Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH:1]1([CH2:7][N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[C:10](=[O:27])[N:9]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NN(CC2CCCCC2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C(c2ccc(Cl)c(Cl)c2)C(c2ccncc2)N1CC1CCCCC1
Temperature: 0 °C

Procedure:
In a 100 mL round bottom flask, was added 0.4 g 1-Cyclohexylmethyl-4-(3,4-dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one and 20 mL THF, stirred at 0° C. under nitrogen. 1.32 mL 1 M LHMDS in THF was added drop wise. After stirred at 0° C. for 30 min. 0.11 mL iodomethane was added drop wise. The resulted mixture was stirred from 0° C. to rt for 2 hour, quenched with 50 mL sat. NH4Cl, extracted with dichloromethane 3×25 mL. The organic phase was dried over anhydrous Na2SO4. After purification by flash chromatography, obtained the title compound 0.4 g as light solid. MS (ES+): 418 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][N:26]5C(=O)C6C(=CC=CC=6)C5=O)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:26][CH2:25][C:21]1[CH:20]=[C:19]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[O:10][C:11]=3[CH:17]=2)[CH:24]=[CH:23][N:22]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)-isoindoline-1,3-dione (6.2 mg, 0.013 mmol, 1 eq) was dissolved in 0.5 mL of ethanol. And then hydrazine monohydrate (6.4 mg, 0.13 mmol, 10 eq) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. And then the solvents were removed. The crude product was purified by reverse phase prep HPLC to give the title compound. MH+=353.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[CH2:26][CH2:27][NH2:28])([CH3:24])[CH3:23]>CN1C(=O)CCC1.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:28][CH2:27][CH2:26][N:25]([CH:29]([CH3:31])[CH3:30])[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)N(CCN)C(C)C
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Yield: 99.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (100 mg, 0.225 mmol) and N,N-diisopropylethylenediamine (395 μl, 2.25 mmol) in 5 ml of NMP is heated at 150° C. by microwave using an “Emrys™ Optimizer” machine for 20 minutes. The crude reaction product is taken up in 50 ml of ethyl acetate and the resulting solution is washed with 5 times 50 ml of water. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure to give 100 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester.
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:22][B-:23]([F:26])([F:25])[F:24].[N:27]#[O+].[K+].[Br-]>C(#N)C.C(Cl)Cl>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:1]([C:15]1[CH:16]=[CH:17][C:18]([N+:19]#[N:27])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#[O+]
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCc1ccc([N+]#N)cc1
Yield: 69 %

Procedure:
The 4-tetradecylaniline was dissolved in a 1:1 mixture of acetonitrile and dry methylene chloride prior to addition to the nitrosonium tetrafluoroborate. Yield: 69%. MP 82° C. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.02 (ABq, J=8.8 Hz, Δv=370.6 Hz, 4H), 2.76 (t, J=7.7 Hz, 2H), 1.61 (quin, J=7.8 Hz, 2H), 1.23 (s, 22H), 0.85 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.92, 133.26, 131.94, 110.96, 37.49, 32.34, 30.87, 30.12, 30.10, 30.07, 30.04, 29.91, 29.78, 29.75, 29.72, 23.11, 14.55.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([CH3:29])[C:7]2[N:8]=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]3[CH:20]=[CH:19][CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH3:29])[C:7]2[N:8]=[C:9]([NH:2][CH3:1])[C:10]3[CH:20]=[CH:19][CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1
Reactant: CN
Reactant: CCN1c2ncccc2C(OS(=O)(=O)C(F)(F)F)=Nc2c(C)cc(C)nc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(NC)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Methylamine (3 mL) was added to a solution of 2,4-dimethyl-11-ethyl-6-trifluoromethane-sulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.16 g, 0.4 mmole) in methylene chloride (0.5 mL). The mixture was sealed in a pressure bottle and stirred at room temperature for 4 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated in vacuo to give crude product. This was purified by chromatography over silica gel (eluted 10% ethyl acetate/methylene chloride) and recrystallized from ethyl acetate/hexane to give 0.016 g of the title compound, m.p. 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23](=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH2:30].N1C=CC=CC=1>C(O)C>[CH3:28][O:29]/[N:30]=[C:23](\[C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)/[CH2:24][CH3:25]
Reactant: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC/C(=N/OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-one (630 mg, 1.54 mmol), O-methylhydroxylamine hydrochloride (386 mg, 4.62 mmol) and pyridine (3.9 mL) in ethanol (16 mL) was stirred at 80° C. for 26 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compounds as a colorless crystal respectively (E (Example 121): 266 mg, 0.608 mmol, 39%, Z (Example 122): 159 mg, 0.363 mmol, 24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:23])[CH:19](Br)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:23])[CH:19]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)[CH2:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1csc(SC(CC)C(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and 2-bromobutanoic acid tert-butyl ester to give 2-{[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]thio}butanoic acid tert-butyl ester, followed by operations similar to those of Examples 3, 4 and 34.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].Cl>CS(C)=O>[C:24]([C:20]1[CH:21]=[C:22]([C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:3]#[N:4])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2C#N)cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 87 mg (0.59 mmol) of 3-cyano-1-nitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for 90 minutes and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography and crystallization afforded 98 mg (47% yield) of 2,6-di-t-butyl-4-(2'-cyano-4'-nitrophenyl)phenol.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11].[Cl-]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: C=C(C)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
D-Proline (14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The temperature of the mixture was kept at 10-11° C. during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6)δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C 59.13; H, 7.19; N, 7.61.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:20][CH2:19][O:18][CH3:17])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: COCCBr
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, 2-methoxyethyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 286 (M+, 6), 228 ([M—MeOCH═CH2]+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCC=C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,5-dimethyl-hex-4-enyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2].[CH:19](OC)(OC)[O:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([N:15]=[CH:19][O:20][CH3:21])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2]
Reactant: COC(OC)OC
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=NS(=O)(=O)c1cc(C(C)C)c(C#N)cc1C(C)C

