Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21]([O:23]C)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([F:41])[CH:40]=1)[NH2:37]>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:23])[NH:37][C:36]1[CH:35]=[C:34]([F:33])[CH:40]=[C:39]([F:41])[CH:38]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Nc1cc(F)cc(F)c1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 67.5 %

Procedure:
The title compound was prepared from (S)-methyl 1-(4-(benzyloxy)-2-(tert-butoxycarbonylamino)butanamido)-3-bromo-1H-pyrrole-2-carboxylate (4.0 g, 7.8 mmol) and 3,5-difluoroaniline (5.1 g, 39.0 mmol) following the experimental procedure described in Preparation 44a. 3.2 g (66% yield) of the desired compound were obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([F:17])([F:18])[F:3])[C:12]([F:13])([F:14])[F:15])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccccc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol (244 mg, 1 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 267 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-2-ylamine, yield 71%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCc1cccnc1
Product: Clc1nc(Cl)nc(NCc2cccnc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 3-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [C:1](OC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[CH2:1]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCCCCC/C=C\CCCCCCCCNCC(O)CO
Reaction time: 24 h

Procedure:
5 g of methyl oleat (commercially available under the trade name EDENOR® ME V05 from Cognis GmbH, MW 296) and 1.54 g of 3-amino-1,2-propanediol (MW 91.1, Sigma-Aldrich) were mixed together at 70° C. After addition of 100 mg of Novozym® 435 (lipase B from Candida Antarctica, from Novozymes), the reaction was conducted during 24 h at 70° C. under moderate agitation and vacuum (250-300 mbars). The mixture was filtrated to remove the immobilized enzyme. The product of the reaction was analyzed by HPLC-DEDL, to give an area ratio of N-oleyl-(3 amino-1,2-propanediol)/substrates >83%. Thus N-oleyl-(3 amino-1,2-propanediol) is a substance according to formula (I), wherein R1═—(CH2)7—CH═CH—(CH2)7—CH3 and R2═CH2—OH
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19].O>C(Cl)Cl>[Br:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15])=[O:19]
Reactant: Nc1cccc(Br)c1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(Br)C(=O)Nc1cccc(Br)c1O
Temperature: 25 °C

Procedure:
Pyridine (1.8 ml, 22.3 mmol) was added to a solution of 2-Amino-6-bromo-phenol (4.198 g, 22.3 mmol) in dry CH2Cl2 (200 ml). The mixture was cooled in ice and then a solution of 2-bromo-2-methyl-propionylbromide (2.8 ml, 22.6 mmol) was added slowly. The mixture was stirred at the room temperature for an hour and was poured into CH2Cl2 and water. The organic layer was washed with water, dried and concentrated in vacuo to yield crude 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide, which was used directly in step 2.
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[N+](C1C=CC([O:37][C:38]([NH:40][C@H:41]([CH2:48][N:49]([CH3:59])[C:50]([O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:51])[CH2:42][O:43][Si](C)(C)C)=O)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:38]([NH:40][C@H:41]([CH2:48][N:49]([CH3:59])[C:50]([O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])=[O:51])[CH2:42][OH:43])=[O:37])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Reactant: CN(C[C@H](CO[Si](C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (19.9 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added the solution of (2R)-2-(p-nitrophenoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(trimethylsilyloxy)propane (0.05 mmol), followed by DIEA (26 μL, 0.15 mmol). The resulting yellow solution was stirred at rt for 30 min. CH2Cl2 was removed in vacuo and the residue was redissolved in acetonitrile, and purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N-((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (10.0 mg, 30%). MS m/z 672 (M+H+).
Reaction SMILES: CS(O[CH2:6][C:7]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8]1)(=O)=O.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=O)=O.OCC1(C(OCC)=O)CC1>ClCCl.O>[CH3:22][S:23][CH2:6][C:7]1([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CCOC(=O)C1(CO)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSCC1(C(=O)O)CC1
Temperature: 23 °C
Reaction time: 20 h
Yield: 115.7 %

