Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:39][C:40]([C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][N:46]=[CH:45]2)=[NH:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:39]=[C:40]([C:42]3[CH:43]=[C:44]4[C:48](=[CH:49][CH:50]=3)[NH:47][N:46]=[CH:45]4)[N:41]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (712 mg), EDCl.HCl (699 mg) and HOBT (493 mg) were dissolved in DMF (16.5 ml) and stirred at RT for 10 minutes. N-hydroxy-1H-indazole-5-carboximidamide (D2) (584 mg) was added and the mixture heated to 80° C. for 12 hours. The reaction mixture was then cooled to RT and left to stand for the weekend, evaporated to dryness and re-dissolved in H2O. This solution was extracted with EtOAc (×3) and the combined extracts washed with brine, evaporated and triturated with DCM twice, sonicated for 4 mins before filtering, drying and repeating once to give the title compound (407 mg) as a pink solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 4.89 (1H, septet), 7.46 (1H, d), 7.73 (1H, d), 8.04 (1H, d), 8.13 (1H, d), 8.20 (1H, s), 8.28 (1H, s), 8.58 (1H, s). MS (ES): C18H15ClN4O2 requires 354; found 355 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[N:24]=[C:23]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)[CH:22]=[CH:21][N:20]=3)=[C:12]2[CH:11]=1)#[N:9].C(=O)([O-])O.[Na+]>ClCCl>[NH:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([NH:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][C:12]=34)[N:24]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
Trifluoroacetic acid (0.61 mL, 7.97 mmol) was added to a stirred solution of (R)-tert-butyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (Preparation 7a, 0.12 g, 0.27 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 4 hours. 4% Aqueous sodium hydrogencarbonate solution and solid sodium hydrogencarbonate were then added until the pH was basic and the mixture was further extracted with more dichloromethane. The organic layer was separated, dried (MgSO4) and evaporated to give the title compound (0.06 g, 62%) as a pale yellow solid which was used in the next synthetic step without further purification.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]3[CH:22]=[N:21][N:20]([CH3:23])[C:18]3=2)[N:13]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:12]=1)[CH3:10]>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:8][C:22]1[C:17]2[C:18](=[C:19]3[C:11]([CH2:9][CH3:10])=[CH:12][N:13]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=4)(=[O:26])=[O:25])[C:14]3=[N:15][CH:16]=2)[N:20]([CH3:23])[N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3cnn(C)c3c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc3c(Br)nn(C)c3c12
Temperature: 25 °C
Yield: 75.4 %

Procedure:
NBS (0.708 g, 3.98 mmol) was added to a solution of 8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.41 g, 3.98 mmol, Preparation #2, Step F) in THF (60 mL). The mixture was allowed to stir at rt. After 16 h additional NBS (0.106 g, 0.597 mmol) was added and reaction was stirred for about 3 h, then another portion of NBS (0.142 g, 0.796 mmol) was added. After another 1 h three equal portions of NBS (0.213 g, 1.19 mmol) were added over about 6 h. The mixture was then diluted with saturated aqueous Na2S2O3 (50 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in Et2O (10 mL) and sonicated for about 3 min. The precipitate was collected by filtration, washed with Et2O (10 mL) and dried in a vacuum oven at about 60° C. for about 3 h to give 3-bromo-8-ethyl-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (1.3 g, 75%): LC/MS (Table 2, Method c) Rt=1.58 min.; MS m/z: 433 (M+H)+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9]P(=O)(OCC)OCC)([O-:5])=[O:4].[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8](/[CH:9]=[CH:31]/[C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)[CH:18]=[CH:19][CH:20]=1)([O-:5])=[O:4]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.75 g) in N,N-dimethylformamide (20 ml) was added a solution of diethyl 3-nitrobenzylphosphonate (4.40 g) in N,N-dimethylformamide (20 ml). The mixture was stirred at room temperature for 15 minutes, then a solution of 4-quinolinecarbaldehyde (2.81 g) in N,N-dimethylformamide (20 ml) was added thereto. After stirring at 50° C. for 30 minutes, the mixture was poured into aqueous sodium bicarbonate, and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (chloroform-methanol (50:1)) to give 4-[(E)-2-(3-nitrophenyl)vinyl]quinoline (1.57 g) as a solid.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:26]1([O:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[O:32]([C:33]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)N1CC(Oc2ccc(F)cc2)C1

Procedure:
A solution of 20.0 g of 1-benzhydryl-3-(4-fluorophenoxy)azetidine and 10.3 g of phenylchloroformate in 200 ml. of toluene is refluxed for 16 hours. The reaction mixture is cooled, and the toluene is removed under reduced pressure to give a yellow oil. The oil is triturated with hexane to give a white solid of 1-phenoxycarbonyl-3-(p-fluorophenoxy)azetidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=CC1CCCCC1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCCC1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with cyclohexanecarbaldehyde (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.35 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one as a brown solid (Yield 2.71 g, 91%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[O:18][CH3:19])=[C:15]([CH2:20][CH3:21])[CH:14]=[C:13]([C:22]([O:24]CC)=[O:23])[C:12]3=[O:27])[CH2:3]1.[OH-].[Li+].C(O)(=O)C>O.C1COCC1>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[O:18][CH3:19])=[C:15]([CH2:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]3=[O:27])[CH2:3]1
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCCC(N)C3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCCC(N)C3)c(OC)c12
Temperature: 60 °C
Reaction time: 96 h

