Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN1CCN(C2C=CC(C(O)=O)=CC=2)CC1.CCN(C(C)C)C(C)C.[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:57]=2)[C:52]([NH2:70])=[N:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([O:47][C:48]([N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][CH2:60][CH2:61][O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[CH:57]=2)[C:52]([NH:70][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([N:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[N:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(OCCOCc3ccccc3)cc21
Agent: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(OCCOCc5ccccc5)ccc34)cc2)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride, prepared from 248 mg (1.13 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoic acid as described above in preparation 3, and DIPEA (0.386 ml, 2.25 mmol) in dry THF (10 ml) was treated dropwise at r.t., under argon atmosphere, with a solution of 3-amino-6-(2-benzyloxy-ethoxy)-indazole-1-carboxylic acid tert-butyl ester (143 mg, 0.374 mmol) in 10 ml of dry THF. The reaction mixture was heated up to 50° C. and stirred for 12 h. The volatiles were removed under reduced pressure, the residue taken up in DCM (100 ml) and washed with a saturated solution of NaHCO3 (75 ml). The organic layer was separated, dried over sodium sulfate and evaporated to dryness and the crude residue purified by flash chromatography over silica gel eluting with DCM/MeOH 98:2 then 90:10 affording 124 mg (yield: 57%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[CH2:21]([O:23][P:24]([O-:28])[O:25][CH2:26][CH3:27])[CH3:22]>O1CCCC1>[CH2:21]([O:23][P:24]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])[OH:13])(=[O:28])[O:25][CH2:26][CH3:27])[CH3:22]
Reactant: CCOP([O-])OCC
Reactant: O=Cc1ccc2ccccc2c1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 250.6 %

Procedure:
To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vaccum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester
Reaction SMILES: [CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3OC)=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5].[CH3:39]N(C1C=CC=CC=1)C(=O)CC(O)=O>>[CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([N:27]([CH3:39])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5]
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)CC(=O)N(C)c4ccccc4)cc3F)c2s1
Yield: 44 %

Procedure:
Following the procedure described above for compound 236 (example 95, scheme 63) but replacing acid 27 with 3-(methyl(phenyl)amino)-3-oxopropanoic acid (31), title compound 240 was obtained in 44% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 10.08 (br, 0.3H), 9.52 (s, 0.7H), 8.58 (dd, J=5.5 Hz, 3=8.4 Hz, 1H), 8.20 (m, 1H), 7.79 (m, 1H), 7.49-7.30 (m, 7H), 6.75 (d, J=5.5 Hz, 1H), 3.21 (s, 2H), 3.2 (s, 3H), 2.64 (s, 3H) 2.59 (s, 3H). MS (m/z): (M+1) 522.1 (100%).
Reaction SMILES: [OH:1]O.[O:3]1[CH2:14][CH:4]1[CH2:5][S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Na+].[Cl-]>O.CO>[O:3]1[CH2:14][CH:4]1[CH2:5][S:6]([C:7]1[N:8]=[CH:9][C:10]([Cl:13])=[CH:11][N:12]=1)=[O:1]
Reactant: Clc1cnc(SCC2CO2)nc1
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(CC1CO1)c1ncc(Cl)cn1
Yield: 24 %

