Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[Cl:10]Cl>>[Cl:10][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: ClCl
Reactant: Cc1ccc(F)c(F)c1
Product: Cc1cc(F)c(F)cc1Cl

Procedure:
As shown in the above reaction, a mixture of 4-chloro-1-methyl-4,5,5-trifluorocyclohexene (IIIa) and 5-chloro-1-methyl-4,4,5-trifluorocyclohexene (IIIb) is prepared by reacting chlorotrifluoroethylene (CTFE) (I) and isoprene (II) at temperature range of 390 to 480° C. through continuous vapor phase condensation in a flow reactor and distilling the resultant. The mixture is dehydrohalogenated in the presence of alkali metal hydroxide and a phase transition catalyst to form 3,4-difluorotoluene (IV). The 3,4-difluorotoluene is reacted with chlorine gas in the presence of catalysts consisting of ferro-shaving and ferric chloride at temperature range of -10 to 40° C. without using any organic solvent to form 2-chloro-4,5-difluorotoluene (V). The 2-chloro-4,5-difluorotoluene is photo-reacted with chlorine gas under a lighting mercury lamp at temperature range of 80 to 140° C. without using any organic solvent to form 2-chloro-4,5-difluorobenzotrichloride (VI). The 2-chloro-4,5-difluorobenzotrichloride is reacted with aqueous acid solution at temperature range of 35 to 80° C. without using any organic solvent to give 2-chloro-4,5-difluorobenzoic acid (VII). The 2-chloro-4,5-difluorobenzoyl chloride (VIII) according to the present invention is prepared by reacting 2-chloro-4,5-difluorobenzotrichloride (VI) with zinc oxide.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=7.4, 1H), 7.57 (d, J=4.2, 2H), 6.63 (d, J=8.7, 2H), 4.44-4.37 (m, 1H), 3.56 (dd, J=10.2, 2.9, 1H), 3.39 (dd, J=10.0, 7.6, 1H), 3.30-3.21 (m, 2H), 3.03 (dd, J=9.9, 3.5, 1H), 2.79-2.68 (m, 2H), 2.47 (s, 3H), 2.12 (dt, J=12.4, 6.9, 1H), 2.08-2.01 (m, 1H), 2.00-1.88 (m, 2H), 1.79-1.57 (m, 3H), 1.39 (dtd, J=13.1, 8.0, 5.1, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:31]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[C:11]1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl2-tert-butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 115, 33 mg, 0.080 mmol) in DMF (1 ml) was added benzyl bromide (47 μl, 0.40 mmol) and K2CO3 (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 24 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) followed by PTLC (5% MeOH—CH2Cl2) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[C:4]([NH2:16])[CH:3]=1.[OH-:17].[Na+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].O>[NH2:16][C:4]1[CH:3]=[CH:2][C:15]([C:15]2[CH:2]=[CH:3][C:4]([NH2:16])=[C:5]([C:6](=[O:17])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=2)=[CH:14][C:5]=1[C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: [Na+]
Solvent: O
Solvent: C1=CCCC=CCC1
Product: Nc1ccc(-c2ccc(N)c(C(=O)c3ccccc3)c2)cc1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
4-Bromo-2-aminobenzophenone (0.55 g, 2.0 mmol) was dissolved in dry and deoxygenated dimethylformamide (10 ml) in an inert atmosphere box. To this was added in portions bis(1,5-cyclooctadiene)nickel (O) (0.55 g, 2.0 mmol). The reaction was moved from the inert atmosphere box to a vacuum-argon manifold using standard Schlenk-wave techniques. The reaction was heated at 5°-55° C. for 4 hrs. and left at room temperature overnight. The mixture was poured into 200 ml of water which was made slightly basic with sodium hydroxide. The water was extracted several times with ethyl acetate which after drying with sodium sulfate and evaporation gave a dark brown liquid (0.48 g). Recrystallization from hexane yielded 100 mg of yellow brown solid mp 180°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3Cl)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-chloroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 168bp. 1H (500 MHz, CDCl3) δ 7.53 (d, J=7.7 Hz, 1H), 7.35-7.41 (m, 3H), 6.97 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 6.56 (s, 1H), 5.00 (s, 2H), 3.39 (s, 3H), 2.26 (s, 3H). LCMS (ESI) m/z: 370.1
Reaction SMILES: IC1N(S(C2C=CC(C)=CC=2)(=O)=O)C2N=CC=C(C#N)C=2C=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[N:44](S(C2C=CC(C)=CC=2)(=O)=O)[C:37]2[N:38]=[CH:39][CH:40]=[C:41]([C:42]#[N:43])[C:36]=2[CH:35]=1>C(OCC)(=O)C.CCCCCCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[C:34]1[NH:44][C:37]2[N:38]=[CH:39][CH:40]=[C:41]([C:42]#[N:43])[C:36]=2[CH:35]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: Cc1ccc(S(=O)(=O)n2c(I)cc3c(C#N)ccnc32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4[nH]3)c2c1

