol). The mixture was stirred 4 h at RT. The reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3 solution, then diluted with an equal volume of water and extracted (×3) with CH2Cl2. The combined organics were dried (Phase Separator) and concentrated in vacuo to give the title compound. MS (LC-MS): 206 [M+H]+; tR (HPLC conditions k): 3.30 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)[OH:4].[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[N:17]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:3]([OH:4])[C:2]([F:13])([F:12])[F:1])[N:16]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: OC(c1ccccc1I)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(-c2ccccc2C(O)C(F)(F)F)n1
Temperature: 130 °C
Yield: 44.4 %

Procedure:
2,2,2-Trifluoro-1-(2-iodo-phenyl)-ethanol (0.331 g, 1.1 mmol), 3,5-dimethylpyrazole (0.096 g, 1.0 mmol), CuI (0.019 g, 0.1 mmol), K2CO3 (0.290 g, 2.1 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.028 g, 0.2 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube and the mixture was heated at 130° C. (oil bath temperature) for 12 h. The mixture was diluted with ethyl acetate and washed with H2O (2×20 ml), brine, and dried over sodium sulfate. Removal of solvent gave crude product, which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to give 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:18]3[C:17]4[CH2:19][NH:20][CH2:21][CH2:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:18]3[C:17]4[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:16]=4[NH:15][C:14]=3[N:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc(C)c(F)c4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
(3-Fluoro-4-methyl-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (50 mg, 0.17 mmol), acetic anhydride (17 μL, 0.17 mmol), and triethylamine (70 μL, 0.51 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred overnight at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 58 (9 mg, 14% yield) as a tan powder. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)(Cl)Cl.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>O.C(N(CC)CC)C>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1)=[O:27]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)c2c(Cl)cccc2Cl)n2oc(=O)nc2n1

Procedure:
5.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are mixed with 150 ml. of chloroform, 10 ml. of triethylamine and 4.5 ml. of 2,6-dichlorobenzoyl chloride and heated to reflux for 7 hours. The mixture is then cooled, diluted with water, adjusted to pH 4 with hydrochloric acid and extracted with chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using a mixture of methylene chloride and methanol (99:1) for the elution. Recrystallization from diisopropyl ether and methylene chloride yields pure 2,6-dichloro-N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 133°-135° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:7]=1)=O)C.[NH3:24]>CO>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH:9]=[CH:10][C:6]([C:4]([NH2:24])=[O:3])=[N:7]2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: CCOC(=O)c1ccn(-c2ccc(Oc3ccccc3)cc2)n1
Solvent: CO
Product: NC(=O)c1ccn(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of 3-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (120 mg, 0.39 mmol) in 5 mL of a 2N solution of ammonia in MeOH was stirred at rt for 4 d. TLC showed incomplete reaction and the solution was transferred to a sealed tube and heated at 70° C. overnight. The reaction was concentrated and purified by preparative TLC, eluting with 50% EtOAc/hexane, to yield 1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide (Rf=0.26, 56 mg, 52%), mp 165-167° C. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J=2.7 Hz, 1H, pyrazole), 7.92 (d, J=9.0 Hz, 2H, Phenyl), 7.71 (br, 1H, NH2), 7.43 (m, 2H, Phenoxy), 7.39 (br, 1H, NH2), 7.18 (m, 1H, Phenoxy), 7.17 (d, J 9.0 Hz, 2H, Phenyl), 7.07 (m, 2H, Phenoxy), 6.87 (d, J=2.7 Hz, 1H, pyrazole).
Reaction SMILES: FC1C=CC(OC)=CC=1C1C=CC(O[Si](C(C)C)(C(C)C)C(C)C)=CC=1[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:47]=2[F:54])=[CH:42][C:41]=1[CH:55]=[O:56])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(OCC)C.C1COCC1>[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:47]=2[F:54])=[CH:42][C:41]=1[CH:55]([OH:56])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2CC(C)(C)C)c1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C=O)c2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(O)CC(C)(C)C)c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of neopentylmagnesium bromide (2.00 g) prepared in Example 2, step F, in diethyl ether (10 mL) was added dropwise to a mixed solution of 4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (2.00 g) in THF (10 mL) and diethyl ether (10 mL) at room temperature, and the mixture was stirred at 40° C. for 1 hr. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added dropwise, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:24]C1C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[N:24]1[CH2:2][C:3]2[C:4](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])[C:5]1=[O:7]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: Cc1cccc(Nc2ccccc2)c1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(N2Cc3c(cccc3[N+](=O)[O-])C2=O)c1C

