Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[CH:8][C:7]2[C:10]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[O:11][CH2:12][C:6]=2[CH:5]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]>CN(C=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]2([C:40]([F:43])([F:42])[F:41])[O:1][N:2]=[C:3]([C:4]3[N:9]=[CH:8][C:7]4[C:10]5([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]5)[O:11][CH2:12][C:6]=4[CH:5]=3)[CH2:39]2)[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ncc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ncc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6′-((hydroxyimino)methyl)-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-carboxylate (0.15 g, 0.49 mmol, 1 eq) in DMF (5.0 mL) was added NCS (84 mg, 0.63 mmol, 1.2 eq) at room temperature in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 45° C. for 1 hour. After chloro intermediate formation, 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (0.163 g, 0.63 mmol, 1.2 eq.) was added followed by addition of KHCO3 (79 mg, 0.79 mmol, 1.5 eq). Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere. After complete consumption of chloro intermediate, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.2 g, crude). Crude compound was purified by column chromatography in 100-200 mesh size silica gel. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as off white solid (0.14 g, 51%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.88 (d, J=18.4 Hz, 1H), 4.12-4.16 (m, 2H), 4.25 (d, J=18.16 Hz, 1H), 4.35 (dd, J1=3.3 Hz, J2=9.34 Hz, 2H), 5.12 (s, 2H), 7.57 (d, J=6 Hz, 2H), 7.90 (s, 1H), 8.70 (s, 1H). LC-MS (m/z): 562.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[N:3]=1.[C:15]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:15]([CH:19]1[CH2:24][CH2:23][C:22]2([O:14][CH:11]([CH2:10][NH:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:12][O:13]2)[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(C)nc(NCC(O)CO)n1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C)nc(NCC2COC3(CCC(C(C)(C)C)CC3)O2)n1
Yield: 90 %

Procedure:
3-(4,6-dimethylpyrimid-2-ylamino)-propane-1,2-diol (4.0 g, 20 mmol), 4-t-butyl cyclohexanone (3.08 g, 20 mmol) and p-toluenesulfonic acid (4.3 g, 22 mmol) in 50 ml benzene were refluxed on a water trap for 1 hour. The reaction mixture was washed twice with saturated aqueous sodium carbonate (50 ml), dried with magnesium sulphate and evaporated in vacuum. Kugelrohr--distillation of the resulting oil yielded 6.0 g of a colourless oil (b.p. 200° C./0.2 mbar) which was recrystallised from light petroleum to yield 5.0 g of colourless crystals (m.p. 121°-124° C.). GLC-MS analysis indicates an approximately 1:1 mixture of diastereoisomers (cis/trans).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(Nc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 21 h
Yield: 14 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(N(CC)CC)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:18])[CH2:14][C:15]([O:17][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:16])[CH2:10][C:9]1=[O:19])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h

Procedure:
The crude carboxylic acid is suspended in anhydrous acetonitrite (150 ml) and treated with p-nitrobenzyl bromide (7.56 g, 35 mμol) and triethylamine (4.9 ml, 35 mμol). The resulting solution is kept at room temperature for 2 days and then in a refrigerator for 3 days. The reddish orange solution is evaporated under vacuum and the residue shaken with ethyl acetate (100 ml, 2×50 ml) and filtered to remove triethylammonium bromide. The ethyl acetate filtrate is washed with water (3×100 ml) and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to an amber oil (13.62 g). Crystallization from diethyl ether affords N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]azetidin-2-one (6.84 g) as an off-white powder. Chromatography of the mother liquors on a silica gel column using 1:1 toluene-ethyl acetate as eluting solvent affords addition product (3.14 g) as an oil which solidifies.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[CH:9]=O.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[C:16]([F:18])[CH:17]=1>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]3[CH:9]=[N:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1cc(F)cc(Cl)c1
Solvent: CN1CCCC1=O
Product: Fc1cc(Cl)cc(-n2ncc3c(I)ccnc32)c1
Temperature: 185 °C
Yield: 78.8 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 4-iodo-2-fluoro-3-formylpyridine (714.6 mg, 2.85 mmol), (3-chloro-5-fluorophenyl)hydrazine (457.6 mg, 2.85 mmol) and anhydrous NMP (8.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1 h, 45 min. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 839 mg (76.9%) of the title compound (contains approximately 45% of the hydrazone intermediate) as a dark red solid. LC/MS (Condition B): ret. T=4.8 min, (M+H)+ 373.87.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:19]=[C:17]([CH3:18])[CH2:16][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:8](=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=c1cccccc1N1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)CN1CCN(c2cccccc2=O)CC1
Yield: 42 %

