Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:19])[C:5]([OH:18])=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][C:29](=[O:33])[CH:30](Cl)Cl)[CH3:27].Cl>COCCOC>[CH2:26]([O:28][C:29]([CH:30]1[O:18][C:5]2[CH:6]=[C:7]([S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)(=[O:10])=[O:9])[C:2]([CH3:1])=[CH:3][C:4]=2[O:19]1)=[O:33])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)c2cc(O)c(O)cc2C)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3ccc(C)cc3)cc2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of 12.0 g (43.1 mmol) of 4-methyl-5-(4-methylphenylsulphonyl)-1,2-benzenediol and 30 g (216 mmol) of freshly calcined potassium carbonate in 200 ml of dry 1,2-dimethoxyethane is stirred for 5 minutes, under nitrogen, using a high-speed stirrer. In the course of this the temperature rises to 75°. Then, while stirring moderately (propeller stirrer), there is added dropwise thereto, in the course of one hour, a solution of 6.77 g (43.1 mmol) of dichloroacetic acid ethyl ester in 50 ml of dry 1,2-dimethoxyethane and the mixture is then boiled under reflux for 15 hours. It is subsequently poured onto an ice/water mixture and adjusted to pH 1-2 with concentrated hydrochloric acid. Some of the 1,2-dimethoxyethane is evaporated off in a rotary evaporator and the solution remaining is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in a rotary evaporator. The resulting black oil is dissolved in ethanol, 0.5 g of p-toluenesulphonic acid is added, and the whole is boiled under reflux in a vessel provided with a Soxhlet attachment that is filled with molecular sieve. The ethanolic solution is then concentrated completely by evaporation and chromatographed over silica gel (solvent ethyl acetate/hexane in a ratio of 1:1). The uniform fractions containing the desired substance are combined and concentrated by evaporation. In this manner 5-methyl-6-(4-methylphenylsulphonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester is obtained in the form of a yellow oil, which can be hydrolysed directly.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[H-].[Na+].I[CH3:47]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][O:13][CH3:47])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (25 mg, 0.039 mmol) in dimethylformamide (0.5 mL) at 0° C. was added sodium hydride (60%, 3.15 mg, 0.079 mmol). After 5 min, the reaction was treated with iodomethane (4.93 μL, 0.079 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×). then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% ethyl acetate/n-hexane) gave 22 mg (86%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.9, 5.2 Hz, 2H), 7.02 (dd, J=8.9, 8.5 Hz, 2H), 6.74 (s, 1H), 5.67 (d, J=10.7 Hz, 1H), 5.63 (d, J=10.7 Hz, 1H), 5.06 (dd, J=7.3, 2.7 Hz, 1H), 3.50-3.80 (m, 6H), 3.48 (d, J=9.2 Hz, 1H), 3.41 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 3.06 (m, 2H), 2.23 (m, 1H), 2.07 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.69 (bs, 1H), 1.44 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=245 Hz), 155.1, 145.7, 138.84, 138.82, 130.8, 128.9 (d, J=7.7 Hz), 128.1, 124.3, 122.8, 122.2, 118.3, 115.2 (d, J=21), 81.9, 79.4, 78.7, 77.9, 76.1, 67.7, 59.4, 41.4, 40.2 (br), 32.4, 32.0, 28.6, 17.9, −1.4. Mass spec.: 648.38 (MH)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>>[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH:42][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: NCc1ccccn1
Product: CC(C(=O)NCc1ccccn1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 2-pyridinemethanamine (Aldrich and Cat. No. A65204). LCMS (M+H)+: m/z=564.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[CH:35]=[CH:36][C:31]([CH2:30][OH:29])=[CH:32][CH:33]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.5 g, 3.5 mmol), (4-(hydroxymethyl)phenyl)boronic acid (0.65 g, 4.30 mmol) and Pd(PPh3)4 (0.41 g, 0.35 mmol) in 1,4-dioxane (20 mL) was purged with argon for 10 min. 2 M Na2CO3 solution (1.37 g, 12.91 mmol) was then added to it and argon purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(hydroxymethyl)phenyl)-1H-indazole-4-carboxamide (1.5 g, 89.3%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=[CH:3]1.[CH2:11]=[O:12]>CO>[OH:12][CH2:11][C:3]1[N:2]([CH3:1])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1cncn1C
Reactant: C=O
Solvent: CO
Product: COC(=O)c1cnc(CO)n1C
Yield: 65.9 %