Procedure:
A mixture of 35% H2O2 (1.9 mmol) and SeO2 (1.9 mmol) in water (1.5 ml H2O) was added to a solution of 2-(2,3-epoxypropyl)thio-5-chloropyrimidine (1.9 mmol) in methanol (7 ml). The mixture was stirred at room temperature for 4 h before saturated NaCl aq. (30 ml) was added and the mixture extracted with chloroform (3×15 ml). The dried (MgSO4) chloroform solution was evaporated and the residue purified by preparative TLC on silica gel using CHCl3 : EtOH (95:5); yield 24%, m.p. 92° C. 1H NMR (CDCl3): δ2.4-3.6 (5H, m), 8.84 (H-4, H-6). IR (KBr): 1050 cm-1 (SO).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[F:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[CH:5][CH:4]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CC(C)=O>[N:22]([CH2:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[F:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[CH:5][CH:4]=1)=[N+:23]=[N-:24]
Reactant: O=C(NC1CC1)c1ccc(F)c(-c2ccc(CCl)nn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(-c2cc(C(=O)NC3CC3)ccc2F)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide. A solution of N-cyclopropyl-4-fluoro-3-(6-methylpyridazin-3-yl)benzamide (430 mg, 1.58 mmol) in 35 mL of DCE was treated with trichloroisocyanuric acid (122 mg, 0.52 mmol) and heated at 90° C. for 1.5 h. Additional trichloroisocyanuric acid (16 mg, 0.07 mmol) was added to the reaction mixture, which was heated for another 30 min at 90° C. The reaction mixture was cooled to RT and the white solid was filtered and rinsed with 2×25 mL of DCM. The filtrate was washed with 5 mL of 0.5 N NaOH followed by 5 mL of brine. The organic layer was concentrated and the residue was purified by silica gel chromatography (35-95% EtOAc in hexanes) to give 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 47% yield). MS (ESI, pos. ion) m/z: 306.2 (M+1). A solution of 3-(6-(chloromethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (228 mg, 0.75 mmol) in 1 mL of DMF and 1 mL of acetone at RT was treated with NaN3 (68 mg, 1.04 mmol) and the mixture stirred at RT for 5 h. The reaction mixture was filtered through a fritted funnel and the solid was rinsed with 2×5 mL of EtOAc. The solid was discarded and the filtrate was concentrated. The brown residue was purified by silica gel chromatography (55-75% EtOAc in hexanes) to give 3-(6-(azidomethyl)pyridazin-3-yl)-N-cyclopropyl-4-fluorobenzamide (215 mg, 92% yield) as an off white amorphous solid. MS (ESI, pos. ion) m/z: 313.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1 H, d, J=3.7 Hz), 8.46 (1 H, dd, J=7.3, 2.1 Hz), 8.15 (1 H, dd, J=8.8, 1.8 Hz), 8.07 (1 H, m), 7.90 (1 H, d, J=8.8 Hz), 7.52 (1 H, dd, J=10.5, 8.9 Hz), 4.87 (2 H, s), 2.88 (1 H, m), 0.72 (2 H, m), 0.60 (2 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −114.48.
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH:14]([CH3:18])[CH:15]([OH:17])[CH3:16]>C(O)C>[OH:17][CH:15]([CH3:16])[CH:14]([S:13][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: ClCc1ccncc1
Reactant: CC(O)C(C)S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(C)SCc1ccncc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium methoxide (3.40 g., 63 mmoles) was dissolved in 30 ml. of absolute ethanol under nitrogen and cooled in an ice bath. To the chilled solution there was added a suspension of finely ground 4- picolyl chloride hydrochloride (5.07 g., 30 mmoles) suspended in approximately 30 ml. of absolute ethanol over 15 minutes, followed by the addition of a solution of 3-mercapto-2-butanol [3.19 g., 30 mmoles, Price et al., J. Am. Chem. Soc. 75, 2396 (1953)]in 6 ml. of absolute ethanol over 5 minutes. The reaction mixture was warmed to room temperature and allowed to stir for 14 hours. The reaction mixture was filtered, the solids being extracted with additional ethanol. The ethanol solutions were combined and evaporated to an oil containing solids (6.31 g.), which was taken up in chloroform, solids removed by filtration and concentrated to an oil. The resulting oil was chromatographed on 200 g. of silica gel with chloroform as eluant. Product fractions were combined and stripped to an oil (5.03 g.). Dissolution in approximately 50 ml. of ethyl acetate, filtration through diatomaceous earth and removal of solvent gave purified 4-(3-hydroxy-2-butylthiomethyl)pyridine [oil; ir (film): 3.08, 3.40, 3.45, 6.24, 7.08, 9.20, 12.27 μ; m/e calcd: 197, found: 197; pnmr/CDCl3 /TMS/delta: 8.57 (m, 2H), 7.30 (m, 2H), 3.85 (m, 1H), 3.76 (s, 2H), 3.12 (s, broad, 1H, exchanges with D2O), 2.75 (m, 1H) and 1.20 (d, 6H)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN(C[C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])C>>[C:17]1([CH2:25][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]5[CH:35]=[CH:34][CH:40]=[CH:39][CH:38]=5)[N:7]=4)=[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][N:11]4[N:10]=3)[CH:18]=2)=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: CN(C)Cc1cccc(N)c1
Product: O=C(Cc1ccccc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Yield: 78 %

