Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](OC)([CH3:26])[CH2:4][C:5]1[C:10]([F:11])=[C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24].Cl>C1COCC1.CO>[C:3]([CH2:4][C:5]1[C:10]([F:11])=[C:9]([N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[CH:8]=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=[O:2])[CH3:26]
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F)OC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
2-(2,2-Dimethoxypropyl)-3-fluoro-4-phthalimidonitrobenzene (5.5 g, 14 mmol) was suspended in a mixture of THF (200 ml) and methanol (100 ml). HCl 2N (1 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. The solvents were evaporated off and the residue redissolved in methylene chloride, dried (MgSO4), filtered and the solvent evaporated off. The residue was triturated in pentane and collected by filtration to give 2-(acetylmethyl)-3-fluoro-4-phthalimidonitrobenzene (4.8 g, 100%) as a pale yellow solid.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:27][C:28]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[CH3:27][C:28]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: Cc1ccc(CCl)c(C)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCN(Cc3nnc4nc(N)nc(N)c4n3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 2,4-dimethylbenzyl chloride (0.020 mL; 0.13 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 10 mg of yellow colored 3-[4-(2,4-Dimethyl-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt. 1H NMR (dmso-d6, ppm): 9.40 (bs, 1H), 8.17 (bs, 2H), 7.00-7.40 (m, 3H), 4.28 (bs, 2H), 4.10 (bs, 2H), 2.95-3.35 (m, 8H), 2.34 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:78][O:79][C:80]1[CH:86]=[C:85]([O:87][CH:88]2[CH2:93][CH2:92][N:91]([CH3:94])[CH2:90][CH2:89]2)[CH:84]=[CH:83][C:81]=1[NH2:82].NC1C=CC=CC=1>O1CCOCC1.C(O)C>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:82][C:81]4[CH:83]=[CH:84][C:85]([O:87][CH:88]5[CH2:89][CH2:90][N:91]([CH3:94])[CH2:92][CH2:93]5)=[CH:86][C:80]=4[O:79][CH3:78])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1cc(OC2CCN(C)CC2)ccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Nc1ccccc1
Solvent: C1COCCO1
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1cc2c(cn1)cc(-c1cnn(C(=O)OC(C)(C)C)c1)n2C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 10 (50 mg, 0.108 mmole) was added cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %), then a solution of 2-methoxy-4-(1-methylpiperidin-4-yloxy)aniline (30.6 mg, 0.13 mmole, 1.2 eq) in dioxane (0.7 ml). Dioxane (0.5 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 4 hours. The reaction was cooled and diluted with ethyl acetate (11 mL). The solution was washed with water (4 mL). The organic layer was washed with brine, dried and evaporated. The residue was applied to two 1 mm 20×20 cm silica prep tlc plates, which were eluted with 10:1 ethyl acetate:2M ammonia in methanol. The product band was recovered with ethanol containing a little 2M ammonia in methanol. This gave a gum, 60 mg, containing (by NMR) ethanol (35%) and residual aniline. This gum was applied to one 1.5 mm alumina prep tlc plate (Merck) which was eluted with 30:1 dichloromethane:2-propanol. The product band was recovered with 30% 2-propanol in dichloromethane to give a gum, 36 mg. The residue was triturated with ether to give (after removal of the ether) the title compound as a solid (22 mg, 33%). 1H-NMR (CDCl3, 500 MHz): δ 1.50 (s, 9H), 1.69 (s, 9H), 1.84-1.93 (m, 2H), 2.02-2.09 (m, 2H), 2.29-2.39 (s, 3H over m, 2H), 2.71-2.80 (m, 2H), 3.87 (s, 3H), 4.26-4.32 (m, 1H), 6.53 (dd, J=2.52, 8.83 Hz, 1H), 6.56 (d, J=0.63 Hz, 1H), 6.58 (d, J=2.52 Hz, 1H), 6.67 (s, 1H), 7.45 (s, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.81 (d, J=0.63 Hz, 1H), 8.20 (d, J=0.63 Hz, 1H), 8.44 (d, J=0.95 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[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][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-(indan-2-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:6][C@H:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:2]=[O:3].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([OH:21])[CH2:14]2>>[C:7]1([C@@H:5]2[CH2:6][C@H:4]2[NH:1][C:2](=[O:3])[O:21][CH:15]2[CH:16]3[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]3)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: OC1CN2CCC1CC2
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)OC1CN2CCC1CC2
Yield: 28 %