Procedure:
By proceeding in a similar manner to Reference Example 12(a) but using 2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [Reference Example 62(a)] there was prepared the title compound as a yellow solid, m.p. 303–304° C., TLC RF=0.07 (ethyl acetate/heptane 1:1) and 2-(5-methoxy-1H-indol-3-y)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile [Reference Example 100] as a brown oil. MS: 443 (MH+). TLC: RF=0.38 (ethyl acetate/heptane 1:1).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[Cl:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[CH2:12][C:13](=[O:14])[CH3:15])[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a solution of methyl-2-chloroisonicotinate (11.93 g, 69.53 mmol) in THF (200 mL) was added acetone (14.19 mL, 153 mmol). The solution was warmed to 35° C. when sodium methoxide (94.13 g, 76.48 mmol) was added sequentially over 20 minutes. The mixture was stirred for 30 minutes, and then brought to reflux for 2.5 hours. The solvent was removed under reduced pressure and then taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to yield 1-(2-chloro-4-pyridinyl)-1,3-butanedione (4.97 g, 76%) as a light brown colored solid. This was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:49][CH3:50].COC(C)(C)C>CN(C)C=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH:34]([N:37]([CH2:49][CH3:50])[S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: CCI
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCN(C1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 150 mg (0.227 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml dimethylformamide were added 14 mg (0.35 mmol) sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 30 min. 22 mg (0.27 mmol) iodoethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml tert-butyl methyl ether and washing with 20 ml water and with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 86 mg (55%) of the title compound as an off-white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17](Cl)[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=[O:28])C.[Na+].C(=O)(O)[O-].[Na+].Cl>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[NH:16][C:17](=[O:28])[N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Reactant: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 120 °C
Reaction time: 22 h
Yield: 21 %

Procedure:
4-(2,8-Dichloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (1.0 g) was dissolved in dimethylsulfoxide (10 mL), and then sodium acetate (425 mg) and sodium bicarbonate (326 mg) were added to this solution. After stirring the reaction solution at 120° C. for 22 hours, 1 N aqueous hydrochloric acid (5.0 mL) and water (80 mL) were added to the reaction solution, and this was extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (200 mg).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30](O)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30]([NH:1][N:2]4[C:7](=[O:8])[C:6]5[S:9][CH:10]=[CH:11][C:5]=5[C:4]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:3]4)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(O)(C3)C1)C2
Product: O=C(CC12CC3CC(CC(O)(C3)C1)C2)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(3-hydroxyadamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.70-7.73 (m, 2H), 7.56-7.58 (m, 4H), 4.39 (s, 1H), 2.12 (s, 2H), 2.07-2.12 (m, 2H), 1.41-1.62 (m, 12H); MS (APCI+) M/Z 436 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>C1COCC1.C(=O)([O-])O.[Na+]>[C:41]([O:44][CH2:45][C:46]([NH:2][CH2:3][CH2:4][N:5]([C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7])[CH3:33])=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)N(C)CCNC(=O)COC(C)=O)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of the compound of Example 103 (150 mg, 0.31 mmol) and triethylamine (69 mg, 0.68 mmol) in THF (10 mL) was added acetoxyacetyl chloride (46 mg, 0.34 mmol) under ice-cooling. After stirring at room temperature for 1 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (140 mg, 82%) as white crystals.
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.0345 g, 0.089 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 0.0613 g, 0.11 mmol) in toluene (2 mL) at ambient temperature. After stirring overnight, the homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (1.34 g). Methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.250 g, 1.11 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) was added to the toluene solution, the solution was heated to 55° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol) was added. After 2 hours at 55° C., the solution was diluted with acetonitrile (11.5 mL). Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 84% yield (84% chemoselectivity) and 84% enantiomeric excess of the S-enantiomer.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:4][CH2:3]1.C1C(O)=CC=CC=1C.[CH3:23][N:24]([CH3:27])[C:25]#[N:26].[OH-].[Na+]>O>[CH3:23][N:24]([CH3:27])[C:25]([NH2:26])=[N:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[N:5]1[CH2:4][CH2:3][O:2][CH2:7][CH2:6]1
Reactant: CN(C)C#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: O
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-morpholinoaniline hydrochloride (19.2 g), m-cresol (80 ml) and dimethylcyanamide (9.45 g) was heated at 100° C. for five hours, cooled and added to the mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid separated by filtration, washed with water and dissolved in dichloromethane. The solution was dried and the solvent removed to give a residue which wa recrystallised from hexane to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 142°-143° C.).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]2=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.FC(F)(F)C([O-])=O.[Tl+].[I-:25].[K+]>>[I:25][C:3]1[C:4]2[C:15](=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=[CH:1][CH:2]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: [I-]
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Agent: [Tl+]
Product: O=c1c2ccccc2ccc2cccc(I)c12

