Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: O=C1Cc2[nH]c3cc(F)ccc3c2CCN1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc2c3c([nH]c2c1)CCNCC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask containing THF (10 mL) at −78° C. under argon was added a 1 M solution of iBu2AlH in CH2Cl2 (16.3 mL). After 5 min, a solution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0.175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture was allowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenched with MeOH (4.5 mL). It was partitioned between CH2Cl2 and aqueous 1 M KO2CC(OH)C(OH)CO2Na. The CH2Cl2 extracts were washed with brine, dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography (92.5:7.5 CH2Cl2/satd NH3 in MeOH) to give the free amine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH (4.0 mL) at rt under argon was mixed with a solution of fumaric acid (0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution was stirred overnight at rt. The MeOH was evaporated. The residue was dissolved in hot MeOH, and the salt was permitted to crystallize. The crystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40 (1H), 3.11 (4H), 2.91 (4H); Anal. C, 63.90; H, 5.83; N, 10.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[N:15]1[CH:16]=[C:12]([CH2:10][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[NH:13][CH:14]=1
Reactant: O=Cc1c[nH]cn1
Reactant: COc1ccccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 2-methoxyaniline (0.62 g, 5 mmol) in methanol (5 ml) was added 4-formylimidazole (0.48 g, 5 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.28 g, 7.5 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by recrystallisation from heptane/ethyl acetate to yield off-white crystals (0.85 mg, 84%); MS (ISP): 204.3 ((M+H)+.).
Reaction SMILES: [N:1]([CH:4]([O:8][CH3:9])[C:5](O)=[O:6])=[N+:2]=[N-:3].S(Cl)([Cl:12])=O>>[N:1]([CH:4]([O:8][CH3:9])[C:5]([Cl:12])=[O:6])=[N+:2]=[N-:3]
Reactant: COC(N=[N+]=[N-])C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(N=[N+]=[N-])C(=O)Cl
Temperature: 80 °C

Procedure:
A solution of 2-azido-2-methoxyacetic acid (4.2 g.) in thionyl chloride (10 ml.) is heated in an oil bath maintained at 80°C. for 20 minutes. After cooling to room temperature, the mixture is evaporated in vacuo to remove excess thionyl chloride and the residue is distilled to yield 2-azido-2-methoxyacetyl chloride (2.26 g.) as a water-white liquid (b.p. 64°-66°C./27 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6].[C:14](O)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:14]([CH3:15])=[O:16])[C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[S:6]
Reactant: CC(=O)O
Reactant: COc1cc(N)c(C)cc1C(O)=S
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(NC(C)=O)c(C)cc1C(O)=S
Temperature: 85 °C

Procedure:
260 g of 2-methoxy-4-amino-5-methyl-thio-benzoic acid and 520 ml of acetic acid are placed in a 2 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. 123 ml of acetic anhydride (density 1.082) is poured in slowly. The temperature rises to reach 40° C. The reaction mixture is heated for 1 hour 30 at 85° C., cooled and poured over 1,000 g of ice and 1,000 ml of water. The precipitate which forms is filtered, washed with water and dried in an oven at 50° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 171.1 using 5-bromo-6-chloro-N-(6-((trifluoromethyl)thio)pyridin-3-yl)nicotinamide (Stage 279.2) and (R)-pyrrolidin-3-ol to afford an off-white powder. HPLC (Condition 4) tR=5.53 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=463.1 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)[C:10]1=[O:24])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[CH2:13][CH2:12][C:11]2([C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)[C:10]1=[O:24]
Reactant: O=C1N(OCc2ccccc2)CCC12CCOc1ccc(F)cc12
Agent: [Pd]
Solvent: CO
Product: O=C1N(O)CCC12CCOc1ccc(F)cc12
Reaction time: 18 h

Procedure:
A solution of 1'-benzyloxy-2,3-dihydro-6-fluoro-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one (1.4 g) in methanol (75 mL) containing 10% palladium on carbon (300 mg) was stirred vigorously under hydrogen gas (1 atm). After 18 hours, more palladium on carbon (300 mg) was added, and the mixture was then filtered after being stirred under hydrogen gas for a further 20 minutes. The filtrate was concentrated in vacuo, and the residue purified by silica gel chromatography, eluting with ethyl acetate, to afford the title compound as a white crystalline solid, 780 mg, m.p. 208°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.N#N>C(OCC)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[C:4]([C:21]([F:24])([F:22])[F:23])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2C(F)(F)F)CC1
Agent: O=[Pt]=O
Agent: N#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 62.6 %