Procedure:
A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one (12.4 g), described in Example 2), 1-chloro-2-propanone (5.55 g), potassium carbonate (11.04 g) and acetonitrile (120 ml) was refluxed for 4 hr and filtered. Chloroform and water were added to the filtrate. The organic phase was separated, washed with water, dried and evaporated. The residue was chromatographed on silica gel using methanol-ethyl acetate and the eluates were evaporated to give an oil (6.21 g) of 2-[4-(2-oxopropyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (VII; R1, R2, R3 and R4 =H and Alk=C--CH2): ir(CHCl3) 3660, 3360, 1720, 1710, 1660 and 1560 cm-1 ; uv max(MeOH) 351 (ε=9310), 255 (ε=13915) and 221 nm(ε=11750); nmr(CDCl3) δ2.12 (s, 3H), 2.62 (t, 4H), 3.21 (s, 2H), 3.35 (s, 4H) and 6.40-7.10 (m, 5H); and Anal. Calcd for C14H18N2O2 : C, 68.26% H, 7.37% N, 11.37% and Found: C, 67.33% H, 7.59% N, 11.44%.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:31][CH2:30][C:27]([CH2:32][C:33]([O-:35])=[O:34])([CH2:28][CH2:29]4)[O:26][CH2:25]5)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:29][CH2:28][C:27]([CH2:32][C:33]([OH:35])=[O:34])([CH2:30][CH2:31]4)[O:26][CH2:25]5)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)[O-])(CC4)OC5)cc3)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-(4-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (159 mg, 0.325 mmol) in THF (3 ml) at room temperature was added 1N LiOH (0.391 ml, 0.391 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with 1N HCl (0.391 ml, 0.391 mmol) and diluted with H2O. The THF was removed in vacuo to afford off-white slurry. The slurry was stirred for 15 min then filtered. The filter cake was washed with H2O, heptane, and dried to afford the title compound as off-white sold (135 mg, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CI
Reactant: O=c1[nH]c2ccccc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-quinolin-2-one (0.21 g, 0.6266 mmol) in DMF (5.0 mL) is added HNa (30.1 mg, 60%, 0.752 mmol) and IMe (120.1 mg, 0.846 mmol) at 0° C. After the mixture is stirred for two hours at 0° C., the mixture is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (95/5), t give the titled intermediate as a solid (78 mg, 35.8%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[I:11][C:12]1[N:13]=[C:14]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)[N:15]2[C:20]=1C(=O)NC=N2>N1C=CC=CC=1>[NH2:1][C:5]1[C:20]2=[C:12]([I:11])[N:13]=[C:14]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)[N:15]2[N:2]=[CH:3][N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1H-1,2,4-triazole (0.881 g, 0.0128 mol) in pyridine (3.00 mL) was charged with POCl3 (0.396 mL, 0.00425 mol) and stirred at rt for 15 min. To this mixture was drop wise added methyl trans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.570 g, 0.00142 mol) in pyridine (6.00 mL) and stirred at rt for an additional 2.45 h. The reaction was quenched with excess 2 M of NH3 in i-PrOH (40.00 mL) at 0° C. and allowed to stir at rt for an additional 3 h. The reaction was concentrated in vacuo and partitioned between EtOAc and sat. NaHCO3 and, separated. The aqueous was washed with EtOAc (3×) and the combined organic fractions were washed with brine (1×). The aqueous was re-extracted with CHCl3 (3×) and the organic was added to the EtOAc fractions. The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude brown/red solid was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 438 mg, (76% yield) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.54 (m, 2H), 1.55-1.71 (m, 2H), 1.92-2.07 (m, 4H), 2.35-2.46 (m, 1H), 3.06-3.19 (m, 1H), 3.61 (s, 3H), 6.77 (br. s., 1H) 7.86 (s, 1H) and 8.44 (br. s., 1H); MS (ES+): m/z 401.85 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][N:12]([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][Sb-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[Na+]>CO>[F:20][Sb-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:12]([CH3:19])([CH3:11])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN(C)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C[N+](C)(C)c2ccccc2)cc1

