Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O>[CH:15]1[C:16]2[N:2]=[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]3[CH2:9][O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc[n+]1COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C1=CC2=Nc3ccccc3OCN2C=C1

Procedure:
A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)-methyl]pyridinium chloride, 8.3 g of potassium carbonate, 0.4 g of copper-bronze in 150 ml of n-propanol and 25 ml of water under N2, is heated under reflux for 12 hours while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dyrness. The residue is dissolved in 400 ml of ether, the ether solution is washed, dried and the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 9 of the title product, mp about 125°-127°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[F:28][C:26]([F:29])([F:27])[CH2:25][N:21]1[C:20]([C:14]2[CH:15]=[C:16]3[N:12]([C:11]4[CH:30]=[C:7]([CH:4]5[CH2:3][CH2:2][N:1]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:6][CH2:5]5)[CH:8]=[CH:9][C:10]=4[O:19][CH2:18][CH2:17]3)[N:13]=2)=[N:24][CH:23]=[N:22]1
Reactant: NC(=O)CBr
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (180 mg, 0.43 mmol) in DMF (1 mL) was treated with potassium carbonate (89 mg, 0.65 mmol) and bromo acetamide (77 mg, 0.56 mmol) and then stirred at RT for 18 h. The reaction mixture was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 143 as a pale yellow solid (115 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): δ 8.21 (s, 1H); 7.75 (d, J=2.2 Hz, 1H); 7.28 (dd, J=8.4, 2.2 Hz, 1H); 7.20 (d, J=8.3 Hz, 1H); 7.15 (s, 2H); 6.97 (s, 1H); 5.73 (q, J=8.8 Hz, 2H); 4.49 (t, J=6.0 Hz, 2H); 3.20 (t, J=6.0 Hz, 2H); 2.96-2.85 (m, 4H); 2.62-2.52 (m, 1H); 2.24-2.14 (m, 2H); 1.84-1.66 (m, 4H). LCMS: RT=6.55 min, M+H+=476
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1.[CH2:22]([N:24](CC)[CH2:25]C)C.CNC>CCCCCC.CC(C)=O>[CH3:22][N:24]([CH3:25])[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1
Reactant: CCN(CC)CC
Reactant: CCC(CC)Nc1nc(SC)nc(NC(C)C)c1[N+](=O)[O-]
Agent: CNC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCC(CC)Nc1nc(N(C)C)nc(NC(C)C)c1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
15.6 g of 2-methylmercapto-4-isopropylamino-5-nitro-6-(3-pentyl-amino)-pyrimidine (0.05 mol) are dissolved in 250 ml of alcohol. Then 20 ml of triethylamine and 3 g of dimethylamine are added. The reaction mixture is kept for 16 hours under high pressure (12 bar) at 100° C, until no more starting material can be detected in a thin-layer chromatogram (silica gel. hexane/acetone 5:1). The mixture is evaporated, the residue is treated with water and extracted twice with ether. The ethereal extracts are dried over MgSO4, filtered and evaporated, to yield 13.5 g of 2-dimethylamino-4-isopropylamino-5-nitro-6-(3-pentylamino)-pyrimidine; b.p. 160° C/0.001 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[C:4]([Br:19])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Compound 87 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over. MgSO4, and the product was purified by column chromatography (eluant 25% EtOAc/hexanes) to give a solid (0.12 g, 18%); Mp=203–205° C.; 1H NMR (DMSO-d6) δ 10.04 (br s, 1 H), 7.83 (d, 1 H, J=1.5 Hz), 7.75 (d, 2 H, J=8.3 Hz), 7.68 (d, 1 H, J=2.0 Hz), 7.28 (s, 1H), 6.91 (d, 2 H, J=8.3 Hz); MS 365/367/369 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12](OCC)=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[NH3:22]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH2:22])=[O:13])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: N
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(N)=O)C1
Reaction time: 0.08 h