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 3-(dimethylaminomethyl)aniline using displacement conditions described in Example 1, Step D to generate the product in 78% yield. ES-LC/MS m/z=532 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:6][CH2:5][CH:4]([F:7])[F:3])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 122.5 %

Procedure:
0.6 g 60% NaH was added in portions to a solution of 1.23 g 2,2-difluoroethanol in 20 ml THF and stirred at room temperature for 15 minutes. 2.02 g (3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazoline-4-yl)-amine was added as a solid and the mixture was heated to 65° C. for 1 hour, then cooled to room temperature. Water was added and the THF was removed under vacuum. The mixture was sonicated and the resulting solids collected by filtration and dried under vacuum overnight to give 2.93 g of crude (3-Chloro-4-fluoro-phenyl)-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:33][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(OCCN4CCOCC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-triflouromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(morpholin-4-yl-ethoxy)-phenylamine (0.130 g, 0.58 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 81%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.55 (d, J=5.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.77 (d, J=6.8 Hz, 1H) 6.71 (s, 1H) 6.65 (d, J=7.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.89 (s, 3H), 3.78-3.71 (m, 4H), 2.86-2.76 (m, 2H), 2.64-2.56 (m, 4H). MS=514 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:34])[C:16](=[O:33])[C:17]([O:24]C(=O)C2C=CC=CC=2)=[C:18]([C:20]([O:22]C)=O)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:34])[C:16](=[O:33])[C:17]([OH:24])=[C:18]([C:20]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=2)=[O:22])[N:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C2COCCN2C(=O)OC(C)(C)C)n(C)c(=O)c1OC(=O)c1ccccc1
Solvent: CO
Product: Cn1c(C2COCCN2C(=O)OC(C)(C)C)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The methyl ester 8B in dry MeOH was treated with 4-fluorobenzylamine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and residue triturated with Et2O to obtain the title product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH3:33])[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:32][O:31][C:27]1[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=[C:25]([CH3:33])[C:26]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: CCOC(=O)CCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(OC)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Under cooling with ice, aluminum chloride (4.08 parts) was added in small portions to a mixed solution of ethyl 9-chloroformylnonanoate (3.52 parts) and 3,4,5-trimethoxytoluene(formula VII wherein R32H3CO, X=H, Y=H3CO) (2.21 parts) in nitrobenzene (20 volume parts). The mixture was stirred at 0° C. for 16 hours and, then, at room temperature for 1.5 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. By a procedure similar to that described in Example 1 (2), the extract was hydrolyzed and subjected to column chromatography on silicic acid. The fraction eluted by benzenediethyl ether (9:1) yielded 9-(2', 3', 4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 wherein R=H3CO, X=H, Y=OCH3, n=8, in the free form) (1.82 part). From the fraction eluted by benzene-diethyl ether (5.7:1), there was obtained 9-(2'-hydroxy-3', 4' -dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1 , R=H3CO, X=H, Y=OH, n=8, in the free form) (0.67 part) as colorless needles melting at 75°-76.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]3[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[N:9]3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: OCCc1cn(-c2cccc(Cl)n2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-n4cc(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-[1-(6-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethanol (90 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH:16]=[CH:15][CH2:14][C@@H:13]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:30].[Na+].OO>O1CCCC1>[CH2:22]([O:21][C:19]([NH:18][C@@H:13]1[CH2:14][CH2:15][CH:16]([OH:30])[CH2:17][C@@H:12]1[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [OH-]
Reactant: O=C(N[C@H]1CC=CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC(O)CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
cis-N1,N2-Bis(benzyloxycarbonyl)-4-cyclohexene-1,2-diamine (10 g) was dissolved in absolute tetrahydrofuran (70 ml), borane-dimethyl sulfide complex (7.4 ml) was added at 0° C., and the mixture was gradually heated to room temperature and stirred for 14 hours. Ice was added to the reaction mixture to decompose excessive borane, and a 1N aqueous solution (80 ml) of sodium hydroxide and 30% aqueous hydrogen peroxide (80 ml) were added to stir the mixture for 1 hour. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:1) to obtain the title compound (9.2 g) as a colorless wax.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]2)[CH:7]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH:11]([C:13]#[N:14])[CH2:12]1
Reactant: N#CC1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CC1CC(Nc2cc(F)ccc2N)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 3-(5-fluoro-2-nitrophenylamino)cyclobutanecarbonitrile (0.38 g, 1.61 mmol), iron powder (0.36 g, 6.44 mmol) and ammonium chloride (0.50 g, 9.66 mmol) in methanol (10 mL) and water (4 mL) was stirred at 90° C. for 2 hours. After cooling the solid material was filtered off and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (3×) and water, then the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound as a dark green gum (0.26 g, 79%). LCMS (Method B): RT 1.75 min [M+H]+ 206.0
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([Cl:7])[Cl:6].[Cl:11]C(Cl)(Cl)C(Cl)(Cl)Cl.[OH-].[Na+]>ClC(Cl)=C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:11])([Cl:7])[Cl:6])[CH:8]=[CH:9][CH:10]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cccc(C(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)=C(Cl)Cl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 84.7 %