Procedure:
To a mechanically stirred mixture of 27 parts of 4-cyano-2,5-diisopropylbenzenesulfonamide and 22 parts trimethyl orthoformate was added a trace of p-toluenesulfonic acid. The reaction was heated at reflux for 4 hours. It was filtered, the filtrate stripped to dryness in vacuo, and the resulting solid recrystallized from methanol to give the title product, m.p. 130°-132°.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8].OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:1])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8]
Reactant: COC(=O)CN(C)C(=O)c1c(OC)ccc2cc(OC)ccc12
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(Br)c(OC)ccc12
Yield: 66.8 %

Procedure:
A solution of bromine (1.75 mL, 34.05 mmol) in acetic acid (40 mL) was added over 25 minutes to a stirred solution of N-[(2,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (10.70 g, 33.72 mmol, described in Example 2) in acetic acid (120 mL). After an additional 10 minutes the reaction was diluted with water (900 mL) and NaHSO3 (2.0 g) was added. The resulting precipitate was collected by filtration, washed with water and dried to give 8.93 g (67% yield) of the title compound, m.p. 142°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([CH3:29])[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC1NC(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 205-206° C.
Reaction SMILES: CO.[H-].[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:31])=[CH:14][CH2:15][C@H:16]1[O:18][C@@:17]1([C@@H:20]1[C@:25]2([O:27][CH2:26]2)[CH2:24][CH2:23][C@@H:22]([OH:28])[C@H:21]1[O:29][CH3:30])[CH3:19]>O>[O:18]1[CH:16]([CH2:15][CH:14]=[C:13]([CH3:31])[CH3:12])[C:17]1([CH:20]1[CH:21]([O:29][CH3:30])[CH:22]([OH:28])[CH2:23][CH2:24][C:25]1([CH2:26][S:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:27])[CH3:19]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C(O)CCC(O)(CSc2ccccc2)C1C1(C)OC1CC=C(C)C
Reaction time: 15 h
Yield: 95 %

