Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH3:12][OH:13].Cl>O1CCCC1>[CH3:12][O:13][CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)CCl
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)CC(=O)OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 73695.8 %

Procedure:
In a 2 liter four-necked flask were charged 88.0 g (2.2 mol) of 60% sodium hydride and 753 ml of tetrahydrofuran in a nitrogen stream, and a mixture of 150.6 g (1.0 mmol) of methyl 4-chloro-3-oxo-butyrate and 35.2 g (1.1 mol) of methanol was added thereto dropwise at room temperature (22 to 24° C.). After the addition, the mixture was stirred at room temperature (22 to 24° C.) for 1 hour. The reaction mixture was cooled with ice, and 600 ml (1.2 mol) of 2N hydrochloric acid was added dropwise. The tetrahydrofuran was recovered from the reaction mixture, and 400 ml of toluene was added to the residue. The aqueous phase was extracted with three 200 ml portions of toluene. The organic phase was washed with a 5% sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The residue was distilled under reduce pressure (boiling point: 90° C./1000 Pa) to give 107.7 g (74%) of methyl 4-methoxy-3-oxobutyrate as liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:15]([C:11]3[C:12]([CH3:14])=[N:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][CH:10]=3)=[O:17])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1cn(N)c2ccc(F)nc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 66.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.34 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.34 mmol), DIPEA (158 mg, 4.02 mmol) and HATU (1.60 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×20 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-60% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (340 mg) as a solid. MS: 380 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 2.86 (s, 3H), 6.84 (d, H), 7.12-7.35 (m, 2H), 7.52 (q, H), 7.63 (t, H), 8.10-8.43 (m, 2H), 8.98 (br, N—H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]1)=[O:14])[CH2:6][CH2:5]2.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:3]=4)[CH2:8]3)[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CN1CCc2cc(Br)ccc2C1)N1CCN(C2CCC2)CC1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCc2cc(-n3cccn3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline (120 mg, 0.307 mmol), pyrazole (31 mg, 0.46 mmol), Cu2O (4 mg, 0.03 mmol), salicylaldoxime (16 mg, 0.12 mmol) and Cs2CO3 (300 mg, 0.92 mmol) in CH3CN (8 mL) is degassed by argon and heated at 120° C. in a sealed tube overnight. EtOAc (10 mL) is added and the mixture is filtered. The organic layer is washed with brine (10 mL) and dried. Purification of the residue by PTLC gives title compound as a light yellow solid. MS (M+1): 380.2; 1H NMR (δ, CDCl3): 7.88 (d, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.41 (dd, 1H), 7.08 (d, 1H), 6.45 (dd, 1H), 3.71 (s, 2H), 3.65 (t, 4H), 3.38 (s, 2H), 2.96 (t, 2H), 2.81 (t, 2H), 2.63-2.72 (m, 1H), 2.28 (q, 4H), 1.64-2.08 (m, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(-c4ccco4)n[nH]3)n2)ccc(C#N)c1Cl
Yield: 45.2 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.059 g, 0.331 mmol), 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.091 g, 0.331 mmol), HOBt (0.068 g, 0.497 mmol), DIPEA (0.087 ml, 0.497 mmol) and EDCI (0.096 g, 0.497 mmol) using DCM as solvent using the method of Example 34(d) affording 0.065 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.53 (s, 3H), 4.28-4.38 (m, 2H), 4.43-4.51 (m, 1H), 6.60 (d, 2H), 6.81-6.91 (m, 2H), 7.66 (d, 1H), 7.77 (s, 1H), 7.82 (d, 1H), 7.85 (m, 1H), 8.31 (m, 1H), 13.69 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:41])[CH3:40])[N:34]=4)[CH:21]=3)[CH2:16][CH:15]2[C:42](=[O:51])[N:43]([CH2:45][CH2:46][CH2:47][CH2:48]C=C)[CH3:44])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:48][CH2:47][CH2:46][CH2:45][N:43]([CH3:44])[C:42](=[O:51])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([CH3:40])[CH3:41])[N:34]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2cc(-c3cccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4cccc(C(C)C)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.8 %

Procedure:
1-{2-(hex-5-enylmethylcarbamoyl)-4-[2-(6-isopropyl-2-pyridyl)-7-methoxy-8-methyl-quinolin-4-yloxy]cyclopentanecarbonyl}amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (111, 438 mg, 0.50 mmol) was dissolved in dry 1,2-dichloroethane. Then, nitrogen gas was bubbled through the solution for 30 min before Hoveyda-Grubbs 1st generation (15 mg) was added. The resulting solution was refluxed for 3 h, then more catalyst (20 mg) was added. After 2 h at reflux, another 10 mg of the catalyst was added. After 12 h at reflux, the reaction mixture was cooled down to room temperature. Then, scavenger MP-TMT (Agronaut Technologies Inc.) was added (˜300 mg) and the mixture was stirred at room temperature for 45 min. The catalyst was discarded by filtration on silica gel (gradient of CHCl3/MeOH, 1:0 to 98:2) to give 220 mg (66%) of the title compound 112: m/z=669 (M+H)+.
Reaction SMILES: B(O)(O)O.C1N2CN3CN(C2)CN1C3.[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1O)([CH3:18])[CH3:17].OS(O)(=O)=O.C(O)[CH2:36][OH:37]>>[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)[CH:36]=[O:37])([CH3:18])[CH3:17]
Reactant: OCCO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Temperature: 149 °C
Reaction time: 0.5 h