Procedure:
A solution of 5 g of methyl 1-methyl-1H-imidazole-5-carboxylate and 22.5 g of paraformaldehyde in 50 ml of methanol was heated at 140° C. for 60 hours under a sealed tube condition. The precipitate was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 4 g of methyl 2-(hydroxymethyl)-1-methyl-1H-imidazole-5-carboxylate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[NH:13])[CH2:4][CH2:3]1.C(NC1N=[C:23]([C:25]2[C:26]([CH:34]([CH3:36])[CH3:35])=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)[CH:22]=[CH:21]N=1)(C)C>>[CH:34]([C:26]1[C:25]([C:23]2[CH:22]=[CH:21][N:14]=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:13]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)([CH3:36])[CH3:35]
Reactant: CN1CCN(CCCNC(=N)N)CC1
Reactant: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Product: CC(C)c1nn2ccccc2c1-c1ccnc(NCCCN2CCN(C)CC2)n1

Procedure:
[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-[3-(4-methyl-piperazin-1-yl)-propyl]-amine was prepared from 3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone and N-[3-(4-methyl-piperazin-1-yl)-propyl]-guanidine following the method used in Step 4 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66), except preparative-HPLC purification was used in the place of recrystallization (162 mg, 19%). 1H-NMR (250 MHz, DMSO-d6) δ 8.72 (d, J=6.8 Hz, 1H), 8.28-8.20 (m, 2H), 7.37 (t, J=7.8 Hz, 1H), 7.16-7.10 (m, 1H), 6.99 (t, J=6.6 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 3.78 (sept, J=7.3 Hz, 1H), 2.56-2.32 (m, 10H), 2.22 (s, 3H), 2.10-2.06 (m, 2H), 1.73 (pent, J=6.9 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H); LC/MS 394.3 m/z (M+H+). Compound 1135.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([I:29])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([I:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (50 mg, 0.17 mmol), NIS (94 mg, 0.4 mmol), TFA (20 mg, 13.4 L, 0.17 mmol) in CH2Cl2 (200 L) was stirred at room temperature overnight. After solvent removal, the desired product 18 (6 mg, 8.5%) was purified by silica gel column chromatography (CHCl3:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, DMSO-d6) 7.6 (bs, 2H), 7.38 (s, 1H), 6.95 (s, 1H), 6.03 (s, 2H), 4.12 (s, 2H); MS m/z 414.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I:10]N1C(=O)CCC1=O>CC(O)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (2.0 g, 16.39 mmol) in AcOH (30 mL) was added N-iodosuccinimide (4.5 g, 19.67 mmol). The reaction mixture was stirred at r.t. for 16 h, then filtered. The filtrate was poured onto water (100 mL) and EtOAc (50 mL) was added. The aqueous fraction was separated, then extracted with EtOAc (3×50 mL). The combined organic fractions were washed with water (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.0 g, 50%) as a white solid that was used without further purification. LCMS (ES−) 247.1 (M−H)−, RT 1.44 minutes (Method 9).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[CH:3]=1.[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[NH:5][C:4](=[O:11])[C:3]=1[N:12]=[O:13]
Reactant: O=N[O-]
Reactant: CCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(N)c(N=O)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-1-ethyl-1,3-dihydropyrimidine-2,4-dione (5.0 g, 32.3 mmol) in a mixture of 50% acetic acid/water (50 ml) at 70° C. was added sodium nitrite (4.45 g, 64.5 mmol) in portions over a period of 30 minutes. The mixture was stirred at 70° C. for a further 30 minutes. The reaction mixture was cooled, and the precipitate filtered off, and washed with water, then methanol, to provide 6-amino-1-ethyl-5-nitroso-1,3-dihydropyrimidine-2,4-dione, a compound of formula (14).
Reaction SMILES: [Na].[Cl:2][CH2:3][C:4]#[N:5].[NH2:6][C:7]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10]>CO>[Cl:16][C:14]1[CH:15]=[C:7]2[C:8]([C:9](=[O:10])[NH:5][C:4]([CH2:3][Cl:2])=[N:6]2)=[CH:12][C:13]=1[CH3:17]
Reactant: N#CCCl
Reactant: Cc1cc(C(=O)O)c(N)cc1Cl
Agent: [Na]
Solvent: CO
Product: Cc1cc2c(=O)[nH]c(CCl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a flask containing sodium (36 mg) was added anhydrous MeOH (5 ml). Chloroacetonitrile (0.520 g, 6.9 mmol) was then added and the clear solution was stirred at room temperature for 30 min under argon. A solution of 2-amino-4-chloro-5-methylbenzoic acid (1.13 g, 6.0 mmol) in anhydrous methanol (25 ml) was then added with a syringe via a rubber septum. The reaction mixture was stirred at room temperature for 2 hours under argon, then it was fitted with a condenser and placed in an oil bath preheated to 80° C. Stirring was continued at this temperature for 2 hours under argon, then the reaction mixture was allowed to cool to room temperature. The precipitate was collected by filtration, washed with methanol (10 ml), and water (10 ml), and dried in vacuo over P2O5 to afford a grey solid (1.0 g, 69%), mp 287-290° C.; 1H-NMR (DMSO-d6) 2.47 (s, 3H, 6-CH3), 4.53 (s, 2H, CH2Cl), 7.75, 8.08 (2×s, 2H, 5-H and 8-H); 12.60 (s, 1H, N3—H); MS (FAB, m/z) 243, 244, 245 (M+H)+.
Reaction SMILES: C(OC(=O)[C@H](CO)N[C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12])(C)(C)C.C(N(CC)CC)C.C1(=O)O[C:43](=[O:44])CC1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:43][O:44][C:9](=[O:29])[CH2:10][N:11]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]1[C@@H:27]2[C@@H:22]([NH:23][C:24]([NH:26]2)=[O:25])[CH2:21][S:20]1)[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CN(CC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 12.5 °C
Reaction time: 22 h

