Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH:47]1([C:52](Cl)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>O1CCCC1>[CH:47]1([C:52]([NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:53])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCC1

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added cyclopentanecarbonyl chloride (0.060 mL, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). Completion of the reaction necessitated the addition of 2 more equivalents of reagents and a total reaction time of 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 699 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:17]1[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=1[Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(F)ccc1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 26.9 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 650 mg, 4.4 mmol), 2-chloro-5-fluorophenylboronic acid (Aldrich; 760 mg, 4.35 mmol), copper(II) acetate (807 mg, 4.4 mmol) and triethylamine (623 μL, 4.4 mmol) in 1,2-dichloroethane (4.5 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(2-chloro-5-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (322 mg, 27%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:31][C:32]([F:39])([F:38])[CH2:33][S:34]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:36])=[O:35]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)CC(F)(F)F)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 17.4 %

Procedure:
To the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL) was added 2,-2,-2-trifluoroethanesulfonyl chloride (28 μl, 0.25 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with of 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to give the title compound (5 mg, 17%). 1H NMR (300 MHz, DMSO-d6): δ 0.97 (d, J=6.62 Hz, 6 H) 1.49 (m, 2 H) 1.64 (m, 1 H) 4.31 (t, J=7.53 Hz, 2 H) 4.58 (q, J=9.93 Hz, 2 H) 7.17 (dd, J=7.35, 4.78 Hz, 1 H) 7.43 (m, 4 H) 8.38 (dd, J=7.72, 1.84 Hz, 1 H) 8.57 (d, J=2.94 Hz, 1 H) 10.63 (s, 1 H) 15.90 (s, 1 H). MS (ESI−) m/z 572 (M−H)−.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[O:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nonc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 34% yield: mp 110-112° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.54-8.52 (m, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.72-7.69 (m, 2H), 7.39-7.35 (m, 1H), 7.30-7.28 (m, 1H), 6.14 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.57 (s, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 2.62 (s, 3H): MS (ES+) m/z 450.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33].C(O)C(N)(CO)CO>ClCCCl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32]([NH:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)=[CH:5][CH:6]=1)=[O:33]
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(N2CC[C@@H](N3CCC[C@@H]3C)C2)nc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.1 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 5-fluoro-2-methyl-benzoyl chloride (47 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 10.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: C[C@H]1COc2c(ccc(F)c2F)N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
1.20 g (99.8% ee) of (3S)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was dissolved in toluene (0.5 ml). After adding diethyl ethoxymethylenemalonate (1.92 g), the mixture was stirred at 120 for 30 minutes and then at 140° C. under reduced pressure for 30 minutes. The residue was subjected to silica gel column chromatography. Thus, 2.19 g (99.8% ee) of the title compound was obtained as a yellow oily product. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH:18]1[NH2:24]>>[O:12]1[CH2:13][CH2:14][C@@H:10]([O:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:24][CH:18]3[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][CH:17]3[CH3:16])[N:4]=2)[CH2:11]1
Reactant: Clc1ncc(Br)c(O[C@@H]2CCOC2)n1
Reactant: CC1CCCC(C)C1N
Agent: Cl
Product: CC1CCCC(C)C1Nc1ncc(Br)c(O[C@@H]2CCOC2)n1

Procedure:
Using the procedure of Example 78, Step 2, (R)-5-bromo-2-chloro-4-(tetrahydrofuran-3-yloxy)pyrimidine was reacted with 2,6-dimethylcyclohexanamine HCl salt to provide the title compound. MS (ESI) m/z: Found: 370 (M++1), Calc. 369 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(Br)cc1
Yield: 77.3 %

