Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:77](=[O:78])[NH:76][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:72])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:58][C:56](=[O:57])[C@@H:54]4[NH:55][N:50]([CH2:51][CH2:52][CH2:53]4)[C:48](=[O:49])[C@H:47]([CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)[NH:46][C:44](=[O:45])[C@H:43]([CH:67]([CH3:69])[CH3:68])[NH:42][C:40](=[O:41])[C@@H:32]4[CH2:33][CH2:34][C@:35]([O:38]C)([CH3:37])[O:36][C@@H:31]4[C@@H:30]([CH3:70])[C@@H:29]([OH:71])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:73])[C@H:8]([OH:74])[C@@H:7]2[CH3:75])[C@@H:5]([CH3:79])[CH2:4]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][CH2:2][C@@H:3]1[C:77](=[O:78])[NH:76][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:72])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:58][C:56](=[O:57])[C@H:54]4[NH:55][N:50]([CH2:51][CH2:52][CH2:53]4)[C:48](=[O:49])[C@H:47]([CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[CH:61]=4)[NH:46][C:44](=[O:45])[C@H:43]([CH:67]([CH3:68])[CH3:69])[NH:42][C:40](=[O:41])[C@H:32]([CH2:33][CH2:34][C:35]([CH3:37])=[O:38])[C@H:31]([OH:36])[C@@H:30]([CH3:70])[C@@H:29]([OH:71])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:73])[C@H:8]([OH:74])[C@@H:7]2[CH3:75])[C@@H:5]([CH3:79])[CH2:4]1
Reactant: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C/C=C/[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C\C=C/[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Reaction time: 1.5 h

Procedure:
A solution of 550 mg (0.50 mmol) of sanglifehrin C in 5 mL of 4:1 THF-water is treated with 0.5 mL of 2N aqueous sulfuric acid and stirred for 1.5 h. The reaction is quenched with saturated aqueous sodium bicarbonate and the resulting mixture is extracted twice with ethyl acetate. The organic solution is washed with saturated aqueous sodium bicarbonate solution and twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (90:10 methyl-tert.-butyl ether:methanol) to yield sanglifehrin A as a white amorphous powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[C:27]=2[Br:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][N:43]=1)[C:38](Cl)=[O:39]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[C:27]=2[Br:33])[C:38]([C:37]2[CH:41]=[CH:42][N:43]=[C:35]([Cl:34])[CH:36]=2)=[O:39])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(CNc2ccnc(Cl)c2Br)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)c2ccnc(Cl)c2)c2ccnc(Cl)c2Br)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M solution in THF, 3 ml) was added dropwise to a stirred solution of 4-[(3-Bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.53 g) in tetrahydrofuran (20 ml) at −78° C. under N2. The yellow solution was warmed to 0° C. and then 2-chloroisonicotinoyl chloride (50% solution in toluene, 0.95 g) was added. The solution was stirred at 0° C. for 10 min., quenched by addition of aqueous ammonium chloride, extracted with EtOAc, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 then CH2Cl2/EtOAc 8:2 cyclohexane:ethyl acetate 8:2) to afford 4-{[(3-bromo -2-chloro-pyridin-4-yl)-(2-chloro-pyridine-4-carbonyl)-amino]-methyl }-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (0.63 g), which was identified by its mass and 1H NMR spectra. MS (ES+) 443/445 (MH+—BOC), 484/486 (MH+-isoprene).
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:62]2[CH2:67][CH2:66][N:65]([CH2:68][C:69]3[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=3)[CH2:64][CH2:63]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:61]=[CH:60][C:45]([CH2:46][N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Yield: 73.1 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (10 mg, 0.015 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (6 mg, 71%) as a yellow solid; δH (500 MHz, DMSO-d6 2.46-2.49 (m, 1H, piperazine NCH2), 2.62 (s, br, 4H, piperazine N(CH2)2), 2.93 (s, br, 2H, piperazine NCH2), 3.30 (hidden by DMSO peak, 2H, piperazine NCH2), 3.34-3.38 (m, 2H, piperazine NCH2), 3.56 (s, 2H, NCH2), 3.61 (s, 2H, NCH2), 3.67 (s, br, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.5, 4.5 Hz, 1H, pyridine H-5), 7.68 (d, J=7.8 Hz, 2H, phenyl H-3 & H-5), 7.78 (d, br, J=7.6 Hz, 1H, pyridine H-4), 8.13 (d, J=7.4 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (d, br, J=4.6 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2);
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22](O)[CH2:23][CH2:24][C:19]2=[N:18]1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22]([Cl:3])[CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: O=S(Cl)Cl
Reactant: OC1CCc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc3c(n2)CCC3Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.1 mL, 1.37 mmol) was added to a solution of (62) (100.0 mg, 0.29 mmol) in THF (2 mL). After stirring for 2 hours at ambient temperature, EtOAc (10 mL) was added and the resulting mixture was poured into 5% aq. NaHCO3 (20 mL) at 4° C. The resulting mixture was extracted with EtOAc (10 mL). The organic layer was washed with 5% NaHCO3 (20 mL) at 4° C., dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale solid in quantitative yield. 1H NMR (CDCl3); δ 7.72 (s, 2H), 7.42 (s, 1H), 5.43 (d, 1H, J=5.6), 3.22-2.94 (m, 2H), 2.85-2.70 (m, 2H); MS (M++1) 355.4.
Reaction SMILES: [CH2:1]([C:5](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].Cl.[CH3:19]O>>[CH2:1]([C:5]1[CH2:8][C:9]2[C:14]([C:6]=1[O:7][CH3:19])=[CH:13][C:12]1[O:15][CH2:16][O:17][C:11]=1[CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCC(C=O)=Cc1ccc2c(c1)OCO2
Agent: Cl
Product: CCCCC1=C(OC)c2cc3c(cc2C1)OCO3
Yield: 90 %