Procedure:
To a solution of biotinamido-N-methylglycyl-serine t-butyl ester (6) in anhydrous dimethylformamide is added 3 equivalents of triethylamine, 0.01-0.1 equivalents of 4-dimethylaminopyridine and 1.1 equivalents of succinic anhydride. The mixture is stirred at 0-25° C. for 20-24 h and then concentrated via reduced pressure rotary evaporation. The residue is diluted with ethyl acetate and 1 N aqueous hydrochloric acid. The organic phase is then dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on reverse phase C-18 silica gel, eluting with methanol/water. The fractions containing the product are combined and concentrated to give the final product (4).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>N1C=CC=CC=1>[CH2:1]([NH:8][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(O)c1cccnc1NCc1ccccc1
Yield: 84.3 %

Procedure:
Benzylamine (14 mL, 126.8 mmol) was added to a solution of chloronicotinic acid (10 g, 63.4 mmol) in pyridine and refluxed overnight. The pyridine was distilled and the residue was dissolved in 1N NaOH. The solution was diluted with water to adjust the pH to 10 to 11 and washed by dichloromethane. The aqueous phase was neutralized with cold aqueous 10% HCl solution to adjust the pH to 6 to 7. The solids formed were filtered, washed with cold water, and dried in a vacuum oven to yield 12.2 g (84%) of 2-benzylamino nicotinic acid (1) as white solids. MP: 148° C.; 1H-NMR (DMSO-d6): δ 4.69 (d, J=3.6 Hz, 2H), 6.61 (dd, J=4.9, 7.7 Hz, 1H), 7.23 (m, 1H), 7.29 (m, 4H), 8.08 (dd, J=1.8, 7.0 Hz, 1H), 8.28 (dd, J=1.8, 7.0 Hz, 1H), 8.47 (br. s, 1H), 13.10 (s, 1H); EIMS: 229 (M+1), 251 (M+23).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:35])[N:21]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][OH:34])[CH3:22])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][OH:34])[CH3:22])=[O:35]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.9 %