Procedure:
4,698 g (0.03 mol) of p-methoxybenzyl chloride and 3,638 g (0.03 mol) of N,N-dimethylaniline were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporated in vacuo and ether/water was added to the residue to extract unreacted reactans in the etherial layer. To the aquous layer containing the ammonium chloride was added 7.77 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the titled compound.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:19])([F:18])[O-:17].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[C:3]1([CH:2]([O:17][C:16]([F:19])([F:18])[F:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: [O-]C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Solvent: O
Product: FC(F)(F)OC(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Bromodiphenylmethane, 20.7 g (0.084 mol), was added portionwise at 25° to a stirred solution of 0.093 mole of tris(dimethylamino)sulfonium trifluoromethoxide (prepared as in Example 1) in 75 mL of acetonitrile. The reaction mixture was stirred for 18 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and then distilled to give 8.34 g of trifluoromethyl diphenylmethyl ether as a colorless oil: bp 83.3° (0.7 mm); 1H NMR (CDCl3) δ6.17 ppm (s, 1H), 7.27 ppm (m, 10H); 19F NMR (CDCl3) δ-58.4 ppm (s). Anal. Calcd. for C14H11F3O: C, 66.66; H, 4.40; F, 22.60. Found: C, 66.82; H, 4.57; F, 22.39.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC1=CCCCO1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=C(COCc2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran in 100 ml of dimethylformamide was added dropwise, whilst ice-cooling, to a mixture of 2.18 g of a 55% w/w suspension of sodium hydride in mineral oil and 100 ml of dimethylformamide. The mixture was stirred at room temperature for 60 minutes, after which 6.33 g of benzyl chloride were added. The reaction mixture was stirred for 16 hours, and then poured into 1 liter of water and extracted twice with ethyl acetate. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue, 13 g, was subjected to column chromatography through 200 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 4:100 to 5:100 by volume gave 9.40 g of the title compound as a colorless oily substance, boiling at 125°-130° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:27])=[CH:29][CH:30]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 2-aminobenzoate (5 g, 33.1 mmol) and pyridine (5.3 g, 66 mmol) in dichloromethane (100 mL) was added 4-dimethylaminopyridine (0.2 g, 1.6 mmol). The mixture was cooled to 0° C. and treated with 4-tert-butylbenzoyl chloride (6.5 g, 33.1 mmol). After stirring overnight, the reaction mixture was diluted with dichloromethane (100 mL)and washed twice with 1 M aqueous citric acid (100 mL). The organic layer was then washed sequentially with water (100 mL) and 5 N aqueous HCl. It was dried over MgSO4, filtered and concentrated in vacuo to give 10.68 g (quantitative) of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:7]([C:19]([OH:21])=O)=[CH:6]2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([NH:31][C:19]([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:11][CH:10]=3)=[O:21])=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Reactant: Nc1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)nc1)c1cc2cc(C(F)(F)F)ccc2n1Cc1ccncc1
Yield: 74.4 %

Procedure:
The process is carried out according to the method described in example 3.1, using 0.5 g (1.56 mmol) of 5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-indole-2-carboxylic acid, prepared in step 16.1, and 0.22 g (1.72 mmol) of 2-chloro-5-aminopyridine. 0.5 g of the expected product is isolated by this method, which product is used as it is in the rest of the synthesis.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C([Li])CCC.[CH:18]([CH:20]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[OH:19][CH:18]([C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[CH:20]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:23]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:22][CH2:21]1
Reactant: c1ccc(C2SCCCS2)nc1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)CCC1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(O)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,3-dithian-2-yl)pyridine (2.86 g, 14.51 mmol) in THF (80 ml) was added n-butyllithium (6.77 ml, 2.5 M, 16.93 mmol) by syringe at −78° C. The mixture was stirred at −78° C. for 0.5 h, then tert-Butyl 5-formyl-2-phenylpiperidine-1-carboxylate (3.5 g, 12.10 mmol) in THF (15 ml) was added via syringe. The mixture was stirred at −78° C. for 1 h, then quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. LC-MS m/e 487.03 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30]>CN1CCCC1=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH:30][C:2]1[C:3]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[N:7]=1
Reactant: CCCc1nn(C)c2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc12
Reactant: COc1ccc(CN)cc1Cl
Solvent: CN1CCCC1=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(-c3ccc(C(=O)OC)cc3)nc12
Yield: 87.8 %

Procedure:
A mixture of 1.8 g of methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylcarboxylate (“B”) and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone is heated at 110° for 4 hours. After cooling, it is worked up in the customary manner. 2.2 g of methyl 4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]benzoate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:21])[CH2:13][CH2:12][CH2:11][N:10]([C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: OC1(c2cccc(Cl)c2)CCCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a stirred solution of 13 parts of 3-(3-chlorophenyl)-1-(phenylmethyl)-3-piperidinol in 270 parts of methylbenzene were added dropwise 10.9 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux temperature. After cooling to room temperature, the whole was washed with water and hydrochloric acid. The organic layer was dried, filtered and evaporated, yielding 7 parts (58%) of ethyl 3-(3-chlorophenyl)-3-hydroxy-1-piperidinecarboxylate as a residue (intermediate 50).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[N:9]([CH2:29][O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[N:17]([CH2:26][O:27][CH3:28])[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])=O)C.O.[NH2:33]N.C(O)(=O)C>O>[CH3:28][O:27][CH2:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]([CH2:29][O:30][CH3:31])[C:8]([C:6]1[N:5]=[CH:4][NH:2][N:33]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19]
Reactant: COCN(c1cccc2cc(C(=O)/N=C/N(C)C)n(COC)c12)S(=O)(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylene]-1-(methoxymethyl)-7-[(methoxymethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.06 g), hydrazine monohydrate (0.22 mL) and acetic acid (10 mL) was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried to give the title compound (0.99 g, quantitative) as colorless crystals. melting point 97-99° C.