Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](OC)=[O:23])[CH:17]=1)[C:10]([CH3:27])([CH3:26])[CH2:9]2)=[O:5])[CH3:2].Cl>O1CCCC1.[OH-].[Li+].O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH2:17][C:18](=[C:22]=[O:23])[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:26])([CH3:27])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(C1=CC=CC(=C=O)C1)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 326 %

Procedure:
A mixture of 2-(3-methoxycarbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.16 g, 1 mmol) in tetrahydrofuran (40 mL), 2M lithium hydroxide in water (20 mL) was stirred for 48 h at 25° C. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution, diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.1 g, 98%) as a white solid: LC/MS m/e calcd for C21H23NO4 (M+H)+: 354.42, observed: 354.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:21])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:26][CH2:25]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Product: CN1CCN(S(=O)(=O)c2cccc(NC(=O)c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)c2)CC1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 561.5 [(M+H)+]; mp 147° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH:9][C:10](=O)OC(C)(C)C)=O.C(OC=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[N:9]1[C:4]2[C:3](=[CH:8][CH:7]=[N:6][CH:5]=2)[CH:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C=O
Reactant: CCOC=CC(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc2cnccc2c1

Procedure:
A mixture of tert-butyl 4-formylpyridin-3-ylcarbamate (1.7 g, 7.65 mmol), ethyl 3-ethoxyacrylate (1.27 g, 8.8 mmol) and TFA (5.9 mL, 76.5 mmol) in CHCl3 (30 mL) is heated at reflux for 4 hr. The mixture is cooled and the solvent is removed in vacuo. The residue is dissolved in EtOAc (30 mL) and washed with saturated NaHCO3 solution (20 mL). The organic layer is dried and evaporated. Purification of the residue with flash column with hexane/EtOAc (2:1) gives the title compound as a white solid. MS (M+1): 203.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Into a suspension of methyl 3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate (166 mg, 0.26 mmol) in THF/H2O (2/1) (6 mL) was added NaOH (1.0 N, 1.3 mL). The resulting solution was stirred at rt for 1 hr and quenched with HCl (5 N, 1.3 mL). A yellow solid precipitated out. Filtration, washing with water (4×2 mL) and drying under vacuo at 60° C. for 18 hrs gave the title compound as a yellow powder (133 mg, 81%) in 99.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[OH:1][CH:2]([CH2:24][O:25][C:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A solution of 2 (21 mmol) in 80 ml of dichloromethane/pyridine (1:1) is added dropwise with triphenylmethyl chloride (27 mmol) and stirred at room temperature for 48 hours. The solvent is removed, and the residue is added twice with 50 ml of toluene and concentrated. The residue is diluted with 100 ml of H2O and extracted three times with 50 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by chromatography on silica gel using heptane/ethyl acetate (5:1). Yield: 88% of a colorless oil.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>C(O)(=O)C.CN(C)C=O.[Fe]>[CH3:15][S:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:16]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: CSc1ccc([N+](=O)[O-])c(C=C(C#N)C(N)=O)c1
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1ccc2nc(N)c(C(N)=O)cc2c1
Temperature: 75 °C