Procedure:
A 100 mL round-bottom flask was charged with ethyl 2-(4-bromophenyl)-2-methylpropanoate (0.670 g, 2.47 mmol) in 2.5 mL of MeOH. Potassium hydroxide (2.0 M, 2.47 mL, 4.94 mmol) was added at 0° C. The reaction was heated to reflux for 2 h. After cooling the reaction was extracted with ethyl acetate. The aqueous layer was acidified with 2M HCl and extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 464 mg of 2-(4-bromophenyl)-2-methylpropanoic acid as a white solid.
Reaction SMILES: [CH:1]1([C@H:6]2[C:31](=[O:32])[N:30]3[CH2:33][C@@H:27]([CH2:28][C@H:29]3[C:34]([O:36][CH3:37])=[O:35])[O:26][C:25]3[N:20]([C:21](=[O:38])[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[O:9][C:8](=[O:39])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:47])C(=O)C1>C(#N)C>[Br:47][C:22]1[C:21](=[O:38])[N:20]2[C:25]([O:26][C@H:27]3[CH2:33][N:30]([C:31](=[O:32])[C@H:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[NH:7][C:8](=[O:39])[O:9][C@H:10]4[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:13][CH2:12][CH2:11]4)[C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:28]3)=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(cccc1=O)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCCn1c(ccc(Br)c1=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 25 mL round bottom flask under nitrogen was charged with the product of Example 82 Step 1 (238 mg, 0.438 mmol), NBS (39.0 mg, 0.219 mmol), and acetonitrile (15 ml). Stirred at room temperature 10 minutes. HPLC/MS shows mainly desired; little starting material. Added an additional 10 mg NBS. Still a little starting material remaining. Added another 10 mg NES. HPLC/MS looks good. Cooled. Evaporated. Subjected to ISCO chromatography eluting with a hexane/ethyl acetate gradient. Evaporated fractions containing product to give the title compound as a white solid. (224 mg, 0.360 mmol, 82% yield). LCMS (ES+) m/z 623.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:4]=1/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([CH3:29])=[C:19]([NH:18][C:7](=[O:8])[CH:6]=[CH:5][C:4]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([O:14][CH3:15])[C:3]=2[O:2][CH3:1])[CH:20]=1
Reactant: COc1ccc(/C=C/C(=O)Cl)c(OC)c1OC
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)C=Cc2ccc(OC)c(OC)c2OC)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve trans-2,3,4-Trimethoxycinnamic acid (50) (200 mg, 0.84 mmol) in anhydrous DCM (4.4 mL) at it and add anhydrous DMF (3 drops, cat. amount). Then add slowly oxalyl chloride (96 μL, 1.09 mmol) stir the turbid mixture for additional 2 h at rt. Remove solvent and dry the residue in oil pump vacuum to obtain trans-2,3,4-Trimethoxycinnamic acid chloride (51) (ca. 0.84 mmol) as an yellow solid. Dissolve acid chloride (51) (108 mg, 0.42 mmol) in anhydrous DCM (4.0 mL) and add it to an ice cooled solution of Methyl 3-amino-4-methylbenzoate (52) (69 mg, 0.42 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (1.2 mL). Stir the resulting reaction mixture at rt overnight. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4. Purify the crude product by filtration through a short pad of silica gel with EtOAc and remove solvent to obtain 4-Methyl-3-[3-(2,3,4-trimethoxy-phenyl)-acryloylamino]-benzoic acid methyl ester (53) (99 mg, 61%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 2.35 (s, 3H); 3.87 (s, 3H); 3.88 (s, 6H); 3.91 (br.s, 3H); 6.59 (d, 1H, J=15.6 Hz); 6.68 (d, 1H, J=8.6 Hz); 7.08 (br.s, 1H); 7.20-7.29 (m, 2H); 7.77 (br.d, 1H, J=8.6 Hz); 7.90 (d, 1H, J=15.6 Hz); 8.55 (br.s 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1>CCOCC.CCN(CC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(C)CC[C@H]1c1ccc(Cl)cc1
Yield: 18 %

