Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[NH2:11])[CH3:2].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>C(O)C>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:12]1[CH3:13])[CH3:2]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCNc1ccc(F)cc1N
Solvent: CCO
Product: CCn1c(C)nc2cc(F)ccc21

Procedure:
To 2.92 g of N-ethyl-4-fluorophenylenediamine in 15 ml of ethanol was added 3.49 ml of triethylorthoacetate and the reaction refluxed for 6 hours. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was separated, dried and the solvent removed to give 2.87 g of product as a brown oil.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([CH3:73])[C@H:70]([C:74]([N:76]2[CH2:81][CH2:80][N:79]([CH2:82][CH2:83][OH:84])[CH2:78][CH2:77]2)=[O:75])[CH2:69]1>C(#N)C>[OH:84][CH2:83][CH2:82][N:79]1[CH2:80][CH2:81][N:76]([C:74]([C@@H:70]2[CH2:69][C@H:68]([S:67][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:72][N:71]2[CH3:73])=[O:75])[CH2:77][CH2:78]1
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(CCO)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 41.6 %

Procedure:
600 μl of diphenylphosphoryl chloride and 510 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 1000 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 10 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1800 μl of diisopropylethylamine and a solution of 1680 mg of (2S,4S)-4-mercapto-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-1-methylpyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 52) in 5 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was eluted first with 55% v/v aqueous methanol and then with 60% v/v aqueous methanol. Those fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and lyophilized, to give 710 mg of the title compound, as a powder.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([O:25][CH2:26][C@@H:27]2O[CH2:28]2)(=O)=O)=CC=1>CN(C=O)C>[O:2]1[C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4][CH2:28][C@@H:27]1[CH2:26][OH:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC[C@H]1COc2ccccc2O1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-glycidyl tosylate (22.8 g, 0.10 mol) was added and the reaction was stirred at 60° C. for 24 h. The reaction was cooled to room temperature and diluted with ice water (1 L) and extracted with diethyl ether (4 times). The combined organic solution was washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporated in vacuo to yield a white solid which was purified by flash column chromatography (DCM:Methanol—50:1) to yield ((2S)-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol as a solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:26][C:27](=[O:29])[CH3:28])=[C:7]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:11][C:10]=2[CH3:25])[CH:8]=1.[F:30][C:31]1[CH:36]=[C:35]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[CH:34]=[CH:33][C:32]=1[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:27]([NH:26][C:6]1[C:7]([C:9]2[C:10]([CH3:25])=[CH:11][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:13][C:14]=2[CH3:15])=[CH:8][C:3]([CH2:2][N:37]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:39])=[O:40])[C:35]2[CH:34]=[CH:33][C:32]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[C:31]([F:30])[CH:36]=2)=[CH:4][CH:5]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CC(=O)Nc1ccc(CO)cc1-c1c(C)cc(OCC2(O)CCSCC2)cc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2ccc(NC(C)=O)c(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of N-{5-(hydroxymethyl)-4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-2-yl}acetamide (148 mg, 0.36 mmol), ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (157 mg, 0.40 mmol) and triphenylphosphine (189 mg, 0.72 mmol) in tetrahydrofuran (4 mL) was added diethyl azodicarboxylate (40% toluene solution, 0.33 mL, 0.72 mmol) under stirring at room temperature, and the mixture was stirred for one day. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/3) to give the title compound (262 mg, yield 83%) as a colorless amorphous powder.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ncccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)[CH3:33]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:44][S:41]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:32][CH3:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CCOc1ccc(S(N)(=O)=O)cc1
Product: CCOc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-ethoxybenzenesulfonamide [Chem. Ber., 1982, 25, 1838]: 1H-NMR (CDCl3) δ 7.74 (2H, d, J=8.9 Hz), 7.47-7.24 (9H, m), 6.95-6.92 (21H, in), 6.40 (1H, br.s), 4.07 (2H, q, J=7.1 Hz), 3.53-3.46 (2H, m), 2.86 (2H, t, J=6.8 Hz), 2.33 (3H, s), 2.26 (3H, s), 1.42 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH3:40][N:41]([CH3:48])[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:41]([CH3:48])[CH3:40])[CH2:43][CH2:44]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CN(C)C1CCNCC1
Product: Cc1ccccc1-c1nc(N2CCC(N(C)C)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 86.4 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Example 19; 85.9 mg) was reacted with 4-(dimethylamino)piperidine (23.1 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(dimethylamino)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (80.5 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH2:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[CH3:2].C(O)(=O)C>O>[CH2:19]([O:18][C:9]1[CH:10]=[C:11]([CH3:17])[CH:12]=[C:13]2[C:8]=1[CH:7]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:26])[NH:14]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)Cc1c(OCc2ccccc2)cc(C)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
The solution of 30.6 g of the thus prepared 2-benzyloxy-4-methyl-6-nitrophenyl pyruvic acid ethyl ester in a composition of 250 ml glacial acetic acid and 15 ml water is brought to boiling. The heating is removed and the solution is mixed with 33.6 g zinc dust in such a manner that the boiling temperature is maintained. 5.6 g zinc dust is additionally added and heated to boiling for 30 minutes. The mixture is aspirated from the excessive zinc dust while still hot. The filter cake is washed well with glacial acetic acid and ethanol. The precipitate resulting during the cooling of the filtrate is aspirated and dried. There is obtained 15.7 g (~59% of theory) 4-benzyloxy-2-ethoxycarbonyl-6-methylindole; m.p. 167°-168° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2].[OH:12][CH2:13][C:14](C)(CO)[CH3:15].C(#N)C=C>>[C:13]([O:11][CH:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:12])[CH:14]=[CH2:15]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)C(O)OCCC#N
Solvent: C=CC#N
Product: C=CC(=O)OC(OCCC#N)C(C)(C)C