Procedure:
Using general procedure A, (+/−)((1S,2R)-2-isocyanatocyclopropyl)benzene (117 uL, 0.780 mmol) and quinuclidin-3-ol gave (+/−) quinuclidin-3-yl(1R,2S)-2-phenylcyclopropylcarbamate (63 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 5.43 (br s, 1H), 4.77 (br s, 1H), 3.23 (dd, J=9.0, 14.0 Hz, 1H), 2.97-2.65 (m, 6H), 2.15-1.12 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.1, 140.7, 140.2, 128.5, 126.8, 126.3, 71.5, 55.7, 47.5, 46.6, 32.7, 25.6, 25.2, 24.5, 19.5, 16.2 ppm. Purity: >99.9% UPLCMS (210 nm); retention time 0.67 min; (M+1) 287.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:11](=[C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]=1[CH3:14])[NH:10][CH2:9][CH2:8]2)[CH3:3].[H-].[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:10]1[C:11]2[C:7](=[C:6]([CH3:22])[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[C:13]([CH3:14])[C:12]=2[NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:8][CH2:9]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.5 h
Yield: 120.4 %

Procedure:
N-(5-Dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (700 mg) was dissolved in DMF (7 ml) and NaH (P=60%, 160 mg) was added under a nitrogen atmosphere at 5° C. After stirring at the same temperature for 30 min, 1-iodooctane (240 mg) was added, which was followed by stirring at 30° C. for 3 hr. AcOEt (200 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=10/1−3/1) to give 500 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.C(Cl)(Cl)Cl>[CH3:21][O:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([S:19][CH3:20])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc(C#N)c(-c2cnc3c(O)cccn23)n1
Agent: [K+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COc1cccn2c(-c3nc(SC)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
150 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 3 mL of dimethylsulfoxide, then 293 mg of potassium carbonate and 40 μL of methyl iodide were added thereto, and stirred at room temperature for 30 minutes. The reaction solution was diluted in 200 mL of chloroform, and washed with water. Then, the organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of a mixed solvent of chloroform and methanol (chloroform:methanol=9:1), and solidified by hexane, to obtain 58 mg of 4-(8-methoxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-2] as a brown solid.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:35]
Reactant: CC(C)(C)Oc1nccnc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
After adding 5 ml of 4N hydrogen chloride/ethyl acetate to 334 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-fluorophenyl)ethanone, the mixture was stirred for 2 hours at room temperature. A 1N sodium hydroxide solution and saturated aqueous sodium bicarbonate solution were added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (260 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38](Br)[CH2:39][CH3:40]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:40][CH2:39][CH2:38][CH:21]4[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 3-[1-(t-butoxycarbonyl)piperidin-4-yl)]propyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22](=[CH2:26])[C:23](Cl)=[O:24]>>[CH3:26][C:22](=[CH2:21])[C:23]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:24]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: C=C(C)C(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-methylacryloyl chloride, there is obtained ethyl N-(2-methylacryloyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 334 (20), 305 (16), 293 (7), 194 (100), 167 (29), 69 (21), 41 (30);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[O:21][CH2:22][O:23]CCOC.Cl.[CH3:29]C(OC(C)=O)=O>>[C:22]([O:21][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:4]=1)(=[O:23])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COCCOCOc1cc(-c2ccc3nc(NC(C)=O)sc3c2)cnc1Cl
Agent: Cl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(OC(C)=O)c3)cc2s1
Temperature: 120 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A 10 mL flask was charged with N-(6-(6-chloro-5-((2-methoxyethoxy)methoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0683 g, 0.167 mmol), 5 mL TFE, a stirbar and 2.0 M HCl (0.251 ml, 0.502 mmol). The flask was fitted with a reflux condenser, heated in a 120° C. oil bath for 45 minutes and cooled. The solvent was removed in vacuo, and the residue was suspended in 3 mL EtOH, and heated with a 120° C. oil bath for 5 minutes and cooled. HPLC-MS showed that a significant amount of de-acetylation had occurred. The solvent was removed in vacuo, the residue was dissolved in 3 mL dry pyridine, and stirred under an Ar atmosphere with 100 mg 5 {acute over (Å)} activated powdered molecular sieves for 1 h. The slurry was filtered, and the molecular sieves were washed with 1 mL dy pyridine. The filtrate was treated with Ac2O (0.0474 ml, 0.502 mmol) and the flask was heated using a 70° C. oil bath for 3 h. An additional aliquot of Ac2O (0.0474 ml, 0.502 mmol) was added, and heating was continued for 2 h. The solution was cooled, and the solvent was removed in vacuo. The residue was treated with 3 mL dry TFE and concentrated in vacuo, and evacuated to 0.4 mm Hg over night. The solids were suspended in 2 mL 10% aqueous EtOH, and filtered. The solids were collected using a glass frit under position pressure nitrogen, and washed with EtOH (2×1 mL). The precipitate was initially dried under a stream of nitrogen, and then at 60° C. and <1 mm Hg for 1 h to afford 5-(2-acetamidobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl acetate (0.0314 g, 51.8% yield). 1H NMR (400 MHz, CF3CD2OD) δ ppm 2.15 (s, 3H) 2.25 (s, 3H) 7.50 (dd, J=8.51, 1.56 Hz, 1H) 7.67 (d, J=8.51 Hz, 1H) 7.71 (d, J=2.05 Hz, 1H) 7.84 (d, J=1.17 Hz, 1H) 8.31 (d, J=2.05 Hz, 1H). 13C NMR (101 MHz, CF3CD2OD) δ ppm 20.74 (s, 1 C) 23.29 (s, 1 C) 121.66 (s, 1 C) 122.72 (s, 1 C) 127.52 (s, 1 C) 133.32 (s, 1 C) 133.39 (s, 1 C) 134.61 (s, 1 C) 139.71 (s, 1 C) 144.50 (s, 1 C) 145.96 (s, 1 C) 146.19 (s, 1 C) 149.75 (s, 1 C) 162.07 (s, 1 C) 172.51 (s, 1 C) 173.47 (s, 1 C). HPLC-MS: retention time=1.95 min (97.0%@215 nm; 98.5% @254 nm; m/z=361.9, calculated for C16H12ClN3O3S+H+=362.0).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.Cl>CC(C)=O>[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncccc1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1c(NC(=O)OCc2ccccc2)ccc[n+]1[O-]
Temperature: 25 °C

