Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2c(F)cccc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2c(F)cccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step F by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.36 (s,6H), 1.43 (s,9H), 1.91 (m,1H), 2.4-2.8 (m,3H), 3.18 (m,2H), 4.54 (m,1H), 5.18 (br s,1H), 6.66 (d,7 Hz,1H), 6.81 (d,8 Hz,1H), 6.94 (t,8 Hz,1H), 7.18 (m,1H), 7.71 (br s,1H). FAB-MS: calculated for C20H28FN3O4 393; found 394 (M+H,26%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[C:13]1[CH:18]=CC=C[CH:14]=1.C(Cl)Cl>CO>[N:3]1[C:2]2[C:7](=[CH:14][CH:13]=[CH:18][N:1]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: c1cnc2ncccc2c1
Temperature: 120 °C

Procedure:
To a mixture of aminopyridine (1.12 g, 5.833 mmol) and AlCl3 (3.11 g, 0.023 mol) was added chlorobenzene (10.0 mL) in a sealed vessel under Ar. The reaction was sealed and heated to 120° C. for 12 h. The reaction mixture was cooled to RT and the mixture was poured over ice/HCl mixture and extracted with EtOAc (3×50.0 mL). The aqueous layer was neutralized via addition of solid NaHCO3 and extracted with EtOAc (5×50 mL). Combined organic layers were dried over Na2SO4 and evaporated to dryness to yield crude compound. Chromatography (Silica gel, CH2Cl2:MeOH, 99:1) yielded pure naphthyridin.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:12]([CH3:30])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1)=[O:14].[K+].[Br-]>O.CN(C)C=O>[C:1]([S:3][CH:12]([CH3:30])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:20][CH:21]=1)=[O:14])(=[O:4])[CH3:2]
Reactant: CC(Br)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
To 20 ml of N,N-dimethylformamide were added 0.54 g of thioacetic acid, 0.98 g of anhydrous potassium carbonate and then 2.0 g of 6-[4-(α-bromopropionylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, and the mixture was reacted for 2 hours at room temperature. The mixture was further reacted for 1 hour after the addition of 2 ml of water. Insoluble matters were removed from the mixture by filtration and the filtrate was concentrated under reduced pressure to obtain a crude end product which was then purified by column chromatography on silica gel (solvent: benzene, acetic acid and methanol in a ratio of 10:3:0.6) whereby 1.8 g of the purified end product was obtained. Amorphous powder. IR-absorption spectra (KBr tablets, cm-1): 3275, 1680, 1540, 1350, 1040 and 840.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: O=Cc1cncc(Br)c1
Agent: Cl
Product: O=C(NC1CCCCC1)C1CCN(Cc2cncc(Br)c2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 5-bromo-pyridine-3-carboxaldehyde and piperidine-4-carboxylic acid cyclohexylamide hydrochloride as in 3.01c: LC-MS A: tR=0.58 min; [M+H]+=380.19.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]2=[CH:20][C:3]=1[CH2:4][N:5]([CH3:55])[C:6](=[O:54])[CH:7]([NH:28][C:29]1[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=1)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:34][CH:33]=[CH:32]3)[C:8]1[CH:25]=[C:24]([CH3:26])[C:11]([C:12]([F:23])([F:22])[CH2:13][O:14][C:15](=[O:21])[NH:16]2)=[C:10]([CH3:27])[CH:9]=1.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C]=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[C:50]([O:49][C:47]([N:39]([C:40]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:46])[C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:7]3[C:6](=[O:54])[N:5]([CH3:55])[CH2:4][C:3]4[CH:20]=[C:17]([CH:18]=[CH:19][C:2]=4[C:15]([O:14][CH3:13])=[O:21])[NH:16][C:15](=[O:21])[O:14][CH2:13][C:12]([F:22])([F:23])[C:11]4[C:10]([CH3:27])=[CH:9][C:8]3=[CH:25][C:24]=4[CH3:26])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)=[O:48])([CH3:51])([CH3:53])[CH3:52]
Reactant: Cc1cc2cc(C)c1C(F)(F)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc2cc1CN(C)C(=O)C(Nc1ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c1)c1cc(C)c(c(C)c1)C(F)(F)COC(=O)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 150.7 %