Procedure:
8-(3-aminopiperidinyl)-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid, ethyl ester (0.028 g) is dissolved in 9 ml of a 2/1 mixture of water and THF and lithium hydroxide (0.035 g) is added. The resulting solution is stirred at 60° C. for 4 days and the solution adjusted to pH 7.2 by addition of acetic acid. The title compound is collected by filtration of the precipitate.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:32]([OH:34])=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:43]>ClCCl>[C:1]([NH:18][C@H:19]([C:32]([F:43])=[O:34])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)F)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
N-FMOC-O-t-Butyl-L-tyrosine (5 g, 10.88 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.88 mL, 10.88 mmol) (Aldrich) and cyanuric fluoride (1.47 g, 10.88 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 5 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-tyrosyl fluoride as a white powder. (Yield 4.43 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: COc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-methoxybenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H),11.2 (s, 1H), 8.81 (s, 1H), 7.55 (m, 6H), 7.20 (d, 1H). 7.05 (m, 2H), 6.50 (s, 1H), 3.79 (s, 3H). M.P. 150-180° C.; LC-MS: 373 (MH+); HPLC RT: 4.45 minutes.
Reaction SMILES: [CH3:1][O:2]S([O-])(=O)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14](C=[CH:16][CH:17]=[CH:18]1)=[NH+:13]2.[OH-].[Na+]>O>[O:2]=[C:1]1[C:14]2[C:19](=[N:20][C:21]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:7])[CH:18]=[CH:17][CH2:16]1
Reactant: Cc1cccc2[nH+]c3ccccc3nc12
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2nc3c(nc12)C=CCC3=O
Reaction time: 5 h
Yield: 58 %

Procedure:
Further steps of the process are conducted as described in Example 1 hereinbefore. The solution of 9-methylphenazinium methylsulphate in distilled water is first irradiated for 3 hours and the reaction mixture is brought to the pH of 8.5 by using a 0.1N solution of sodium hydroxide, whereafter the irradiation is continued for additional 5 hours to give 0.79 g (58%) of 4-keto-9-methylphenazine in the form of blue crystals with the melting point of 133°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Si]([C:17]([F:20])([F:19])[F:18])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[C:17]([F:20])([F:19])[F:18])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)(C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of (4-bromophenyl)(cyclopropyl)methanone (587 mg, 2.60 mmol) in tetrahydrofuran (5.2 mL) were added molecular sieves 4 Å (500 mg), trimethylsilyl trifluoromethane (772 μL, 5.20 mmol) and tetrabutylammonium fluoride (tetrahydrofuran solution, 1 mol/L, 3.9 mL, 3.90 mmol) at 0° C., and the mixture was stirred at room temperature for 18 hours. The solution was filtered through diatomaceous earth, and then thereto was added 1 mol/L hydrochloric acid solution (10 mL), and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→5:1) to give 1-(4-bromophenyl)-1-cyclopropyl-2,2,2-trifluoroethanol (747 mg, 97%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:16](=O)[C:17](=[O:21])[C:18]=1[O:19]C)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+:2]=[N-:3].Cl.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1.CCN(CC)CC>C(#N)C>[N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:21])[C:16]=1[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([CH:31]([O:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33]1)[CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: COCCCOC(c1ccccc1)C1CCCNC1
Reactant: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCCOC(c1ccccc1)C1CCCN(c2c(N[C@@H](CC3CCCCC3)[C@H](O)CN=[N+]=[N-])c(=O)c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (35 mg, 0.11 mmol), the HCl salt of 3-((3-methoxypropoxy)(phenyl)methyl)piperidine (48 mg, 0.16 mmol), and Et3N (100 μL, 0.7 mmol) were dissolved in acetonitrile (1 mL). The reaction was allowed to stir at rt overnight. The solvent was evaporated and the product was isolated by preparative HPLC to give 3-((2S,3R)-4-azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione (41 mg). MS m/z 554 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]([CH3:10])[C:3]=1[C:11]#[N:12].[C:13]1([C:19]2[CH:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]3)[O:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[S:6][C:5]([C:7]([NH:32][CH2:31][CH:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:22]3[O:21][N:20]=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:23]=3)[CH2:30][CH2:29]2)=[O:9])=[C:4]([CH3:10])[C:3]=1[C:11]#[N:12]
Reactant: Cc1c(C(=O)O)sc(N)c1C#N
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: Cc1c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)sc(N)c1C#N