Procedure:
A solution of 6 (0.140 g), 2,3 - dimethylphenyl aniline (0.065 mL), and triethyl-amine (0.142 mL) in acetonitrile (10 mL) was refluxed 18 h. The solution was concentrated in vacuo and the residue was partitioned between methylene chloride and 2% potassium hydrogen sulfate. The methylene chloride was washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to afford the the product as a solid. NMR (300 MHz, CDCl3) δ 8.46 (1H, d, J=8 Hz), 8.30 (1H, d, J=8 Hz), 7.77 (1H, t, J=8 Hz), 7.24 (1H, s ), 7.22 (1H, d, J=2 Hz), 7.12 (1H, m), 5.18 (2H, s), 2.35 (3H, s), 2.14(3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:6]=2[C:5](=[O:21])[NH:4][C:3]1=[O:22].[OH2:23].[OH-].[Na+]>CO>[O:23]=[C:12]([CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][N:4]1[C:5](=[O:21])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:22]
Reactant: CCCCCCCCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Yield: 85 %

Procedure:
80.3 g of 3-methyl-7-n-decyl-xanthine, 140 g of water, 90 g of methanol, 10 g of sodium hydroxide and 44.6 g of 1-bromohexanone-(5) are boiled under reflux for 4 hours. After acidification with 2 ml of concentrated sulphuric acid, the reaction mixture is filtered hot to remove the unreacted 3-methyl-7-n-decyl-xanthine and the filtrate is worked up as in Example 1. 66.1 g of a crude crystalline product are obtained and are recrystallised from 500 ml of diisopropyl ether. The 1-(5-oxohexyl)-3-methyl-7-(n-decyl)-xanthine which is obtained in 85% yield melts at 64°-66° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:10]#[N:11])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2].[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:10]#[N:11])([CH2:16][C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl
Reactant: C=CCCC(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask equipped with a nitrogen inlet 2-cyano-hex-5-enoic acid ethyl ester (2.0 g, 11.96 mmol) and DMF (40 mL) were added. The reaction mixture was cooled to 0° C. followed by addition of NaH (0.48 g, 12.0 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to stir at 0° C. for another 5 min, followed by addition of 2-chloromethyl-1-nitro-4-phenoxy-benzene (2.6 g, 9.86 mmol). The reaction turned a dark purple color. After 3 h the reaction was quenched with 1N HCl, and the solvent was evaporated to yield a crude mixture. The crude mixture was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by a wash with saturated brine solution. The phases were separated, and the organic phase was dried with sodium sulfate and filtered, and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes/ethyl acetate as the mobile phase 9:1 to yield a residue.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)[CH2:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC#Cc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Agent: [Pd+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.1 %

Procedure:
tert-Butyl (S)-5-(3-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pent-4-ynoate (Compound SP430) (4.84 g, 9.99 mmol) was dissolved in ethyl acetate (40 ml), and 10% palladium(II) on carbon (968 mg) was added under a nitrogen atmosphere. The mixture was then stirred at room temperature for 3.5 hours under a hydrogen atmosphere. After filtration through celite, the filtrate was concentrated under reduced pressure to afford the title compound (Compound SP431) (4.74 g, 97%).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CCOCC.C(#N)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[N:15]([CH2:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([CH2:7][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=3)=[O:31])[CH2:13][CH2:12]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:25][CH:24]=1
Reactant: CCCCCNC[C@H]1CC[C@H](CNCCCCC)CC1
Reactant: CN(C)c1ccc(N=C=O)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CCCCCN(C[C@H]1CC[C@H](CN(CCCCC)C(=O)Nc2ccc(N(C)C)cc2)CC1)C(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Trans-1,4-bis[(normalpentylamino)methyl]cyclohexane, 0.56 g, was dissolved in 10 ml of ether. A solution of 0.81 g of 4-dimethylaminophenyl isocyanate in 20 ml of acetonitrile was added. The reaction mixture was stirred at room temperature for 10 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to provide 1.10 g (yield: 89%) of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Cl)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][O:26][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=1
Reactant: COC(=O)Cc1cccc(CCl)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Product: COC(=O)Cc1cccc(COc2ccc(C(C)C(O)(c3cnc4ccccc4c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 140, step 5) was reacted with (3-chloromethyl-phenyl)-acetic acid methyl ester to give {3-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenoxymethyl]-phenyl}-acetic acid methyl ester. This compound was hydrolyzed in analogy to Example 141 to give the title compound as an off-white solid. MS (m/e)=530.1 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O.[ClH:29]>CCOC(C)=O>[ClH:29].[ClH:29].[ClH:29].[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1
Reactant: C[C@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1C[C@H]1CNCCN1
Temperature: 70 °C
Reaction time: 3 h
Yield: 107.8 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1,4-piperazinedicarboxylate (2.46 g, 6.16 mmol, step 2), HCl (4.0 M solution in 1,4-dioxane, 4.62 mL, 18.5 mmol, Sigma-Aldrich, St. Louis, Mo.) and EtOAc (100 mL). The reaction mixture was heated at 70° C. for 3 h. At this time, additional HCl (4.0 M solution in 1,4-dioxane, 5.00 mL, 20.0 mmol) was added and heating at 70° C. was resumed for an additional 3 h. The reaction mixture was cooled to room temperature and the resulting white solid was collected, washed with EtOAc and dried overnight under reduced pressure to afford (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine trihydrochloride (2.05 g) as a white powder.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.[P:11]([OH:14])([OH:13])[OH:12].C>O.ClC1C=CC=CC=1>[NH2:5][CH2:6][CH2:7][C:8]([OH:10])([P:11]([OH:14])(=[O:12])[OH:13])[P:11]([OH:14])(=[O:13])[OH:12]
Reactant: OP(O)O
Reactant: NCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Reaction time: 3 h