Procedure:
Dissolved in 80 ml of methanol was 12 g of 2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, into which hydrogen chloride qas was blown under ice-salt cooling. Upon confirmation of full consumption of the raw material by thin-layer chromatography (eluent: a 5:1 mixture of n-hexane and ether), the bubbling of hydrogen chloride gas was stopped. Water was added to the reaction mixture, followed by extraction of the resultant mixture with ether. After the resultant ether solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water successively, the ether solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of n-hexane and ether) to give 11.4 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene as an oily substance (yield: 90%).
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH2:23])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O>[C:1]1([C:7]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[NH:23][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc2nc(-c3ccccc3)c(-c3ccccc3)nc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2cccc3nc(-c4ccccc4)c(-c4ccccc4)nc23)cc1
Reaction time: 24 h

Procedure:
While agitating 4.0 g (13.4 mmol) of 2,3-diphenyl-5-aminoquinoxaline, 2.1 g (14.9 mmol) of 4-fluoronitrobenzene and 100 ml of dimethylsulfoxide, 5.0 g (44.6 mmol) of potassium t-butoxide was gently added thereto. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 24 hours. After completion of the reaction, 100 ml of water was added to the container while cooling, and an organic phase was extracted with a chloroform solvent, followed by evaporation of the solvent for concentration to obtain the intended product.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=O.[OH-].[Na+]>C(O)CC>[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:17]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Reactant: CN(C)C=CC(=O)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1ccc(-c2ccnc(Nc3cccc(-n4ccnc4)c3)n2)nc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Thirteen and seven tenths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 8.8 g of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one (3), 50 ml of n-propanol and 10 ml of 10N sodium hydroxide is refluxed for 18 hours. The reaction is diluted with 50 ml of n-propanol and filtered. The collected yellow solid is stirred in 300 ml of water for 0.5 hour, filtered and washed with 50 ml of n-propanol followed by 100 ml of diethyl ether. The solid is air dried overnight giving 13.4 g (85%) of the desired product, mp 210°-211° C. The overall yield following this procedure is 73%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22]Br)=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][S:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSCc1cc2c(cc1/C=C/c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A solution of 445 mg (1 mmol) of Methyl-4-[(E)-2-(3-Bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 418 mg (3 mmol) of potassium carbonate and 180 mg (2 mmol) of 1-butanethiol in 10 mL dimethylformamide was heated to reflux. After 40 minutes, the reaction mixture was cooled to room temperature, then diluted with water. The mixture was extracted with ethyl acetate, the organic extracts washed with brine, dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% ethyl acetate/hexane) to give 263 mg (58%) of Methyl-4-[(E)-2-(3-Butylthiomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[O:50][CH2:51][CH2:52][O:53]C(OC(C)(C)C)=O)/[C:33]1=[O:61])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:61])[C:34]3([CH:42]([C:43]4[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=4[O:50][CH2:51][CH2:52][OH:53])[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)OCCOc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
To a toluene solution (10 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10.93 mmol) was added E/Z-3-[2-(2-tert-Butoxycarbonyloxy-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1 g, 1.82 mmol). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 40 min. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid and dichloromethane was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (11 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=O.[OH-].[Na+]>C(O)C.O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[CH:12]=[CH:11][C:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(32) To a solution of the 2,6-dichlorobenzaldehyde (438 mg, 2.50 mmol) and 2,6-dichloroacetophenone (473 mg, 2.50 mmol) in 3.7 ml of ethanol was added 0.1 ml of 40% sodium hydroxide in water at 10° C. After stirring for 2 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 465 mg (53.8%) of white, cottony needles: mp 130-130.4° C. (lit. mp 124-125° C., Kaiser, et al., Monatshefte fur Chemie, 1997, 128, 1247-1254). 1H NMR (250 MHz) δ 7.43-7.17 (m, 7 H), 7.10-7.03 (d, 1 H); 13C NMR (62.7 MHz) 193.0, 141.7, 137.5, 135.3 134.4, 132.1, 131.8, 131.0, 130.6, 129.0, 128.3 ppm.
Reaction SMILES: [CH2:1]([Li])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH3:13][N-:14][CH3:15].C[N-]C.[Zr+4:19]>CCCCCC.CCCCC>[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH3:13][N-:14][CH3:15].[CH2:1]([Zr+3:19])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [Zr+4]
Reactant: [Li]CC(C)(C)C
Agent: C[N-]C
Solvent: CCCCCC
Solvent: CCCCC
Product: CC(C)(C)C[Zr+3]
Reaction time: 48 h