Procedure:
A mixture of α-cyano-β-(2-nitro-5-methylthiophenyl)acrylamide (8,4 g., 0.032 mole) in acetic acid - N,N-dimethylformamide (110 ml. of 1:1) is heated in a 75° C. bath. Iron powder (2.0g.) is added and the mixture stirred until the internal temperature rose to 95° C. Additional iron powder (6.16 g. total iron added=0.146 mole) is added in small portions over a 15 minute period. The reaction mixture is stirred for one hour following completion of addition and then filtered hot. The iron residue is washed with hot acetic acid and the combined filtrate and wash solution poured into IN hydrochloric acid (200 ml.) The hydrochloride salt which separates is filtered off and dissolved in hot dilute aqueous sodium hydroxide. The yellow solid which separates on cooling is filtered off, washed with isopropyl alcohol and air-dried. Yield = 3.26 g. (44%), M.P. 229°-242° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].O.O.O.[C:16]([O-])(=O)[CH3:17].[Na+].C(Br)C>CS(C)=O.C(Cl)(Cl)Cl>[CH2:16]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCBr
Product: CCON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A solution of 24 g (0.147 moles) of N-hydroxyphthalimide in 120 ml of dimethyl sulfoxide is warmed at 40° up to complete dissolution. Then 23.9 g (0.176 moles) of sodium acetate trihydrate and 15.92 ml (0.21 moles) of ethyl bromide are added, while warming at 80° C. After two hours and 15 minutes, the mixture is diluted with 600 ml of chloroform, washed with 10% potassium bicarbonate and dried. Removal of the solvent leaves 19.3 g (68.7%) of N-ethoxy-phthalimide, melting point 95°-97° C. (A. Rougny et al, Bull. Soc. Chim. Fr. 1976, pp. 833).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 10 h
Yield: 34 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) and 4-chloro-3-(trifluoromethyl)phenol (14.52 g, 73.9 mmol) in acetonitrile (200 mL) was added potassium carbonate (18.38 g, 133 mmol) and the reaction mixture was stirred at 80° C. for 10 hr. Then, 200 mL of EtOAc and 200 mL of H2O were added. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by a silica gel column chromatography eluting and was eluted with Hex/EtOAc (5:1) to provide 5-(4-chloro-3-(trifluoromethyl)phenoxy)-2-nitropyridine (8 g, 32.8%),
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[Cl:16].[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br)[CH3:19].[OH-].[Na+]>CC(C)=O.CCOC(C)=O.CCCCCC>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][O:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1)[CH3:19]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (27.5 mmol, 3.75 g) and sodium iodide (0.3333 mmol, 0.0500 g) were added to a reaction mixture of 3,4-dichloro-phenol Compound 16a (30.25 mmol, 4.93 g) and 4-bromo-butyric acid ethyl ester Compound 16b (27.5 mmol, 5.36 g) in acetone (60 mL). The reaction mixture was stirred overnight at room temperature. TLC analysis (4:1 hexane:EtOAc) showed no formation of product. The reaction mixture was refluxed for 3 hrs and TLC analysis (4:1 hexane:EtOAc) showed trace of starting material Compound 16a. The reaction mixture was refluxed overnight, then basified with 1N NaOH solution and extracted with CH2Cl2. The organics were dried over MgSO4. The drying agent was filtered and the solvent was removed in vacuo to yield 4-(3,4-dichloro-phenoxy)-butyric acid ethyl ester Compound 16c (6.9 g, 90.7%) as a pale pink oil, which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 1.21-1.31 (q, 3H), 2.12-2.25 (m, 2H), 2.45-2.53 (t, 2H), 3.95-4.02 (t, 2H), 4.10-4.20 (q, 2H), 6.71-6.78 (dd, 1H), 6.94-6.96 (d, 1H), 7.28-7.31 (d, 1H).
Reaction SMILES: NC1C2CCOC=2C=CC=1.[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:21]2[C:16](=[C:17]([CH3:51])[C:18]([O:49][CH3:50])=[CH:19][CH:20]=2)[N:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:21]2[C:16](=[C:17]3[CH2:51][CH2:50][O:49][C:18]3=[CH:19][CH:20]=2)[N:15]=1)[CH3:12]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: Nc1cccc2c1CCO2
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)CCO3

Procedure:
The title compound (8) was prepared from 4-amino-2,3-dihydrobenzofurane following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carboxylic acid (2): m/z=564 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.[CH2:14]([O:18][C:19]1[N:27]=[C:26]2[C:22]([N:23]=[C:24]([O:28][CH3:29])[NH:25]2)=[C:21]([NH2:30])[N:20]=1)[CH2:15][CH2:16][CH3:17].Br[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[Br-]>CN(C)C=O.O>[NH2:30][C:21]1[N:20]=[C:19]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])[N:27]=[C:26]2[C:22]=1[N:23]=[C:24]([O:28][CH3:29])[N:25]2[CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
Potassium carbonate (650 mg) was added to a solution of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (550 mg) in dry N,N-dimethylformamide (5.5 ml) and the reaction mixture heated at 60° C. for 1 hour. 1,1-Dimethylethyl 4-(bromomethyl)-1-piperidinecarboxylate (500 mg) was added using additional DMF (1.5 ml) to transfer the residual bromide and the reaction mixture stirred at 50° C. for 3 hours. After 16 hours at room temperature, heating at 50° C. was continued for another 5 hours to complete the reaction. Water was added and the reaction mixture extracted three times with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered, concentrated and dried under high vacuum. Purification by chromatography on silica gel eluting with a gradient of 1-2.5% methanol in chloroform afforded the title compound as yellow solid (640 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](Cl)=[O:14])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:22][N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([O:30][CH3:31])=[O:29].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:22][N:23]1[CH:27]=[C:26]([C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:14])[CH:25]=[C:24]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1ccc(C(=O)Cl)c2ccccc12
Reactant: COC(=O)c1cccn1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)c2ccc(OC)c3ccccc23)cn1C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-Methoxy-naphthoic acid chloride (35 g; prepared by action of phosphorous pentachloride on the acid of m.p. 250° C.) followed by methyl 1-methyl-pyrrole-2-carboxylate (22 g) are dissolved in 1,2-dichloroethane (400 ml). To the stirred solution, at about -20° C., is slowly added anhydrous aluminium chloride (23 g). After one hour, the resulting material is poured over 1 kg crushed ice. The organic phase is decanted off and the aqueous phase is extracted with chloroform (500 ml). The organic solution is then dried and the solvents are evaporated off. The solid residue (28 g) is washed with isopropyl ether (200 ml), to give methyl 1-methyl-4-(4-methoxy-1-naphthoyl)-pyrrole-2-carboxylate, m.p.=162° C., in a yield of 50%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[N:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has-been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z 3.96 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[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][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:34]([O:36][CH3:37])=[O:35])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: [2′-(benzylamino-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>O1CCCC1>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([S:33]([CH:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][OH:18])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])(=[O:35])=[O:34])=[CH:37][CH:38]=1
Reactant: CC(C)(C)[Si](OCc1ccccc1C(CCCCCO)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1ccccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
In tetrahydrofuran (5 ml) was dissolved 6-[2-(t-butyldiphenylsilyloxy)methylphenyl]-6-[(4-chlorophenyl)sulfonyl]-1-hexanol (200 mg, 0.322 mmol), followed by the dropwise addition of a tetrahydrofuran solution (1.0M, 0.7 ml, 0.7 mmol) of tetrabutylammonium fluoride under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. Water (0.2 ml) was then added. The residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure, whereby the title compound (86 mg, 0.23 mmol, 70%) was obtained as a colorless oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]1[S:20][C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[CH2:26][CH2:27][NH2:28])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccsc1-c1ccc(-c2sccc2CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccsc1-c1ccc(-c2sccc2CCN)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate L (208 mg, 0.283 mmol) was dissolved DCM (2 ml) and TFA (2 ml) was added. The mixture was stirred at rt for 1 h. Solvents evaporated and residue dissolved in water. The solution was added 1 M NaOH (2 ml) and the aqueous layer extracted with CHCl3. The combined organic layers were dried (MgSO4) and 1.2 M HCl in EtOH (2 ml) was added. Solvents were evaporated to give the HCl-salt of the title compound. Yield: 105 mg (99%); yellow-orange solid. HPLC: RT=2.68 min, 95% (254 nm, 10-40% MeCN in 0.1% TFA, 3 min, ACE) and RT=2.68 min, 94% (350 nm, 10-40% MeCN in 0.1% TFA, 3 min, ACE). 1H NMR (400 MHz, DMSO-d6): δ 3.06 (br s, 12H), 7.14 (d, J 5.2 Hz, 2H), 7.27 (s, 2H), 7.58 (d, J 5.2 Hz, 2H). LC-MS: m/z=335 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH:9]([C:13]#[N:14])[C:10]([NH2:12])=[O:11])=O)=[CH:4][CH:3]=1.CCOCC.C(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[NH:14][C:6]([C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: N#CC(CC(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)[nH]c1Cl
Yield: 46 %