Procedure:
To a pressured-bottle charged with 4B (177 mg, 0.215 mmol), palladium(II) acetate (24.09 mg, 0.107 mmol), TEA (0.089 mL, 0.644 mmol) and DMSO (5 mL)/MeOH (2.500 mL) was added dppp (44.3 mg, 0.107 mmol). The resulting mixture was charged with carbon monoxide at 25 psi and stirred at 80° C. under an atmosphere of CO overnight. The reaction mixture was cooled to rt, filtered though CELITE® and concentrated to about ½ original volume. Water (50 mL) was added to the mixture and then extracted using 50% EtOAc/hexanes (3×). The combined organics were washed with water, dried with NaSO4 then filtered and concentrated. The residue was purified on Isco (40 g) eluting with 0 to 30% EtOAc/dichloromethane to give 4C (130 mg, 0.162 mmol, 75% yield) as a white solid. MS and 1H NMR are consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:27][C:28]1[CH:51]=[CH:50][C:31]([CH2:32][NH:33][C:34]2[CH:35]=[C:36]([CH:48]=[O:49])[N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:30][CH:29]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:48]([C:36]3[N:37]([CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)[N:38]=[C:34]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:51][CH:50]=4)[CH:35]=3)[OH:49])=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C=O)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)cc1
Temperature: -20 °C

Procedure:
In a round bottom flask, 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (4, 1.7 g, 3.9 mmol) was combined with 1.3 mL of tetrahydrofuran and cooled to −20° C. Isopropylmagnesium chloride (2.0 mL, 2 M in tetrahydrofuran, 4.0 mmol) was added dropwise and the reaction stirred at −5° C. The reaction was cooled to −20° C. and 5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazole-3-carbaldehyde (113, 0.622 g, 1.83 mmol) in 2 mL of tetrahydrofuran was added and the reaction stirred at 0° C. The reaction was concentrated under vacuum, diluted with ethyl acetate and washed with sodium bicarbonate and brine. The organic layer was dried with sodium sulfate and purified by silica gel column chromatography, eluting with 5-80% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=648.38 and 649.74.
Reaction SMILES: [C:1]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[S:11][C:10]=1[NH:16]C(=O)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>>[NH2:16][C:10]1[S:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CC(=O)Nc1sc(C)c(C)c1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Cc1sc(N)c(C(=O)c2ccccc2)c1C

Procedure:
General Method B. A solution of 12a (0.3 g, 1.1 mmole) in KOH (3.5 equivalents in methanol-water 1:1) was refluxed for 45 minutes, evaporated and taken up in dichloromethane. The solution was washed three times with water, dried and evaporated to a solid that was recrystallized from ethanol-water as yellow crystals. Yield 0.25 g, 100%. 1H NMR (CDCl3) δ: 1.5 (s, 3H, CH3), 2.1 (s, 3H, CH3), 6.4 (br s, 2H, NH2), 7.2–7.5 (m, 5H, C6H5). 13C NMR (CDCl3) δ: 12.5, 15.2, 114.9, 117.2, 127.8, 128.0, 128.8, 130.4, 141.7, 162.8, 193.0.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)[CH3:7]
Reactant: CCC(=O)CC#N
Reactant: NNc1ccccc1
Solvent: CCO
Product: CCc1cc(N)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:21](/[C:20]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH3:16])[CH:19]=2)\[C:22]#[N:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccc(OC)c(OC)c3)cc2c1
Yield: 91.3 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (400 mg) through Method A (production step 2), to thereby yield the target product (yield: 784 mg, 91%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=[C:7]1[C:5]1[N:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:23]=[CH:24][CH:25]=2)[N:2]=[CH:3][CH:4]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=391.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.Cl[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: ClCc1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SCc2cccnc2)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 3-(chloro-methyl)pyridine hydrochloride (40.5 mg, 0.25 mmol), N,N,N-tributyl-1-butan-aminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: C(OCC)(=O)CC(C)=O.[OH:10][CH2:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])[OH:13]>>[CH2:20]([OH:21])[C@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][OH:10])[OH:13])[OH:15])[OH:17])[OH:19]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CCOC(=O)CC(C)=O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Butyl levulinate was obtained from the Sigma Aldrich Company of St. Louis, Mo. Ethyl acetoacetate was obtained from Acros Organics of Geel, Belgium. Sorbitol was obtained from Acros Organics. Mannitol was obtained from the Sigma Aldrich Company. Pentaerythritol was obtained from the Sigma Aldrich Company. Diglycerol was obtained from Tokyo Kasei Kogyo of Tokyo, Japan. Sulfamic acid was obtained from the Sigma Aldrich Company. Amberlyst®-15 was obtained from the Rohm and Haas Company of Philadelphia, Pa.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH:34]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@@H:2]([OH:1])[C@@H:3]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:4]2)=[CH:25][CH:24]=1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@H]1O)OCc1ccccc1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a mixture of phenylmethyl {[(3R,4R)-4-hydroxy-3-piperidinyl]methyl}carbamate (for a preparation see Example 135(f); 0.72 g; 2.72 mmol) in anhydrous DCM (10 mL) and anhydrous MeOH (2 mL) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 88(a)) (0.559 g; 2.72 mmol) and activated 4A sieves. The reaction was stirred under N2 for 18 h. The crude intermediate was treated with sodium triacetoxyborohydride (2.72 mmol; 577 mg) and stirred for 2 h. The product was obtained as a pale yellow oil after column:chromatography (90:10:DCM:MeOH) to yield 306 mg (25%) of the product as its free base.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.C(O)C.[NH2:21]N>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)/C=C/C(=O)c1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CCO
Product: FC(F)(F)c1cccc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
The (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The reaction was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 3-[3-(trifluoromethyl)phenyl]-1H-pyrazole as an oil (0.25 g, 89%), LC/MS (M+H)+: 213, 1H NMR (CDCl3) δ 8.06 (s, 1H), 7.99(d, 1H, J=7.5), 7.66(d, 1H, J=2.4), 7.57(m, 1H), 7.55(d, 1H, J=7.5), 6.69(d, 1H, J=2.4).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]Triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 155 mg (59%) colorless powder.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH3:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[CH3:21][C:11]1([NH2:10])[CH2:20][CH2:19][C:14]2([O:15][CH2:16][CH2:17][O:18]2)[CH2:13][CH2:12]1
Reactant: CC1(NC(=O)OCc2ccccc2)CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: CC1(N)CCC2(CC1)OCCO2
Yield: 100 %