Procedure:
Preparation of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate—Triethylamine (990 μL, 7.1 mmol, 1.2 equiv) and methanesulfonyl chloride (500 μL, 6.5 mmol, 1.1 equiv) were sequentially added to a stirred solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (840 mg, 5.7 mmol, 1.0 equiv) in dichloromethane (15 mL) at 23° C. The resulting bright yellow solution was stirred at 23° C. for 20 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (1.1 g, 85%): 1H NMR (300 MHz, CDCl3) δ 4.33 (s, 2H), 4.16 (q, J=7 Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J=7, 4 Hz, 2H), 1.26 (t, J=7 Hz, 3H), 1.04 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35]C4CC4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:39](NC)([CH3:41])[CH3:40]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[CH3:35])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: CNC(C)C
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Product: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using N-isopropyl-N-methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@@H:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[C@@H:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)N1CCCc2c1cnn2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (1.5 mL) was added oxalyl chloride (0.050 mL, 0.58 mmol) and DMF (1 drop). After 20 min at room temperature, the mixture was concentrated in vacuo and the residue was added to another flask containing 1-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.050 mL, 0.35 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 20 min, quenched with saturated aqueous NaHCO3 solution (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-6% MeOH/EtOAc) to afford the titled compound (0.022 g, 32%, TFA salt) as a white solid. 1H NMR (free form) (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.44 (m, 4H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.37 (d, J=1.2 Hz, 1H), 5.21 (q, J=7.2 Hz, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 2.86 (dd, J=6.4, 6.4 Hz, 2H), 2.46 (s, 3H), 1.72 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C20H19ClF3N5O [M+H]+ (free form) 438.1, found 438.1; The titled compounds were analyzed by chiral normal phase chromatography (RegisPack, 25 cm×4.6 mm, 5 micron, cat#793104, 0.1% DEA/IPA, 0.7 mL/min). The (S)-enantiomer (major) had a retention time of 8.4 min and the (R)-enantiomer (minor) had a retention time of 6.4 min (isolated in 18:1 er).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 108 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (70) (1.84 g; 3.12 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. ESMS: MH+ 490.4
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:25]2[CH:24]=[CH:23][C:22]3[O:17][CH2:18][CH2:19][O:20][C:21]=3[CH:26]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCCO3)c2cc3c(cc21)OCO3
Yield: 32 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (240 mg) and 1,4-benzodioxan-6-carboxaldehyde (181 mg) by the procedure described in example 10 in 32% yield, mp: 185-187° C. 1H NMR (CDCl3): 6.86-6.75 (m, 3H), 6.67 (s, 1H), 6.30 (s, 1H), 5.91 (s, 1H), 6.89 (s, 1H), 5.18 (s, 1H), 4.99 (br s, 1H), 4.44 (m, 2H), 4.25 (s, 4H), 1.56 (d, J=6.8, 3H), 1.55 (d, J=6.8, 3H). Anal. calcd. for C20H20N2O5.(½)H2O: C, 63.65; H, 5.61; N, 7.42. Found: C. 63.37; H, 5.34; N, 7.07.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[N:32][N:31]=[C:30]1[CH:34]=O>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH2:26][N:2]1[C:34]([C:30]2[N:29]([CH3:28])[CH:33]=[N:32][N:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[NH:6][C:5]2=[O:14])=[N:1]1
Reactant: Cn1cnnc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 4-methyl-4H-1,2,4-triazole-3-carbaldehyde. 460.2 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (3.57 g, 20.9 mmol) in toluene (150 mL), trimethylaluminum (15.6 ml, 2M solution in toluene, 31.4 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-methylbenzonitrile (5 ml, 41.8 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture heated to 80–85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 600 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (5.3 g, 88%) was used in the next reaction without further purification: mp (DSC) 213° C. Anal. Calc'd for C15H16N2SO2: C, 62.48; H, 5.59; N, 9.71. Found: C, 62.00; H, 5.52; N, 9.60.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O>CO.O.Cl>[ClH:66].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:67])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[C:65]([Cl:66])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(Cl)n[nH]c54)c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(Cl)n[nH]c54)c3=O)cc2)CCC1
Yield: 72 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-chloro-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.25 mL), water (3.75 mL) and 1 M HCl (0.15 mL) and chromatographed on a 2 g C18 cartridge {gradient 25 to 60% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (10.2 mg, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.54 (br s, 3H), 7.82 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.44 (m, 3H), 7.41-7.37 (m, 2H), 7.34 (d, J=8.3 Hz, 2H), 2.63-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.87-1.76 (m, 1H). LCMS (Method E): RT=3.51 min, [M+H]+=442/444.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl.Cl[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.[C:43]([O-:46])([O-])=[O:44].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:43]([OH:46])=[O:44].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)[CH:15]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)c1
Reactant: Clc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Nc2nnc(-c3cccc(Oc4ccncc4)c3)[nH]2)ccc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 45 %