Procedure:
A solution of [(1R)-1-(N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methylcarbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tert-butyl ester (519 mg, 1.85 mmol) in dichloromethane (3 ml) was cooled to 0° C. Trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 0° C. for 40 min. Dichloromethane (20 ml) was added. A saturated solution of sodium hydrogen carbonate (10 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia, to give 377 mg of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methyl-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:12]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([OH:13])[C:11]([F:19])([F:18])[Cl:10]
Reactant: O=C(C(F)(F)F)C(F)(F)Cl
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(O)(C(F)(F)F)C(F)(F)Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of ethoxybenzene (67 g), chloropentafluoroacetone (100 g) and aluminium chloride (7 g) was charged to a Hastalloy lined cell at -78° C., the cell sealed and heated to 120° C. for 8 hours. After cooling and venting, the residue was taken up in chloroform and filtered through silica gel. After removal of the solvent by evaporation the residual solid was recrystallised from n-hexane to yield several crops of 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)-3-chloropropan-2-ol. (Total 70 g) mp. 84°-86° C.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:11][CH2:10][C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CCN=[N+]=[N-])CCO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 59.4 %

Procedure:
Step B To the solution of methanesulfonic acid 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl ester (1.48 g, 4.96 mmol) in anhydrous dimethylformamide (10 mL) was added NaN3 (1.6 g, 25 mmol). The reaction mixture was heated at 60° C. for 18 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4 to give (5-azido-3,3-dimethyl-pentyloxy)-tert-butyl-dimethyl-silane as a yellow oil (0.8 g, 67%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].CS(O)(=O)=O.CO[C:24](OC)([CH3:26])[CH3:25]>>[C:1]([CH2:3][C@H:4]1[O:16][C:24]([CH3:26])([CH3:25])[O:15][C@@H:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:5]1)#[N:2]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Agent: CS(=O)(=O)O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Yield: 70.5 %

Procedure:
Crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate (about 150 moles) from Step (2) is diluted with 100 kg of 2,2-dimethoxypropane and acidified with about 1 L of methanesulfonic acid. The reaction is quenched by the addition of aqueous sodium bicarbonate solution and concentrated by vacuum distillation. The residue is diluted with 150 L of hexane, and the layers separated. The organic layer is washed with aqueous sodium bicarbonate solution and cooled to 0° C.±10° C. to crystallize. The product is collected by filtration and washed with cooled hexane, then dried affording 28.5 kg of (4R cis) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:33])=O.C>ClCCCl>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:33])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 78.5 %

Procedure:
79.2 g of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid and 0.5 ml of dimethylformamide were introduced into 150 ml of 1,2-dichloro-ethane. 28.6 g of thionyl chloride were added dropwise at 60° to 65° C. and the mixture was heated under reflux for 1 hour. The solution was clarified with active charcoal and filtered through kieselguhr. The mother liquor was concentrated and the residue was recrystallized from cyclohexane. 65.1 g (79% of theory) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzoic acid chloride, of melting point 95° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH2:10][NH2:11]>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: Nc1nc(Cl)cc(=O)[nH]1
Reactant: NN
Solvent: O
Product: NNc1cc(=O)[nH]c(N)n1
Yield: 45.4 %

Procedure:
A stirred suspension of 15.0 g (103 mmol) of 1 in 250 mL water was added 12 g (375 mmol) of anhydrous hydrazine, and the mixture was heated at reflux for 3 h. The resulting clear solution was cooled, and the precipitate which separated was collected by filtration, washed with water followed by ethanol and dried to give 6.6 g (46%) of white solid. mp decomposes at 313° C. (Literature mp 314-315° C., see Taylor, E. C.; Cocuzza, J. A. Synthesis and Properties of 7-Azaxanthopterin. J. Org. Chem. 1979, 44, 1125-1128).