Procedure:
206 gm (1.5 mols) of phosphorus trichloride are slowly dropped while stirring into a mixture heated in a boiling water bath of 89.1 gm (1 mol) of β-alanine, 123 gm (1.5 mols) of phosphorous acid, and 500 ml of chlorobenzene, and heating on the boiling water bath is continued for a further 3 hours. During this time the contents of the flask become solid. After the reaction is finished, 600 ml of water are added and the product is heated for a short time, treated with animal charcoal and filtered while hot. The 3-amino-hydroxypropane-1,1-diphosphonic acid gradually crystallizes out from the aqueous phase in a cooling cabinet. The mother liquor is concentrated and treated with methanol, whereupon still further diphosphonic acid is precipitated. The 3-amino-1-hydroxypropane-1,1-diphosphonic acid is then recrystallized from water.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Br)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.CC[O:17]C(C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][OH:17])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1sc(CBr)cc1C#N
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(CO)cc1C#N
Temperature: 70 °C
Yield: 17 %

Procedure:
A mixture of 5-Bromomethyl-3-cyano-thiophene-2-carboxylic acid methyl ester (0.89 g, 3.42 mmol) and water (15 ml) in THF (2 ml) was heated at 70° C. for 2 d. The reaction mixture was cooled. The reaction mixture was poured into EtOAc (50 ml), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-40% EtOAc in hexane) to give 0.1114 g (17%) yellow solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:21]([CH:18]1[CH2:20][CH2:19]1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (100.0 mg, 0.43 mmol), cyclopropanecarbonylchloride (45.0 mg, 0.43 mmol) and Hunig's base (83.0 mg, 0.64 mmol) in acetonitrile (4 mL) was heated to reflux under argon for 0.5 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated and the residue was triturated with AcOEt to give a suspension. The solid was filtered to give 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (113.0 mg, 87.6%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:15][C:16]([F:19])([F:18])[F:17])=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1.[N:20]#[C:21][NH2:22]>Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:15][C:16]([F:19])([F:17])[F:18])=[C:12]([NH:14][C:21]([NH2:22])=[NH:20])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: N#CN
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(OC(F)(F)F)c(NC(=N)N)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (275 mg, 1 mmol) in HCl 6N (1 mL), cyanamide (336 mg, 8.0 mmol) was added and the reaction was stirred at 60° C. for 1 h. The mixture was cooled down to room temperature, diluted with water (3 mL), extracted with DCM (10 mL). NaOH 2N was added to pH>11. The aqueous phase was extracted with Et2O (3×10 mL), dried over sodium sulfate and concentrated. The residue was crystallized from diethyl ether to give the title compound (240 mg, 76% yield) as a white solid.
Reaction SMILES: [O:1]1[CH2:4][C:3]2([CH2:9][CH:8]3[CH:6]([CH:7]3[C:10]([O:12]CC)=[O:11])[CH2:5]2)[CH2:2]1.[OH-].[Na+]>C(O)C.O>[O:1]1[CH2:4][C:3]2([CH2:5][CH:6]3[CH:8]([CH:7]3[C:10]([OH:12])=[O:11])[CH2:9]2)[CH2:2]1
Reactant: CCOC(=O)C1C2CC3(COC3)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1C2CC3(COC3)CC21
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of ethyl spiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxylate (1.5 g, 7.6 mmol) in ethanol (15 mL) was added sodium hydroxide (917 mg, 22.9 mmol) in water (5 mL). After 16 h, the reaction mixture was concentrated, and the resulting residue was dissolved with water (20 mL). The resulting solution was extracted with ethyl acetate (15 mL). The aqueous layer was acidified with 1 M aqueous HCl solution to pH=3, and the aqueous solution was extracted with dichloromethane (20 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to provide a white solid (0.80 g, 62% yield).