Procedure:
Following the procedures described in Example 1, cyanoethoxyneopentanol (bp 132°-140° C./2 mm Hg) is prepared from neopentyl glycol and acrylonitrile, acrylation of which gives the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Cl:11])=[CH:7][N:6]=1)=[O:4].[Cl-].[Li+].C(=O)(O)[O-].[Na+]>C(#N)C.CN(C=O)C.O>[Cl:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 160 °C
Yield: 61.3 %

Procedure:
To a solution of methyl-5-chloropyrazine-2-carboxylate (120 mg, 0.70 mmol) in a mixture of acetonitrile (2 mL) and DMF (1 mL) was added lithium chloride (295 mg, 6.95 mmol). The suspension was heated to 160° C. for 5 mins in a Smith creator microwave after which time the reaction was diluted with water (10 mL). Saturated sodium bicarbonate solution (20 mL) was added and the aqueous layered extracted twice with ethyl acetate (30 mL). The combined organics were discarded and the aqueous layer adjusted to pH 4 with 1N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (20 mL) and the combined organics washed with water (2×20 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed to give the title compound as a colourless solid (68 mg).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1Cl>C(O)(C)C>[ClH:12].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nn1ccc2ccccc21
Reactant: Clc1ccncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: Clc1cnccc1Nn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indol-1-amine and 3,4-dichloropyridine hydrochloride in isopropanol at 100° C. for 4 hours in substantially the same manner as in Example 1, m.p.>230° C.
Reaction SMILES: [ClH:1].Cl.N1([CH2:9][CH:10]([C:28]2([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)CCNCC1.FC(F)(F)OC1C=C(C2C=CC=C(C(C3(O)CCCCC3)C[N:52]3[CH2:57][CH2:56][N:55](C(OC(C)(C)C)=O)[CH2:54][CH2:53]3)C=2)C=CC=1>>[ClH:1].[ClH:1].[N:52]1([CH:33]2[CH2:32][CH2:31][CH2:30][CH2:29][C:28]2([CH:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:25])[F:27])[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH3:9])[OH:34])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3cccc(OC(F)(F)F)c3)c2)C2(O)CCCCC2)CC1
Reactant: OC1(C(CN2CCNCC2)c2cccc(-c3cccc(OC(F)(F)F)c3)c2)CCCCC1
Agent: Cl
Product: CC(c1cccc(-c2cccc(OC(F)(F)F)c2)c1)C1(O)CCCCC1N1CCNCC1