Procedure:
36.2 gms of 3-methyl benzal chloride in 207 gms of solvent, tetrachloroethylene, was added into a reaction vessel with 53.9 gms of hexachloroethane, 66.3 gms of 50% sodium hydroxide, and 1.4 gms of Aliquot 4. The mixture was stirred and refluxed under partial vacuum at about 90° C. for about 1 hour. 20.3 ml of water was removed from the mixture via a Dean Stark trap during this period. The mixture was refluxed for another hour an additional 10.5 ml of water was removed. 200 ml of water was added to the cooled mixture and 15 gms of HCl gas was added until the mixture turned acidic. After standing for 2 days, the organic layer was removed and the tetrachloroethylene was distilled off under reduced pressure. The remaining residue was then distilled to give 36.7 gms of a clear oil. b.p. 80° -90° C. (0.6-1.0 mm/Hg-0.8-1.33×105 pascals). (Yield 85% - 97.2 assay).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white foam. MS (ISP): m/z=418.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.O1CCCC1.C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CCCCCC>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[C:6]=1[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Cc1cnn(C2CCCCO2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)cnn1C1CCCCO1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 73.8 %

Procedure:
To a solution of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.258 g, 1.55 mmol) in tetrahydrofuran (6 mL, 70 mmol) at −78° C. was added 2.5 M of n-butyllithium in hexane (0.80 mL). The reaction was stirred at −78° C. for 50 minutes, and then tributyltin chloride (0.60 mL, 2.2 mmol) was added. The reaction was kept at −78° C. for 2 hours and then quenched with saturated aqueous NH4Cl and warmed to room temperature. The reaction mixture was diluted with more water and extracted with ethyl acetate. The organic portion was dried with MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptanes) to yield 520.6 mg (74%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-1H-pyrazole. LCMS (ESI): M+H=457.2; 1H NMR (400 MHz, DMSO-d6) δ 7.31 (s, 1H), 5.11 (d, J=8.3 Hz, 1H), 3.81 (d, J=11.4 Hz, 1H), 3.59-3.48 (m, 1H), 2.23 (dd, J=20.7, 9.4 Hz, 1H), 2.04 (s, 3H), 1.97 (d, J=12.8 Hz, 1H), 1.90 (d, J=13.3 Hz, 1H), 1.48 (m, 9H), 1.30 (dd, J=14.5, 7.3 Hz, 6H), 1.20-0.97 (m, 6H), 0.86 (t, J=7.3 Hz, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[H+].[N:20](OCCCCC)=O>C(O)C.C(OCC)C>[F:14][B-:15]([F:18])([F:17])[F:16].[N+:1](=[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[C:4]([CH3:13])[CH2:3]1)=[N-:20]
Reactant: Cc1cc(N)cnc1CCCCN
Reactant: CCCCCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CCO
Product: CC1=C(CCCCN)N=CC(=[N+]=[N-])C1
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) mixture of 5-amino-2-[4-amino-butyl]-3-methylpyridine (0.86 g) and fluoroboric acid (5 ml) in ethanol (30 ml) was reacted with amyl nitrite (3 ml) over 15 minutes and then stirred for a further 15 minutes, diluted with diethyl ether at 0° C. to give 5-diazo-2-(4-aminobutyl)-3-methylpyridine fluoroborate (1.88 g) m.p. 80°-120° C. (dec).