Procedure:
To methanol (5 ml) was added, under ice-cooling, 60% sodium hydride (213 mg), and the mixture was stirred for 5 minutes at room temperatures, to which was then added thiophenol (0.55 ml), followed by stirring for 15 hours. To the resultant mixture was added fumagillol (500 mg), which was stirred for 30 minutes, followed by adding water to suspend the reaction. The product was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: ethyl acetate-hexane=1:2), followed by crystallization from isopropylether to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)- 3-methoxy-1-phenylthiomethyl-1,4-cyclohexanediol (660 mg: yield 95%) as colorless crystals, m.p. 94° to 96° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:23](OCC)=[O:24])=[C:13]([SH:22])[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1.[NH2:29]OS(O)(=O)=O>O.O1CCCC1>[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]3[C:23](=[O:24])[NH:29][S:22][C:13]=3[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)ccc2c(=O)c3c(=O)[nH]sc3n(C3CC3)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of sodium bicarbonate (316.9 mg, 3.77 mmol) in water (7.5 mL) is added to a solution of ethyl 7-bromo-1-cyclopropyl-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (from above, ˜0.37 mmol) in tetrahydrofuran (7.5 mL) at room temperature. Hydroxylamine-O-sulfonic acid (214.7 mg, 1.90 mmol) is added as a solid and in one portion to this mixture. The resulting amber solution is stirred at room temperature for 2.5 h and quenched by addition of an aqueous solution of 5% hydrochloric acid (50 mL). The solid that formed is collected by filtration, washed with an aqueous solution of 5% hydrochloric acid (3×10 mL), washed with distilled water (3×10 mL), and dried in vacuo to give 17 as a tan solid. This product ids of sufficient purity (≧95% by 1H NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (DMSO-d6): δ 1.00 (m, 2H, c-Pr CH2), 1.20 (m, 2H, c-Pr CH2), 3.79 (s, 3H, OCH3), 3.85 (m, 1H, c-Pr CH), 7.66 (d, J=8.5 Hz, 1H, aromatic H-6), 7.93 (d, J=8.5 Hz, 1H, aromatic H-5), 11.67 (br, 1H). 13C{1H} NMR (DMSO-d6): δ 11.5 (c-Pr CH2), 35.1 (c-Pr CH), 61.9 (OCH3), 107.7, 122.9 (CH, C-5), 123.5 (C—Br, C-7), 127.9 (CH, C-6), 128.0 (C-4a), 136.5 (C-8a), 146.6 (C—OCH3), 164.5, 171.1 (C═O, C-4), 171.2 (br). LCMS m/z calcd for C14H1179BrN2O3S ([M]+) 366. Found 367 ([M+H]+). HRMS m/z calcd for C14H1179BrN2NaO3S 388.9571 ([M+Na]+). Found 388.9577.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]=4)=[O:22])=[CH:16][CH:15]=3)[CH:9]=[C:10]([C:11](O)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[N:25]=4)=[O:22])=[CH:18][CH:19]=3)[CH:9]=[C:10]([C:11]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Reactant: NCC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C(=O)NCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (30.0 mg, 0.066 mmol), 2,2,2-trifluoroethylamine (32.5 mg, 0.33 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58.0 mg, 0.13 mmol), and 4-methylmorpholine (13.3 mg, 0.13 mmol) in DMF (2 mL) was stirred at rt overnight. The crude reaction mixture was purified directly by HPLC using a gradient of 30-90% MeCN in water to afford 16.4 mg (36%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.73 (s, 1 H), 9.40 (t, J=6.6 Hz, 1 H), 8.34 (bs, 1 H), 8.18 (s, 1 H), 8.05 to 7.98 (m, 2 H), 7.58 (d, J=8.6. Hz, 2 H), 7.51-7.49 (m, 1 H), 7.44 (d, J=8.7 Hz, 2 H), 7.24 (s, 1H), 5.94 (bs, 1 H), 4.33-4.24 (m, 2 H); MS [M+H]+=539.0; LCMS RT=3.24 min.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:42]=[CH:41][C:22]([CH2:23][NH:24][C:25]([C:27]3([NH:30][C:31]([C:33]4[CH:34]=[N:35][C:36]([S:39][CH3:40])=[N:37][CH:38]=4)=[O:32])[CH2:29][CH2:28]3)=[O:26])=[CH:21][CH:20]=2)=[C:16]([C:45]([F:48])([F:47])[F:46])[CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]([C:27]3([NH:30][C:31]([C:33]4[CH:34]=[N:35][C:36]([S:39]([CH3:40])=[O:9])=[N:37][CH:38]=4)=[O:32])[CH2:28][CH2:29]3)=[O:26])=[CH:41][CH:42]=2)=[C:16]([C:45]([F:47])([F:48])[F:46])[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(SC)nc4)CC3)cc2)c(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cnc(S(C)=O)nc4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
186 mg (1.08 mmol) of 3-chloroperbenzoic acid were added at approx. 5° C. to a solution of 575 mg (1.08 mmol) of 2-methylthio-pyrimidine-5-carboxylic acid{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-amide (product from Example 144) in 10 mL dichloromethane. Then the cooling was removed and the reaction mixture stirred for a further three hours at ambient temperature. Half the solution was evaporated down and the crude product thus obtained was purified by chromatography (reversed phase HPLC).