Procedure:
2.06 g of dibenzosuberenone [CAS No. 2222-33-5] was subjected to the procedure of Example 1-g using 6.5 g of thallium trifluoroacetate and 2.0 g of potassium iodide, to give 1.0 g of a mixture of the title compound with dibenzosuberenone as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.6 g, 1.23 mmol) was dissolved in NMP (5 mL), morpholine (0.14 mL) was added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.30 (q, J=6.8 Hz, 2H), 3.75 (s, 2H), 3.64 (m, 4H), 3.46-3.21 (m, 8H), 2.69 (s, 3H), 2.41 (m, 4H), 1.38 (s, 9H), 1.33 (t, J=6.8 Hz, 3H); MS m/z 541.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Cl)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
5-Chloro-2-fluoroaniline (25 g, 172 mmol) was added to conc. hydrochloric acid (150 mL, 37%). The mixture was cooled (−10° C.) and a solution of sodium nitrite (11.9 g, 172 mmol) in water (193 mL) was added slowly (<-5° C.). This done, a solution of tin(II)chloride (118 g, 618 mmol) in conc. hydrochloric acid (116 mL) was added slowly (−6° C.). The mixture was stirred for 1 h, filtered through Celite® and the filter cake washed extensively with water. The filtrate was adjusted to pH 14 with conc. sodium hydroxide solution and the suspension extracted with diethylether. Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was removed in vacuo to yield the title compound as yellow solid (22.9 g, 83%), EI-MS: m/e=160.0 (M+).
Reaction SMILES: [CH2:1]([O:8][NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:22]([N:21]([CH3:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CCC(CC)NOCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)N(OCc1ccccc1)C(=O)N(C)c1ccccc1
Temperature: 130 °C
Yield: 59.5 %

Procedure:
A tube was charged with a stir bar, N-benzyloxy-N-(1-ethylpropyl)amine (2.0 g, 10.3 mmole), tetrahydrofuran (5 mL), triethylamine (4.31 mL), N-methyl-N-phenylcarbamoyl chloride (1.75 g, 10.3 mmole), and 4-dimethylaminopyridine (1 mg). The tube was flushed with nitrogen, sealed and then heated to 130° C. After 48 hours the reaction mixture was cooled to ambient temperature and concentrated under vacuum. The residue was purified by chromatography (silica gel; 9:1 hexanes:ethyl acetate) to provide 2.0 g of 1-benzyloxy-1-(1-ethylpropyl)-3-methyl-3-phenylurea.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-:21].[Na+]>Cl>[CH3:1][N:2]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH2:19])=[O:21])[CH:16]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CN(C)c1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Product: CN(C)c1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Yield: 52.1 %

Procedure:
A solution of 3-[4-(dimethylamino)phenyl]-1H-indazole-5-carbonitrile (125 mg, 0.476 mmol) in 5.00 mL of concentrated aq. HCl was heated at 47° C. for 1 h, and then added dropwise with stirring to 20 mL of 6.0 N aq. NaOH that was cooled in a water bath. The mixture was extracted with 2×EtOAc, and the combined organics were dried (Na2SO4). Purification by silica gel chromatography using EtOAc as eluent afforded the title compound (69.3 mg, 52.1% yield): 1H NMR (DMSO-d6) δ 13.19 (s, 1H), 8.58 (s, 1H), 8.10 (br s, 1H), 7.9S–7.82 (m, 3H), 7.56 (d, 1H), 7.30 (br s, 1H), 6.84 (d, 2H), 2.98 (s, 6H); ES-MS (m/z) 281 [M+1]+.