Procedure:
To a solution of benzyl (2-aminopyridin-3-yl)carbamate in acetone was added a solution of m-chloro perbenzoic acid in acetone and the suspension was stirred at room temperature. After 2 hours the suspension was cooled to 0° C., HCl (2N in Et2O) was added, and the precipitate filtered. To the precipitate was added saturated aqueous NaHCO3, EtOAc and MeOH and the mixture stirred until dissolution. The solution was evaporated and the residue washed with water until the pH of the filtrate was neutral. The solid was dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[OH-].[Na+].ClCCl>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:25])([F:24])[F:26])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 150 °C
Yield: 52 %

Procedure:
The mixture of 3-amino-6-chloropyridazine (0.6487 g, 5 mmol) and piperazin-1-yl-(2-trifluoromethylphenyl)methanone (1.936 g, 7.5 mmol) in NMP (30 mL) was heated at 150° C. for 24 hours. To the reaction mixture was added 10 mL of 1 N NaOH and 100 mL of dichloromethane, and the aqueous layer was separated and extracted twice by 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, evaporated to dryness. The crude compound was purified by flash chromatography to give yellow solid. Yield 52%, 1.37 g.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:33][C:34]1([F:44])[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:33][C:34]1([F:44])[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][C:22]2[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:42])[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)CC1CCC(F)(F)CC1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)CC1CCC(F)(F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:13]([CH3:18])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 4-(adamantan-1-yl)-2-methylphenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (3.63 g, 23.29 mmol) and ethyl chloroacetate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate as a white solid (2.6 g, 95.9% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:7][C:8]([F:26])([F:27])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 95.3 %

Procedure:
12.73 ml (12.73 mmol) of a 1 M solution of lithium aluminum hydride in THF are added dropwise to a solution of 6.24 g (21.21 mmol) of ethyl 4′-trifluoromethylbiphenyl-4-carboxylate from Example 21A in 60 ml of dry THF at 0° C. After the reaction is complete, the mixture is mixed with saturated ammonium chloride solution and taken up in ethyl acetate, and the organic phase is separated off and dried over sodium sulfate. After filtration, the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). 5.1 g (20.21 mmol, 95% yield) of a colorless solid are obtained.