Procedure:
3.5 g of boric acid was heated in 150 ml of ethylene glycol at 150° C. for 30 minutes, in a 500 cc flask equipped with a reflux condenser. 25 g of hexamethylenetetramine and 21 g of 2,6-bis(1,1-dimethylethyl)phenol were then added and the solution maintained at 148-150° C. for 15 minutes. After cooling to 125° C. at which stage the first crystals appeared, 150 ml of H2SO4 (30%0 was added and stirring was continued for another 30 minutes. The resulting slurry was filtered and washed with warm water. After drying, 22 g of 3,5-bis(1,1-dimethylethyl)benzaldehyde was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.C([Mg]Cl)CC.CCOCC>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH2:16][CH2:15][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Yield: 97.1 %

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (2.2 g, 11 mmol) and THF (20 mL, 300 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2.0M Propylmagnesium chloride in ether (11.0 mL, 22.1 mmol) was then added dropwise over 1 hour. The mixture was allowed to warm to room temperature slowly overnight. Then saturated aqueous NH4Cl (20 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×50 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×100 mL) and saturated aqueous NaCl (1×100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield a pale, yellow oil (2.6 g). The oil was purified by preparative HPLC in two equal batches of 1.3 g loading in 1:1 AcOH/H2O (6 mL). The diastereomers were separated by gradient (5-70% MeCN/H2O; 0.05% TFA; over 70 minutes on a 2″ BDS column). The fractions for peak 1 were collected and lyophilized to yield an oil. The fractions for peak 2 were lyophilized then repurified. Both products were identified as clean by NMR and HPLC and identified for mass by LCMS:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCC>[CH3:1][O:2][C:3]([C:5]1([C:26]([OH:28])=[O:27])[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C=O
Reactant: COC(=O)C1CCc2cc(C3CCCCCC3)ccc21
Agent: [Li]CCCC
Solvent: CCCCC
Product: COC(=O)C1(C(=O)O)CCc2cc(C3CCCCCC3)ccc21

Procedure:
melting point 140°-141°C (from pentane), from 10 g of 5-cycloheptyl-1-indanecarboxylic acid methyl ester, 12.8 ml of a 2.6 N solution of butyl-lithium and carbon dioxide.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14]C3C=CC=CC=3)[CH2:10][CH:9]2[C:21]([O:23]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[C:27]1([CH2:26][C:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH:9]2[CH2:10][N:11]([CH2:14][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:13][N:8]2[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[OH:23])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Br[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)(Cc1ccccc1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Ethyl 1,4-bis(phenylmethyl)-2-piperazine carboxylate (8.2 g, 24 mmol) was dissolved in tetrahydrofuran (100 mL) under argon atmosphere. With ice cooling, a 1.0 M solution of benzyl magnesium bromide in tetrahydrofuran (100 mL, 0.10 mol) was added dropwise thereto over 30 minutes. After stirring at room temperature for 14 hours, an aqueous saturated ammonium chloride solution (300 mL) was added dropwise thereto with ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane to hexane:ethyl acetate=5:1) to obtain the title compound (5.1 g, yield 44%).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]=[CH:6][C:5]1=[O:56])[CH:2]=[CH2:3]>C(O)(=O)C.[Zn]>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[CH:19]([OH:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)CCC1=O
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a stirred solution of the title compound of example 14 (60 mg) in glacial acetic acid (5 ml) was added powdered zinc (1 g). Stirring was continued for 1 hour when the reaction was complete. The reaction mixture was then extracted with ethyl acetate, washed with saturated NaHCO3 solution followed by brine, dried (MgSO4) and concentrated in vacuo. Chromatography on silica eluting with ether/methanol (15:1 then 10:1) gave the title compound as an oil (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[K+].[I:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:13])[C:3]=12
Reactant: II
Reactant: Clc1ccnc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]cc(I)c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
250 g (1.64 mol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine and 328 g (5.85 mol) of powdered potassium hydroxide are initially charged in 3000 ml of DMF and cooled to 0° C. With cooling, a solution of 416 g (1.64 mol) of iodine in 3000 ml of DMF is added dropwise to this suspension, and the mixture is, after the end of the addition, stirred at 0° C. for 4 h. To bring the reaction to completion, the mixture is added with stirring to ice-water and the solid formed is filtered off with suction and then dried under high vacuum. This gives 403 g (88% of theory) of the title compound as a solid.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[C:20](O)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]1([C:35]2[C:39]([NH2:40])=[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.C(#N)C.O>[C:29]1([C:35]2[C:39]([NH:40][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: c1ccc(CNc2c(-c3ccccc3)n[nH]c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
574 mg of hydroxybenzotriazole and 822 μl of diisopropylcarbodiimide were added to a solution of 260 mg of benzoic acid in 10 ml of methylene chloride, after which 500 mg of 3,5-diphenyl-1H-pyrazol-4-ylamine in 2 ml of acetonitrile were added dropwise, at 0° C.; the mixture was then stirred at room temperature (RT) for 12 hours (h), after which water was added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue contained the title compound and was used in the following reaction without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(C1C=CC=CC=1)CC>COCCOC>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC#Cc1ccccc1
Solvent: COCCOC
Solvent: CCCc1ccccc1
Product: CC=Cc1ccccc1
Yield: 79 %