Procedure:
Dissolve (8-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamic acid benzyl ester (13.12 g, 43.0 mmol) in MeOH (400 mL). Exchange air with nitrogen for three times and then add Pd—C (1.0 g, 10%). Exchange the nitrogen with H2 for three times. Stir the reaction mixture under H2 for over night then remove the Pd—C by filtration. Remove the solvent under reduced pressure to give 7.36 g (100%) of the crude 8-Methyl-1,4-dioxa-spiro[4.5]dec-8-ylamine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](OC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:4]([N+:18]([O-])=O)[CH:3]=1>[Fe].CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:18][C:14](=[O:15])[C:8]3([CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(Br)cc2[N+](=O)[O-])CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(Br)ccc2C12CCOCC2
Temperature: 100 °C

Procedure:
Prepared according to procedure J using methyl 4-(4-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-carboxylate (6.67 g, 19.4 mmol), AcOH (97 mL) and Fe powder (5.42 g, 96.97 mmol) and heating the mixture at 100° C. for 2 h. After purification 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one was obtained as an orange solid. Mass Spectrum (ESI) m/e=282 [(M+1) (79Br)] and 284 [(M+1) (81Br)].
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH3:28])([C:9]1[CH:14]=[CH:13][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11][CH:10]=1)[CH3:8])(=[O:3])[CH3:2].Br[C:30]1[N:31]=[C:32]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:46]([N:43]1[CH2:42][CH2:41][N:40]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:39]=[C:30]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([CH3:8])([CH3:28])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=3)[N:31]=2)[CH2:45][CH2:44]1)[CH3:47]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(C)(C)CCOC(C)=O)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C(C)(C)CCOC(C)=O)cc3)cc3ccccc23)CC1
Yield: 86.2 %

Procedure:
3-Methyl-3-(4-tributylstannylphenyl)butyl acetate (4.05 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.10 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.16 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.32 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-acetoxy-1,1-dimethylpropyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-chlorophenyl)-2-(4-(3-dimethylaminopropyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C=C>CCOCC>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:2][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: CCOC(=O)C=Cc1ccccc1O
Reactant: C=CCCCCCCCCO
Solvent: CCOCC
Product: C=CCCCCCCCCOC(=O)/C=C/c1ccccc1O
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 21.5 %

Procedure:
A mixture of 5.0 g 3-(2-hydroxy-phenyl)-acrylic acid ethyl ester, 6.1 g dec-9-en-1-ol and 1.0 g tetraisopropyl-ortho-titanate was heated to 150° C. removing the ethanol formed. After stirring for 2.5 hours at this temperature, the reaction mixture was cooled, diluted with ether and washed with brine. The organic phase was dried and evaporated to dryness. The resulting oil was Kugelrohr-distilled, crystallized and recrystallized to yield 1.69 g of colourless crystals.