Procedure:
A solution of tert-butyl 4-(4-fluoro-2-(tri-fluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.29 g, 3.74 mmol) in ethyl acetate (20 mL) andacetic acid (0.22 mL) was sparged with N2. Platinum dioxide (84 mg) was added and the resulting suspension was sparged with N2 for 5 min. The mixture was placed under an H2 atmosphere at 1 atm. After 18 h the reaction was sparged with N2 for 15 min, filtered through a diatomaceous earth pad, recharged with platinum dioxide (100 mg) and stirred under a 1 atm hydrogen atmosphere. The filtration and recharging of the reaction was repeated thrice over the next 64 h. The reaction was filtered through diatomaceous earth. The obtained filtrate was washed with sodium bicarbonate solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0% to 100% EtOAc in hexanes) to provide tert-butyl 4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as a yellow oil (0.813 g, 63%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.20 (m, 3H), 4.27-4.22 (m, 2H), 3.07-2.99 (m, 1H), 2.85-2.75 (m, 2H), 2.04-1.46 (m, 13H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:39][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([CH2:31][N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:37][CH:36]=4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: CN1CCN(Cc2ccc(CN)cc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(NCc4ccc(CN5CCN(C)CC5)cc4)sc3c2)ccn1
Temperature: 80 °C

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25 mg, 0.072 mmol, 1.0 eq) in 2 mL of NMP was added (4-((4-methylpiperazin-1-yl)methyl)phenyl)methanamine (23 mg, 0.108 mmol, 1.5 eq) and DIPEA (37 μL, 0.216 mmol, 3.0 eq) and reaction mixture heated at 80° C. in oil bath for 12 hours. Thereafter, the product was purified via reverse phase HPLC. LC/MS (m/z) [503.1] (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:34]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol) in pyridine (5 mL) was added dropwise 2,2-dimethylpropanoyl chloride (49 μL, 0.399 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and precipitated from ethyl acetate/hexane to give the title compound (90 mg, 50%) as a white powder.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:32])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([O:22][CH3:23])[C@H:18]([NH:24]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:35]=1B(O)O>>[NH2:24][C@H:18]1[C@@H:19]([O:22][CH3:23])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:32])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[C:34]([F:33])=[CH:39][C:38]([O:40][CH3:41])=[CH:37][C:36]=3[F:42])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3csc(Br)n3)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](OC)CO3)cs2)c(F)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluoro-4-methoxyphenyl)boronic acid gave 265. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 7.94 (s, 1H), 7.08-6.97 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 1H), 3.71 (s, 3H), 3.47-3.38 (m, 1H), 3.31-3.22 (m, 1H), 3.04 (s, 3H), 2.49-2.36 (m, 1H), 1.75-1.49 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=[O:19])[CH2:13]1.C(N(C(C)C)CC)(C)C>>[NH2:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=[O:19])[CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-3-nitropyridin-2-amine (0.175 M, 35 mL, 6.125 mmol) was added to (R)-piperidine-3-carboxylic acid, prepared during the previous step, followed by diisopropylethyl amine (2.275 mL, 12.25 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to afford (R)-1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylic acid which was used for the next step without further purification.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2[CH2:54][C:55]#[N:56])O1>CCCCCCC.CCOC(C)=O>[CH3:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH2:54][C:55]#[N:56]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2ccccc2CC#N)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1ccccc1CC#N

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile (CAS RN 325141-71-7) after a reaction time of 6 days and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow solid (69%). MS (ESI): m/z=224.118 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16]([NH2:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].CC(C)([O-])C.[K+]>O1CCOCC1>[CH3:18][CH:17]1[CH2:19][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[C:13]([CH3:14])[NH:21][C:16]1=[O:20]
Reactant: CC(=O)Cc1ccc(-n2ccnc2)cc1
Reactant: C=C(C)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1=C(c2ccc(-n3ccnc3)cc2)CC(C)C(=O)N1

Procedure:
Similar to example 1, the reaction is carried out with 3 g 1-[4-(1-imidazolyl)-phenyl]-2-propanone, 30 ml 1,4-dioxane, 1.45 g methacrylic acid amide and 1.74 g potassium tert-butoxide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:18])=[CH:5][N:4]=[N:3]1
Reactant: C1CCC2OC2C1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nncc1[C@H]1CCCC[C@@H]1O
Yield: 4.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 8a by using 1-methyl-1H-1,2,3-triazole (2.00 g, 24.1 mmol), n-butyl lithium (2.69 M solution in hexane; 9.0 mL, 24.2 mmol), cyclohexene oxide (2.40 g, 24.5 mmol) and THF (70 mL), to yield the title compound (197 mg, 4.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:8]([Cl:17])[C:7]([Cl:18])=[C:6]([C:19]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=1)[CH:2]=[CH2:3].CCOCC>CCCCCC>[CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([Cl:17])[C:7]([Cl:18])=[C:6]([C:19]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)OCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=CCc1cc(C(=O)c2ccnn2C)c(Cl)c(Cl)c1OCC(=O)O
Yield: 88.9 %