Procedure:
Ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (0.1 g, 0.35 mmol) was taken in 4 ml aqueous ammonia and heated at 120 deg C. for 5 min in microwave. The solid product precipitated out after the reaction was filtered through a Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash. Product was vacuum dried and was taken in 5 ml ethanolic HCl, stirred for 15 min, concentrated in vacuo to afford 38 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetamide as hydrochloride salt. 1H NMR (DMSO)HCl Salt 10.38 (bs, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.43 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 4.79 (d, 2H), 4.62 (d, 1H), 4.21-4.31 (m, 1H), 3.68-3.81 (m, 1H), 3.42-3.53 (m, 1H), 3.04-3.14 (m, 2H), 2.96 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]([O:38][C:39]1[CH:40]=[C:41]([NH2:49])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)([CH3:37])[CH3:36]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:19])[CH3:20])([C:15]([NH:49][C:41]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:39]([O:38][CH:35]([CH3:37])[CH3:36])[CH:40]=2)=[O:16])[CH2:10]1
Reactant: CC(C)Oc1cc(N)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(OC(C)C)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-isopropoxy-5-(trifluoromethyl)benzenamine (39 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.91 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.04-7.16 (m, 3H), 6.90-6.94 (m, 1H), 4.65 (septet, J=6.0 Hz, 1H), 3.97 (d, J=10.4 Hz, 1H), 3.66 (d, J=10.8 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.66 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 2.00 (s, 3H), 1.29 (d, J=6.0 Hz, 6H), 0.96 (t, J=6.4 Hz, 6H). LC-MS Rt (retention time): 3.08 min; MS: (ES) m/z 477 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:22][CH2:23][OH:24])[C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=1F)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CN(C=O)C>[CH2:3]([N:10]1[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[O:24][CH2:23][CH2:22]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(F)c(F)c1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(F)c(F)c2OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
Sodium hydride (25 mg, 0.615 mmol, 60% dispersion in mineral oil) was added slowly to a solution of N-benzyl-2,3,4-trifluoro-N-(2-hydroxyethyl)benzamide (190 mg, 0.615 mmol) in DMF (3 mL) and the pale yellow solution was stirred at RT for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (4×30 mL). The combined organic phases were washed with water (3×20 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as a colourless oil (130 mg). 1H NMR δ (CDCl3): 3.5 (t, 2H), 4.3 (t, 2H), 4.8 (s, 2H), 6.92 (dd, 1H), 7.3-7.4 (m, 5H), 7.7 (m, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12]1[CH:16]=[C:15]([CH:17]=O)[O:14][CH:13]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][CH2:17][C:15]2[O:14][CH:13]=[CH:12][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: O=Cc1ccco1
Product: Nc1cc(NCc2ccco2)cc(C(=O)O)c1

Procedure:
This compound was prepared from 3,5-diaminobenzoic acid and 2-furfuraldehyde according to the procedure of Example 18.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[CH:15]=3)[N:10]([C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(Oc3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
1-(1′-Acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (40 mg, 0.122 mmol) was dissolved in methylene chloride (1.5 mL). Thereafter, 4-fluorophenylboronic acid (34 mg, 0.244 mmol), copper(II) acetate (22 mg, 0.122 mmol), triethylamine (62 mg, 0.610 mmol), and molecular sieves 4A (40 mg) were added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 18 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate) to obtain 1-(1′-acetyl-5-(4-fluorophenoxy)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (30 mg, 56%) in the form of a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)([CH2:6]3)[CH2:4]1)[CH2:10]2.[I:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[I:20][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:5]23[CH2:6][CH:7]4[CH2:8][CH:9]([CH2:10][C:3]([O:2][CH3:1])([CH2:12]4)[CH2:4]2)[CH2:11]3)[C:18]=1[CH3:19]
Reactant: O=C1CCC(=O)N1I
Reactant: COC12CC3CC(CC(Cn4nccc4C)(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC12CC3CC(CC(Cn4ncc(I)c4C)(C3)C1)C2

Procedure:
A mixture of EXAMPLE 16D (0.116 g) and N-iodosuccinimide (0.11 g) in 1 mL DMF was stirred overnight. The mixture was taken up in ethyl acetate, and the resulting solution was washed three times with water, and brine, then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[C:21]([OH:22])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:21]([O:22][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[C:14]([Br:23])[N:13]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Triethylamine (0.759 g, 7.50 mmol) was added to a suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (6, 1.415 g, 5.000 mmol) in chloroform (5 mL) over 5 min maintaining the temperature at 20-50° C. to give a yellow suspension. p-Toluenesulfonyl chloride (1.15 g, 6.00 mmol) was added over 5 min maintaining the temperature at 20-40° C. to give a yellow solution. The mixture was aged at 40° C. for 2 h during which a crystalline solid precipitated out of the mixture and the color faded (HPLC analysis indicated <0.5% starting material remaining). The mixture was cooled to 20° C. over 15 min. MeOH (10 mL) was added over 30 min then a 1:1 mixture of MeOH:water (10 mL) was added over 30 min. The mixture was cooled to −40° C. over 30 min and aged at −40° C. for 30 min. The cold mixture was filtered and the solid was washed with 1:1 MeOH:water (10 mL), MeOH (5 mL), MTBE (10 mL) and hexanes (10 mL) all at 10-20° C. The off-white crystalline solid was dried under a stream of nitrogen to provide 2.112 g (97% yield) of 5-bromo-8-(p-toluenesulfonyloxy)-1,6-naphthyridine-7-carboxylic acid methyl ester (7)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn(C)c3nc(N)ncc23)cc1F
Temperature: 70 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (1.2 g, 5.2 mmol) is dissolved in THF (40 ml), under an inert atmosphere of argon. To this is added Pd(PPh3)2Cl2 (0.224 g, 0.32 mmol), [3-fluoro-4-methoxyphenyl]boronic acid (0.98 g, 5.8 mmol) and a solution of Na2CO3 (1.5 g, 14 mmol) dissolved in distilled water (4 ml). The reaction mixture is heated to reflux at 70° C. for 24 hours. After cooling to room temperature the reaction mixture is pre-absorbed onto silica and purification by flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1) affords the title compound as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([N:10]=[C:11]=[O:12])([CH3:9])[CH3:8])([CH3:3])=[CH2:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:11]([NH:10][C:7]([C:6]2[CH:13]=[CH:14][CH:15]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:5]=2)([CH3:9])[CH3:8])=[O:12])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Solvent: ClCCl
Product: C=C(C)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)cc2)c1
Yield: 110.3 %