Procedure:
A solution of 0.50 g of neopentyllithium in hexane was added to a hot solution of zirconium tetrakis(dimethylamide) in hot hexane with stirring. Lithium dimethylamide precipitated immediately. The total amount of hexane in the reaction mixture was about 50-100 ml. The mixture was cooled and filtered, and the filtrate was evaporated to give a sticky solid. The latter was dissolved in pentane, and the solution was kept at -40° C. for 2 days. During this time yellow crystals of neopentylzirconium tris(dimethylamide) separated. They were isolated by filtration and dried; yield 0.5 g. Nmr in C6D6 : δ (NMe) 2.92, δ (CH2) 0.9, δ (CMe3) 1.20 ppm downfield from tetramethylsilane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:46][C:45]3[CH:48]=[CH:49][C:42]([Cl:41])=[CH:43][CH:44]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (0.29 g, 0.553 mmol) in dry DMF (5 ml) was stirred under nitrogen and treated with sodium hydride (0.024 g, 0.608 mmol, 60% dispersion in oil). The mixture was stirred for 0.5 h and a solution of 4-chlorobenzyl chloride (0.090 g, 0.559 mmol; Aldrich) in DMF (5 ml) was added). The mixture was stirred at 23° for 16 h, evaporated in vacuo, treated with water (10 ml) and extracted with dichloromethane (3×20 ml). The extracts were evaporated in vacuo and purified by flash chromatography on silica gel (Merck 9385), eluant ether:cyclohexane:triethylamine (50:50:2 to 100:0:2), to give the title compound as a colourless gum (0.157 g, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>O1CCCC1.CCCCCC>[OH:23][CH:22]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6])[C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1
Reactant: CNC(=O)c1cccc(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1cccc(C(O)c2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A solution of 3-bromo-N-methylbenzamide (3.48 g, 16.25 mmol) in dry tetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwise over 10 min. with 13 ml (32.5 mmol) of a 2.5 M solution of n-butyllithium in hexane. After 15 min. at −78° C., a solution of 4-fluorobenzaldehyde (2.5 g, 20.1 mmol) in tetrahydrofuran (10 ml) was added dropwise over 10 min. and the resulting mixture was stirred for another 45 min at the same temperature. The temperature was then allowed to reach −20° C. and the mixture was quenched by the addition of saturated ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer was washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue from ethyl acetate gave 1.60 g (38%) of the title compound as a white solid: mp: 138-139° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.0 and 3.01 (3H, 2 s, NCH3), 5.88 (1H, s, CH), 6.19 (1H, broad, NH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics), 7.41 (1H, t, J=7.6 Hz, aromatic), 7.49 (1H, d, J=7.6 Hz, aromatic), 7.66 (1H, d, J=7.6 Hz, aromatic), 7.79 (1H, s, aromatic). Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 69.41; H, 5.41; N, 5.63.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C[C@@H]1C[C@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50 mg, 0.38 mmol), benzyl bromide (0.050 mL, 0.42 mmol), potassium carbonate (58.4 mg, 0.42 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44.0 mg, 0.200 mmol, 52%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8].CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(CO)cc1F
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc(C=O)cc1F
Temperature: 35 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
To a solution of (5-fluoro-6-methyl-3-pyridinyl)methanol (468 mg, 3.32 mmol) in DCM (4 ml) was added CrO2 (Magtrieve) (4.2 g, 49.7 mmol). The mixture was stirred at 35° C. for 4 h. TLC (5% MeOH in DCM) showed starting material remaining. An excess of CrO2 (Magtrieve) (2.8 g, 33.3 mmol) was added. The mixture was stirred at 35° C. for 48 h. The solids were filtered off and the solvent evaporated to afford 144 mg (28%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=4)[CH:20]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]3[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=4)[CH:20]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c(N)cn2)c1

Procedure:
The product from Step 2 (2.7 g, 5.2 mmol) was dissolved in MeOH (20 mL), Pd/C (5% on C, 100 mg) was added the mixture was hydrogenated with a balloon of hydrogen for 2 days, then filtered through celite. The filtrate was concentrated to give the title compound which was taken on without purification. MS (ES+) m/e 491 [M+H]+.