Procedure:
Concentration of the mother liquor from Example 1 gave a mixture of compounds 1 and 2. Flash chromatography on silica gel using ether/Et3N 9/1 as eluent gave compound 2 (2.0 g, 18%): 1H NMR (benzene-d6) δ—1.4-1.5 (m, 1H), —1.62 (dq, 1H, J=3.9 and 12.6 Hz), 1.75 (dt, 1H, J=2.7 and 12.0 Hz), 2.06 (s, 3H), 2.0-2.15 (m, 1H), 2.54-2.63 (m, 1H), 2.68 (dt, 1H, J=4.2 and 11.7 Hz), 2.86-3.0 (m, 2H), 3.08 (s, 3H), 6.87 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.7 Hz); 13C NMR (CDCl3) δ 33.1, 44.0, 46.1, 49.1, 51.5, 55.7, 58.1, 128.6, 128.7, 132.3, 141.9, 173.4; MS m/z (%) 267 (M+, 17), 208 (30), 128 (16), 114 (16), 43 (100).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][C:4]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere biphenyl (50 g) was stirred in dichloromethane (450 mL). The flask was placed in an ice bath and to it was added benzoyl chloride (46 mL) via addition funnel slowly over 20 minutes. To that mixture was added anhydrous aluminum chloride (51 g) via solid addition funnel, slowly over 10 minutes. After the aluminum chloride addition was complete the reaction mixture allowed to warm to room temperature and to stir for 16 hours. The reaction mixture was slowly poured into a beaker containing ice and a 10% aqueous solution of hydrochloric acid (600 mL) while stirring vigorously. A separatory funnel was used to separate the organic and aqueous layers. The recovered organic layer was then washed with water (2×500 mL), washed with a saturated aqueous solution of sodium chloride (500 mL), dried over sodium sulfate and concentrated by rotary evaporation. The resulting solid was slurried in a 25% v/v mixture of ethyl acetate in hexanes. The solid was collected by vacuum filtration, and then washed with cold diethyl ether (2×200 mL) to yield 57 g of [1,1′-biphenyl]-4-yl(phenyl)methanone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:23][CH2:22][CH2:21][S:20]1.[CH3:24][N:25]=[C:26]=[S:27].C>CCCCCC.C(O)C.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:24][NH:25][C:26]([C:19]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH2:23][CH2:22][CH2:21][S:20]1)=[S:27]
Reactant: CN=C=S
Reactant: c1ccc(C2CCCS2)nc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=S)C1(c2ccccn2)CCCS1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
A solution of diisopropylamine (22.5 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47:53 by volume; 182 cc) is added dropwise, in the course of 14 minutes, to a 1.6 M solution of n-butyllithium in hexane (142 cc), which has been cooled to -55° C. The mixture is stirred for 5 minutes at a temperature of about -60° C. and a solution of 2-(pyrid-2-yl)tetrahydrothiophene (30 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47:53 by volume; 182 cc) is added in the course of 13 minutes. After stirring for 7 minutes at -65° C., a solution of methyl isothiocyanate (16.8 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47:53 by volume; 90 cc) is added in the course of 13 minutes at a temperature of the order of -60° C. The reaction mixture is subsequently stirred for 1 hour at the same temperature and then for 1 hour whilst allowing the temperature to rise gradually to +5° C. After adding distilled water (900 cc), the reaction mixture is extracted twice with ethyl acetate (900 cc in total). The combined organic extracts are washed three times with distilled water (2700 cc in total), dried over anhydrous sodium sulphate and concentrated to dryness. The residue (43 g) is dissolved in boiling ethanol (180 cc). After filtering hot, the solution is kept for 24 hours at a temperature of about 4° C. The crystals which have appeared are filtered off, washed with ethanol (10 cc) and then twice with diisopropyl ether (30 cc in total) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C., in the presence of potassium hydroxide pellets. 1.9 g of a product prepared under the same conditions are added to the product thus obtained (12.5 g), the whole is then dissolved in boiling ethanol (95 cc) and the solution, to which decolourising charcoal (1 g) is added, is filtered hot and then kept, after cooling, for 1 hour at a temperature of about 5° C. The crystals which have appeared are filtered off and washed with ethanol (10 cc) and then twice with diisopropyl ether (30 cc in total). After drying under reduced pressure (1 mm Hg) at 55° C., N-methyl-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (12.5 g) melting at 131° C., is obtained.
Reaction SMILES: [CH2:1]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C(=O)C)=[C:15]([O:23]C(=O)C)[CH:14]=1)[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>CO>[CH2:1]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:23])[CH:14]=1)[C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(C(N)=O)c1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(C(N)=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a chilled solution of 16.88 g of the mixture containing octyl 3,4-diacetoxyphenylacetamide and 100 ml of methanol was added 16 ml of 5 N NaOH. The reaction mixture was stirred for two hours at room temperature. The methanol was removed on a rotary evaporator, the residue dissolved in 100 ml of 0.1 N NaOH and the solution extracted with 100 ml of ether. The resulting aqueous phase was acidified with conc. HCl and thrice extracted with 150 ml of ether. The combined ether extracts were washed with 100 ml H2O, dried (Na2SO4), filtered and evaporated to yield 8.91 g of crude product. This material was chromatographed on silica gel with 60% ethyl acetate/hexane and subsequently recrystallized from ether-pentane to yield 2.3 g of white crystalline octyl 3,4-dihydroxyphenylacetamide, mp. 83°-85° C. Anal. Calc'd for C16H25NO3 : C, 68.78; H, 9.02; N, 5.01. Found: C, 68.69; H, 9.08; N, 4.98.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1ccccc1NC(=S)Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: N
Product: N=C(Nc1ccccc1F)Nc1ncccc1OCc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of yellow mercuric oxide (4.13g, 0.019 mol), N-[3-(2-chloro-6-fluoro -benzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)thiourea (3.10g, 0.0076 mol) and methanolic ammonia solution (60 ml) was stirred for 24 hours at room temperature. The mixture was filtered through celite and the filtrate evaporated to a yellow solid, which was recrystallised from ethyl acetate/pet. ether. Yield 1.51 g (51%), m.p 138°-140 ° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH2:23]([NH:25][CH3:26])[CH3:24]>>[CH2:23]([N:25]([CH3:26])[C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:20][CH:19]=1)[CH3:24]
Reactant: CCNC
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: CCN(C)C(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid and N-ethylmethylamine using a similar procedure to that described for Example 2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(O)=[O:2].S(=O)(=O)(O)O.[CH2:41]([OH:43])[CH3:42]>>[CH2:41]([O:43][C:4](=[C:1]=[O:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH3:42]
Reactant: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=C=O)CCCCCCn1c(-c2ccc(OC)cc2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl-imidazole (0.4 g) was reacted with ethanol and concentrated sulphuric acid in a method similar to Example 18 to give, after work-up and column chromatography on silica gel eluted with a dichloromethane:ethanol gradient, 1-(7-ethoxy-carbonylheptyl)-2-(4-methoxyphenyl)-4,5-diphenylimidazole (0.21 g, 50%) as an oil. Found: C, 77.39; H, 7.55; N, 5.96%; C32H36N2O3 requires: C, 77.39; H, 7.31; N, 5.64%.