Procedure:
Into a mixture of 3-(p-chlorobenzoyl)-2-cyanopropionamide (1.0 g, 0.0042 mol), ether and chloroform is bubbled dry hydrogen chloride for about 10 minutes. TLC shows no remaining 3-(p-chlorobenzoyl)-2-cyanopropionamide. Solvent is removed in vacuo and the residue is distributed between ethyl acetate and water. The organic phase is separated, washed with water and brine and dried over magnesium sulfate. Solvent is removed and the resulting solid is triturated with ether and collected to give the title compound as a light brown solid (0.50 g, 46%, mp >200° C.). Identified by IR and NMR spectral analyses.
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1.[Li].[B:30](OC)([O:33]C)[O:31]C>C1COCC1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[C:17]=1[B:30]([OH:33])[OH:31]
Reactant: COc1cccc(C(=O)N2CCCC2)c1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N2CCCC2)c1B(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.3 %

Procedure:
s-BuLi (70 mL, 1.3M in cyclohexane) was added to TMEDA (15.3 g, 131.9 mmol) at −78° C. dropwise within 30 min. After stirring for 20 min, (3-methoxyphenyl)(pyrrolidin-1-yl)methanone (16 g, 78 mmol) in THF (40 mL) was added into the lithium solution slowly. The solution was stirred at −78° C. for 1.5 h and trimethyl borate (36 mL, 322.6 mmol) was added. The mixture was warmed to room temperature and stirred at rt overnight. The solution was acidified to pH=5-6 and the precipitate were filtered. The filter cake was washed with water and ethyl acetate to give 2-methoxy-6-(pyrrolidine-1-carbonyl)phenylboronic acid (5.5 g, 28%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(O[CH:15](O)[C:16]([F:19])([F:18])[F:17])C.[BH3-]C#N.[Na+]>FC(F)(F)C(O)=O>[F:17][C:16]([F:19])([F:18])[CH2:15][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCOC(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(NCC(F)(F)F)c(O)c1
Yield: 72.8 %

Procedure:
This compound was prepared by General Method 7 (EXAMPLE 5) from 2-amino-5-nitrophenol (5.0 g, 32 mmol), 2,2,2-trifluoroacetaldehyde ethyl hemiacetal (9.4 g, 65 mmol) and NaBH3CN (4.1 g, 65 mmol) in 90 mL trifluoroacetic acid to afford 5.5 g (72%) of 2-(trifluoroethyl)amino-5-nitrophenol, a yellow solid, after flash chromatography (3:1 hexanes:EtOAc). Data for 2-(trifluoroethyl)amino-5-nitrophenol: 1H NMR (400 MHz, acetone-d6) 9.48 (broad s, 1H), 7.79 (dd, 1H, J=9.1, 2.4), 7.67 (d, 1H, J=2.4), 6.96 (d, 1H, J=8.8), 6.20 (broad s, 1H), 4.26-4.18 (m, 2H).