Procedure:
In an analogous manner to Example 135, step 4 1-{2-piperazin-1-yl-1-[3′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(3′-trifluoromethoxy-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ESI) m/z 449; HRMS: calcd for C25H31F3N2O2+H, 449.24159; found (ESI, [M+H]+), 449.2434.
Reaction SMILES: Cl.[C:2]1([NH:12][NH2:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:22][CH:23]=[C:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>O>[OH:22][C:23]1[N:12]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:30][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: NNc1cccc2ccccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2cccc3ccccc23)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of naphthalen-1-ylhydrazine hydrochloride (1 g, 5.1 mmol) and potassium carbonate (1.4 g, 10.3 mmol) in water (30 mL) was added diethyl ethoxymethylenemalonate (1.1 g, 5.1 mmol) at room temperature. The reaction mixture was stirred for 3 hours at room temperature and then extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl to pH 2 and then extracted with ethyl acetate again. This organic layer was dried over sodium sulfate and concentrated to give ethyl 5-hydroxy-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylate as a solid.
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[CH2:45]([O:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][N:59]([C:62](=O)[CH2:63][CH:64]3[C:73]4[C:68](=[CH:69][C:70]([Br:74])=[CH:71][CH:72]=4)[CH2:67][CH2:66][O:65]3)[CH2:58][CH2:57]2)=[CH:52][CH:51]=1)[CH2:46][CH2:47][CH3:48]>>[CH2:45]([O:49][C:50]1[CH:51]=[CH:52][C:53]([N:56]2[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][CH:64]3[C:73]4[C:68](=[CH:69][C:70]([Br:74])=[CH:71][CH:72]=4)[CH2:67][CH2:66][O:65]3)[CH2:58][CH2:57]2)=[CH:54][CH:55]=1)[CH2:46][CH2:47][CH3:48]
Reactant: CCCCOc1ccc(N2CCN(C(=O)CC3OCCc4cc(Br)ccc43)CC2)cc1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: CCCCOc1ccc(N2CCN(CCC3OCCc4cc(Br)ccc43)CC2)cc1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 4-butyloxyphenylpiperazine (XI) and the resulting amide, 1-(4-butyloxyphenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 4.2 mmol) is reduced according to the general procedure of EXAMPLE 50 making non-critical variations, to give the title compound, NMR (300 MHz, CDCl3) 7.32, 7.06, 6.85, 4.80, 4.13-4.08, 3.71, 3.28, 3.10-2.72, 2.65, 2.40, 2.22, 1.74, 1.46, 1.25 and 0.96 δ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 35.3 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 4-tributylstannanyl-pyridine (119 mg, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified sequentially by flash chromatography (20-100% EtOAc/hexanes+1% AcOH) and preparative TLC (100% EtOAc+1% AcOH) to give 36 mg of the title compound. MS: (+) m/z 464.35 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:17]([CH2:16][C:15]#[N:20])[C:18]#[N:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C=C/C#N
Solvent: CS(C)=O
Solvent: O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (1.0 g) and fumaronitrile (1.0 g) in dimethylsulfoxide (10 ml) was heated at 100° C. for 7 hours. The cooled mixture was diluted with water and extracted (ether) to give, after evaporation and crystallization from dichloromethane/hexane, the title compound (0.828 g, 63%), m.p. 101-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH:42]=1>[N+](C1C=C(C=CC=1)CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)([O-])=O.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:30])=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:32])=[O:33])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: [Pd+2]
Agent: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 79.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.34 mmol) was reduced with palladium hydroxide (250 mg) in ethyl acetate/ethanol 10/10 mL to afford 200 mg (80.0% yield) of the titled compound. MS: m/z=738.6 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:23])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])(=O)=O>C(Cl)Cl>[Si:39]([O:23][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a mixture of (18C)-isomer A, ethyl 2-((R)-1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidin-3-yl)acetate (6.00 g, 18.96 mmol) and DIPEA (5.96 ml, 34.1 mmol) in DCM (63 mL) was added tert-butyldimethylsilyl trifluoromethane-sulfonate (5.67 ml, 24.65 mmol) slowly. The reaction was monitored with HPLC and the reaction was complete in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted twice with DCM. The organic phase was combined, dried with Na2SO4, filtered, and concentrated. The crude material was purified with on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to give ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidin-3-yl)acetate (8 g, 18.58 mmol, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12][C:13](=[O:27])[CH:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][O:12][C:13](=[O:27])[CH:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([O:9][CH3:10])[CH:4]=1)[CH3:15]
Reactant: COc1cc(O)ccc1Br
Reactant: COC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Br)c(OC)c1
Temperature: 65 °C
Reaction time: 96 h

Procedure:
4-Bromo-3-methoxyphenol (209 mg, 1 mmol, 1 eq.) was dissolved in MeCN (4 mL). (±)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (258 mg, 1 mmol, 1 eq.) and K2CO3 (276 mg, 2 mmol, 2 eq.) were added and the mixture was stirred at 65° C. for 6 hours and further at r.t. for 4 days. The mixture was partitioned between water and Et2O. The layers were separated and the aq. phase was extracted with Et2O (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to the title compound as a colorless oil.