Procedure:
In 1.0 ml of DME were heated 1.0 mmol of 1-phenyl-1-propyne and 0.01 mmol of tetraethylammonium μ-hydride-bis(pentacarbonylchromium(O)) at 100° C. and at a hydrogen pressure of 50 atm for 18 hours with stirring. GLC analysis of the reaction mixture revealed that propylbenzene and β-methylstyrene were produced in a yield of 79% and 19%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][O:15][S:32]([CH3:35])(=[O:34])=[O:33])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethanol (250 mg, 0.72 mmol; example 1.4) in dry dichloromethane (5 ml) was added triethylamine (0.32 ml, 1.19 mmol) at 25° C. Mesyl chloride (0.16 ml, 0.725 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 25° C. for 2 h, diluted with water (5 ml), and the aqueous layer was extracted with dichloromethane (3×10 ml). The combined organic layers were washed sequentially with ice water (10 ml), 10% aqueous NaHCO3 solution (10 ml), brine (10 ml) and finally dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as light yellow oil (250 mg, 0.58 mmol; 81%), which was sufficiently pure to be used in the next reaction step.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:20])=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]>[Pt]=O.C(O)C>[CH2:1]([C:4]1[C:5]([OH:20])=[C:6]([CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: C=CCc1cc(-c2ccc(F)cc2)cc(C(=O)O)c1O
Agent: O=[Pt]
Solvent: CCO
Product: CCCc1cc(-c2ccc(F)cc2)cc(C(=O)O)c1O

Procedure:
A solution of 0.8 g. of 3-allyl-5-(4'-fluorophenyl)-2-hydroxy-benzoic acid in 25 ml. of ethanol is subjected to hydrogenation at 40 p.s.i. and 25° C. in the presence of 0.1 g. of platinum oxide. After the uptake of the required amount of hydrogen, the catalyst and solvent are removed, and the crude product is recrystallized from benzene. The yield of 3-propyl-5-(4'-fluorophenyl)-2-hydroxy-benzoic acid is 0.72 g., m.p. 188°14 190° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C@H:7]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]3[C@@H:15]([O:19][CH2:20][CH3:21])[C:16](=[O:18])[O:17][C@@H:8]23)[CH2:4][O:3]1.O>C(O)(=O)C>[OH:6][C@@H:5]([C@H:7]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]2[C@@H:15]([O:19][CH2:20][CH3:21])[C:16](=[O:18])[O:17][C@@H:8]12)[CH2:4][OH:3]
Reactant: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H]1COC(C)(C)O1
Solvent: CC(=O)O
Solvent: O
Product: CCO[C@H]1C(=O)O[C@@H]2[C@H]1OC(C)(C)O[C@@H]2[C@H](O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
2.62 g of 48 (8.28 mmol) are introduced into a 100 mL three-necked flask containing 16 mL of water and 16 mL of acetic acid. The medium is stirred for 24 h at RT and then the reaction medium is concentrated under vacuum. The residues are disintegrated with 25 mL of isopropyl ether, filtered and dried under vacuum. 2.15 g of expected product 49 (white solid) are obtained.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:2].[ClH:15].[CH2:16]([O:18]CC)[CH3:17].C(O)C>>[ClH:15].[CH2:16]([O:18][C:1](=[NH:2])[CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOC(=O)c1ccc(C)n1CC#N
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)Cn1c(C)ccc1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A high pressure reaction vessel charged with ethyl 1-(cyanomethyl)-5-methyl-1H-pyrrole-2-carboxylate (848 mg, 4.41 mmol) cooled to 0° C. was treated with a 2M solution of hydrochloric acid in diethyl ether (30 mL, 60 mmol) and absolute ethanol (406 mg, 8.82 mmol). The mixture was stirred at 0° C. for 10 min and then was warmed to room temperature where it stirred over the weekend. At this time, the mixture was diluted with hexanes. The resulting precipitate was collected by filtration to afford ethyl 1-(2-ethoxy-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate hydrochloride (1.16 g, 95.7%) as a white solid. LC-MS calcd. for C12H19N2O3 [(M+H)+] 239, obsd. 239.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[NH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:36])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: NN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NN4CCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Yield: 73.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (50 mg, yield 73%).