Procedure:
3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 rug, 0.705 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 4-chloro-pyridine hydrochloride (46.5 mg, 0.31 mmol) was added, followed by anhydrous K2CO3 (19.5 rug, 0.141 mmol). Then the vial was capped and microwaved at 250° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (34.6 mg of beige solid).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-fluoro-1H-indazole (5.50 g, 40.4 mmol) in DMF (150 ml) at room temperature was added potassium hydroxide (6.8 g, 121 mmol) and iodine (15.4 g, 60.6 mmol). The maroon reaction mixture was stirred at room temperature for 8 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 8.6 g (81%) of 6-fluoro-3-iodo-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.48 (dd, J=8.9, 5.1 Hz, 1H), 7.20 (dd, J=8.9, 2.1 Hz, 1H), 7.02 (td, J=9.1, 2.1 Hz, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13](O)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=O)[C@@H]1C[C@H](O)CN1C(OC(C)(C)C)=O.C(N(S(F)(F)[F:47])CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]1[CH2:14][C@@H:13]([F:47])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
A mixture of 3 (3.6 g, 11 mmol) and N-(tert-butoxycarbonyl)-(2S,4S)-4-hydroxyproline methyl ester (0.75 g, 3.0 mmol) was dissolved in 30 mL dry CH2Cl2 under Ar(g). The solution was cooled to −78° C., and diethylaminosulfur trifluoride (DAST; 5.6 mL, 42 mmol) was than added by syringe. The mixture was stirred for an additional 45 min at −78° C. and then allowed to warm to room temperature. After 20 h, the mixture was transferred to a separatory funnel and carefully washed with 80 mL of saturated NaHCO3(aq). A considerable amount of gas was released during wash. The organic layer was washed with an additional 2×30 mL of saturated NaHCO3(aq) and 30 mL of water, dried over MgSO4(s), and concentrated to a dark oil by rotary evaporation at reduced pressure. Flash chromatography (hexanes/EtOAc 4:1) afforded 4 (1.98 g, 6.12 mmol, 55%) as an oily yellow solid.
Reaction SMILES: N[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[N:6][C:7](N)=[C:8]([C:11]#[N:12])[CH:9]=2)[O:4][NH:3]1.[N:20]([O-])=O.[Na+].[OH2:24]>Cl>[NH2:20][C:9]1[C:8]([C:11]#[N:12])=[C:7]([OH:24])[N:6]=[C:5]2[O:4][N:3]=[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]=12
Reactant: N#Cc1cc2c(nc1N)ONC2(N)c1ccccc1
Reactant: O=N[O-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: N#Cc1c(O)nc2onc(-c3ccccc3)c2c1N
Reaction time: 1 h

Procedure:
0.4 g (1.59 mmole) of 3,6-diamino-5-cyano-3-phenyl-isoxazolo [5,4-b] pyridine (4a) is dissolved in 25 ml of 6 N HCl in heat. Then 5 ml of H2O is added and mixed drop by drop with a solution of 0.4 g of NaNO2 in 5 ml of H2O. The solution is heated to boiling for 60 minutes. The precipitate is sucked off (removed) hot. The yield is 0.2 g (50 percent) of colorless plates, from glacial acetic acid, having a melting point of 251° C.