Procedure:
1.44 g of ethyl [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetate are treated in the same manner as described in Example 18 except that a mixture of ether and hexane is used as the crystallization solvent. 1.19 g of [6-allyl-2,3-dichloro-4-(1-methyl-5-pyrazolylcarbonyl)phenoxy]acetic acid are obtained as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:42][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(OCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and 1-benzyl-4-hydroxymethylpiperidine (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24% yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19H22FNO: 299.1684; Found: 299.1685.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[C:9]([CH3:18])[N:8]=[C:7]([S:19][CH3:20])[N:6]=1)([CH3:3])[CH3:2]>C(O)(=O)C>[CH:1]([N:4]1[C:5]2[N:6]=[C:7]([S:19][CH3:20])[N:8]=[C:9]([CH3:18])[C:10]=2[CH:11]=[CH:12][C:13]1=[O:14])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C)nc(SC)nc1NC(C)C
Solvent: CC(=O)O
Product: CSc1nc(C)c2ccc(=O)n(C(C)C)c2n1
Reaction time: 6 h
Yield: 56.9 %

Procedure:
(E)-Ethyl 3-(4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl)acrylate (2.5 g, 8.46 mmol) was dissolved in acetic acid by gentle warming. Sample was placed in microwave reactor for 6 h at 180° C., 300 W, and 200 PSI. The product was purified by silica gel column chromatography eluting with 20% ethyl acetate/hexane. Desired fractions were combined and reduced into 8-isopropyl-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a yellow powder (1.20 g, 57% yield) which was then dried under heavy vacuum overnight. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=9.6, 1H), 6.58 (d, J=9.6, 1H), 5.84 (br s, 1H), 2.65 (s, 3H), 2.63 (s, 3H), 1.63 (d, J=6.8, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:20]=[O:21]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Cl)cc12
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To stirred dimethylformamide (20 mL) at 0° C. was added dropwise phosphorus oxychloride (4.6 mL, 49 mmol). The mixture was stirred for 10 min and a solution of 5-chloroindole (5.0 g, 33 mmol) in dimethylformamide (5 mL) was added dropwise. The mixture was heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide (5.9 g, 148 mmol) in water (20 mL). The mixture was heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice (100 mL) and filtered. The filter cake was recrystallised (methanol) to give the product as a white solid (3.5 g, 59%): mp 215-216° C.; Found: C, 60.13; H, 3.40; N, 7.75%. C9H6ClNO requires: C, 60.19; H, 3.37; N, 7.79%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>CCO>[CH2:25]([N:17]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[NH:34])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 3-(5-amino-1H-indol-3-yl)cyclohexyl(ethyl)carbamate (0.62 g, 1.73 mmol) in dry EtOH (25 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.00 g, 3.47 mmol) and the reaction left to stir at room temperature for 48 hours. The solvent then was evaporated and the mixture dissolved in dichloromethane (20 mL) and washed with 2N NaOH (10 mL). The organic layer was extracted and evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to give the title compound as a yellow solid (0.80 g, quantitative). 1H-NMR (DMSO-d6) δ 1.04 (t, 3H, J=6.9 Hz), 1.36 (s, 9H), 1.44-1.68 (m, 5H), 1.84-2.04 (m, 3H), 3.05-3.20 (m, 2H), 3.42-3.53 (m, 1H), 4.19-4.26 (m, 1H), 6.21 (s, 2H), 6.64 (dd, 1H, J=1.8, 8.4 Hz), 6.92 (s, 1H), 7.09 (dd, 1H, J=3.6, 5.1 Hz), 7.26 (s, 1H), 7.29 (s, 1H), 7.58 (d, 1H, J=5.1 Hz), 7.70 (d, 1H, J=3.9 Hz), 10.67 (s, 1H). ESI-MS (m/z, %) 467 (MH+, 100)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:1][S:2]([O:30][CH:15]([CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])[CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CC(C)[Si](OCCCC(O)COCc1ccccc1)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCCC(COCc1ccccc1)OS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.35 mL of methanesulfonyl chloride was added dropwise to a solution of 1.5 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol and 0.7 mL of triethylamine in 15 mL of ethyl acetate at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 100 mL of ethyl acetate and 50 mL of 1 mol/L hydrochloric acid. The organic layer was fractionated. The obtained organic layer was successively washed with 50 mL of a saturated sodium hydrogen carbonate aqueous solution, 50 mL of water and 50 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.8 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate in the form of a colorless oily product.