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 227 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[CH2:9]([N:11](CC)[CH2:12][CH3:13])[CH3:10].N1CCCC1>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([N:11]1[CH2:12][CH2:13][CH2:10][CH2:9]1)=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(CCl)C(=O)N1CCCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethyl-propionyl chloride (0.5 g, 3.2 mmol) was stirred in dichloromethane (20 mL) at RT with triethylamine (0.9 mL, 6.4 mmol). The reaction mixture was cooled to 5° C. and then pyrrolidine (0.32 mL, 3.9 mmol), was added drop wise. After addition the reaction was stirred at RT for 1 hr, and then the reaction mixture was washed with saturated sodium hydrogen carbonate solution (2×50 mL), brine (50 ml), dried (Na2SO4) and concentrated in vacuo to afford 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one as a yellow solid, 0.576 g, 94%. To this intermediate, 3-chloro-2,2-dimethyl-1-pyrrolidin-1-yl-propan-1-one (0.57 g, 3 mmol) in anhydrous THF (20 mL) was slowly added a 1M anhydrous THF solution of lithium aluminium hydride (7.5 mL, 7.5 mmol) at room temperature. The resulting clear solution was stirred overnight at room temperature under nitrogen to give a cloudy suspension. Water (0.3 mL) was carefully added to the reaction mixture followed by 15% w/v aqueous sodium hydroxyde solution (0.3 mL) and water (0.9 mL). The reaction was filtered and the filtrate evaporated to dryness to give the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:31])[C:29]#[CH:30]>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:30]#[C:29][CH2:28][OH:31])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: C#CCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol were converted to yield 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as off-white solid, MS: 333 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([N:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14](I)[C:13]([CH3:22])=[N:12]2)=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:14]2[C:13]([CH3:22])=[N:12][N:11]([C:6]3[C:7]([O:9][CH3:10])=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(I)c(C)nn1-c1cnc(OC)nc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 1-(2,4-dimethoxypyrimidin-5-yl)-4-iodo-3-methyl-1H-pyrazole-5-carboxylate (Step 52.2) and 4-chlorobenzaldehyde at RT for 30 min. tR: 5.02 min (HPLC 1); tR: 1.11 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.38 (hexane/EtOAc 1:1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=C.[C]=O.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(C(CC)=O)C>[C:1]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccccc1
Reactant: c1ccccc1
Agent: C=C
Agent: [C]=O
Solvent: CCC(=O)CC
Product: C(=C/c1ccccc1)\c1ccccc1
Temperature: 220 °C

Procedure:
Charged in an autoclave having an inner capacity of 200 ml were 50 ml of benzene and 0.019 g of Rh6 (CO)16, followed by supply of ethylene under 30 kg/cm2 and carbon monoxide under 25 kg/cm2. The charge in the autoclave was heated at 220° C. under agitation for 7 hours. The reaction mixture was cooled and analyzed by GC and it was confirmed that 0.925 g of styrene was formed. The yield of styrene was 8900% based on the Rh atom. Furthermore, it was confirmed that 1.129 g of diethylketone and 40 mg of trans-stilbene were formed.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[CH:16][CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(C)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A mixture of methyl [1-methyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (662 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetic acid (601 mg, yield 94%), which was then recrystallized from ethanol-hexane. melting point: 133–134° C.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[C:1]1([CH:7]2[CH:12]([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH3:19])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1CCCC(O)C1c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CC1CCCC(O)C1c1ccccc1
Yield: 1852.5 %

Procedure:
A solution of 0.53 g (2.26 mmole) of 2-(SR)-phenyl-3-(SR)-hydroxy-(SR)-cyclohexylacetic acid in 35 mL of methanol was treated with 22 mg (0.11 mmole) of p-toluenesulfonic acid monohydrate and the mixture was heated at reflux for 27 hr. The mixture was cooled, treated with 0.02 mL of triethylamine and concentrated in vacuo. The residue was purified by flash chromatography on 67 g of silica eluting with 1.6 L of 8:1 hexanes:ethyl acetate to give 0.506 g (90%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:17]
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: CCCc1cc(C(=O)OCC)c(NC=O)s1
Temperature: 137.5 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A mixture of compound 2c [Formula 2 wherein R1=COOEt, R2=H and R3=Pr] (5.0 g, 0.023 mol), ammonium acetate (1.80 g, 0.023 mol) and formic acid (17.70 mL, 0.469 mol) was stirred at 135-140° C. for 7 h, cooled to room temperature, diluted with water (250 mL), extracted with ethyl acetate (3×150 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3c); 5.27 g; Yield: 95%; 1H NMR (200 MHz, CDCl3): δ 0.96 (t, J=7 Hz, 3H), 1.38 (t, J=7 Hz, 3H), 1.59-1.76 (m, 2H), 2.69 (t, J=8 Hz, 2H), 4.33 (q, J=7 Hz, 2H), 6.88 (s, 1H), 8.49 (s, 1H) 10.93 (bs, 1H).