Procedure:
To a solution of 3-isopropenyl α, α-dimethylbenzyl isocyanate 2 (473 mg, 2.35 mmol) in dichloromethane (6 mL) at 0° C. was added 4-chloroaniline (300 mg, 2.35 mmol) in dichloromethane (3 mL). The reaction was stirred until complete consumption of starting materials. The precipitated product was collected by filtration and washed with dichloromethane to give 5b (852 mg, 80%). mp 234-236° C. Yield 80%; 1H NMR (DMSO-d6, 400 MHz) δ 1.58 (s, 6H), 2.08 (s, 3H), 5.06 (s, 1H), 5.36 (s, 1H), 6.64 (s, 1H), 7.20 (d, J=6.4 Hz, 2H), 7.23-7.32 (m, 5H), 7.47 (s, 1H), 8.55 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 22.24, 30.30, 55.0, 113.06, 119.50, 122.35, 123.69, 124.86, 124.95, 128.65, 129.09, 140.11, 140.73, 143.60, 148.95, 154.53; ESI-HRMS for C9H22N2OCl (M+H)+ calcd. 329.1421. found 329.1418.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[C:35](=[O:39])([O:37][CH3:38])[NH2:36]>C1C=CC=CC=1>[CH3:38][O:37][C:35]([NH:36][C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:7])=[O:39]
Reactant: COC(N)=O
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)NC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
2-Methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (2.00 g, 4.89 mmol) obtained in Example 1 was dissolved in benzene (15 ml), and thionyl chloride (392 μl, 5.38 mmol) was added at room temperature. The mixture was refluxed under heating for 1.5 hr and the solvent was evaporated. The residue was dissolved in toluene (6 ml), and methyl carbamate (440 mg, 5.87 mmol) was added. at room temperature. The mixture was stirred at 80-90° C. for 30 min. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol=30:1). The obtained white solid was recrystallized from methanol to give the title compound (1.40 g, yield 61%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.[C:10]([OH:27])(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:10]([O:27][CH2:7][CH:5]([CH2:4][OH:3])[OH:6])(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CC1(C)OCC(CO)O1
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
This compound was synthesized according to the procedure described hereinabove (example 2a) starting from solketal and palmitic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26](=O)[CH3:27])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]([NH:35][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH3:27])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)=O)c3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(C)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of 4-(4-acetyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 39 (45 mg, 0.11 mmol) in MeOH (4 mL) was added cyclohexylarnine (31 mg, 0.22 mmol) and sodium cyanoborohydride (34 mg, 0.69 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo to give a solid. The resultant solid was purified by reverse phase HPLC providing the title compound (G-30). 1H NMR (300 MHz, MeOD) δ 8.84 (m, 1H), 8.42 (s, br, 1H), 8.35 (m, 2H), 7.82 (m, 3H), 5.55 (d, 1H), 4.02 (q, 2H), 3.80 (d, 2H), 3.22(m, 1H), 3.00 (m, 1H), 2.77(s, br, 2H), 2.19 (d, 1H), 2.05 (d, 1H), 1.78 (m, 4H), 1.50 (m, 5H), 1.24 (m, 9H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: O[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c([N+](=O)[O-])c(C)c1C#N
Solvent: O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinonitrile (step 2, 3.2 g, 16.6 mmol) and phosphorus oxychloride (20 mL) was stirred at 100° C. for 16 h. After cooling, the mixture was poured in water (100 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated to afford 2.3 g (66%) of the title compound as brown solids: 1H-NMR (DMSO-d6) δ 2.82 (3H, s), 2.52 (3H, s).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (3.70 mL, 18.77 mmol) was added to 4-(1-(3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenol (6.2 g, 17.06 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (2.368 g, 18.77 mmol) and triphenylphosphine (4.92 g, 18.77 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 1 day. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford crude product. Product was dissolved in DCM (100 mL) and washed with 2M NaOH (100 mL) twice. Organic layer was evaporated to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (4.95 g, 61.5%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:11][CH:10]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1O[Si](C)(C)C(C)(C)C
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, (>99%). LCMS (m/z): 423.2 (MH+); LC Rt=3.78 min.