Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: CC(C)(C)O
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of 2-trifluoromethylphenol (25 g., 0.15 moles), tert-butyl alcohol (12 g., 0.16 mole), trifluoroacetic acid (100 ml.) and 96% sulfuric acid (2 ml.) is stirred at about 20° C. for 48 hours. The mixture then is evaporated as far as possible under reduced pressure at 35°-40° C. The residue is dissolved in benzene (500 ml.) and the solution is washed with water, saturated NaHCO3 solution and saturated salt brine and dried over anhydrous MgSO4. The dried solution is again evaporated under reduced pressure and the temperature is finally raised to 140°-145° C. under 65 mm. pressure to remove unchanged 2-trifluoromethylphenol. The residue is distilled at 65 mm. after collecting a small fore-run (75% unchanged starting phenol and 25% product), 2-trifluoromethyl-4-(1,1-dimethylethyl)phenol (13.6 g.) is collected at 120°-132° C. as a pale pink oil that is 98% pure by gas liquid chromatography analysis and can be used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[C:5]=1[N+:22]([O-:24])=[O:23])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][S:19](=[O:26])[CH2:20][CH2:21]2)[C:5]=1[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
3.6 gm (0.01 mol) of 6-ethoxy-5-nitro-2-piperazino-4-thiomorpholino-pyrimidine were dissolved in 100 ml of methanol, a solution of 2.2 gm (0.01 mol) of sodium metaperiodate in 50 ml of water was added, and the mixture was refluxed for 4 hours. The reaction mixture was then poured into water, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, the chloroform was distilled off in vacuo, and the residue was recrystallized from ethanol. Yield: 2.9 gm (77% of theory); m.p. 223°-224°C.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(OCC)C>[C:19]([O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=CC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A three-neck round-bottom flask fitted with an addition funnel, thermometer and a mechanical stirrer was charged with 100 ml of water, 40 g (0.20M) of p-hydroxybenzophenone and 8.8 g of sodium hydroxide. The flask was cooled in an ice bath to 8°-10° C., then 20 g (0.22) of acryloyl chloride were added dropwise while holding the temperature at 8°-10° C. When the addition was complete, the reaction mixture was stirred for an additional half hour. Then 150 ml of diethyl ether was added to dissolve the product of the reaction. The ether layer was separated from the water layer and washed twice with 3% sodium hydroxide and twice with water. The solution was dried over magnesium sulfate, filtered and stripped. An amount of 43.0 g of an oily product was obtained and purified by recrystallization from absolute ethanol, from which an amount of about 34.7 g of white crystalline product was isolated.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=CC=CC=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:19]1(=[O:29])[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.Cl>CCOCC.C1C=CC=CC=1>[C:5]1([C:9]2[CH:18]=[C:17]([CH:16]=[CH:11][CH:10]=2)[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([OH:24])=[O:29])=[O:23])[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: Brc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
Under an argon atmosphere, 132 g of magnesium were dispersed in 500 mL of ether. A solution of 142 g of 2-(3-bromophenyl) naphthalene in 500 mL of ether was added to the dispersion, and then the mixture was stirred at room temperature for 1 hour. A solution of 74 g of phthalic anhydride in 150 mL of benzene was added to the mixture, and then the resultant reaction solution was stirred for 3 hours under reflux. After having been cooled to room temperature, the reaction solution was poured into ice water, and then 1 L of 10% hydrochloric acid was added to the mixture. The organic layer was separated and extracted with an aqueous solution of potassium carbonate. The alkaline extract was acidified, and then the resultant solid was washed with boiling water. The resultant crude product was recrystallized with acetic acid. Thus, 121 g of 2-(3-phenylbenzoyl)benzoic acid were obtained (in 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C@H:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][OH:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:33][CH2:32][C@H:31]([NH:30][C:27]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[C@H:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]1)=[O:29])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d, (R)-2-amino-4-methyl-pentan-1-ol (35.16 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (30-95% of MeCN/water) to give (2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-1-hydroxymethyl-3-methyl-butyl)-amide (26.2 mg, 24.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Agent: Cl[Fe](Cl)Cl
Solvent: O
Product: O=c1[nH]c(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
To a stirred suspension of 2-amino-4-(trifluoromethyl)benzamide (33.6 g, 0.16 mol) in water (750 mL) was added dropwise 4-chlorobenzaldehyde. Iron trichloride hexahydrate (133 g) was then added in portions. The reaction mixture was then heated at reflux for 24 h. After allowing the suspension to cool to room temperature, the precipitate was isolated by vacuum filtration washing with water (3×500 mL) and dried under vacuum (10 mbar, 50° C.). Yield=50 g, 94%; HPLC-mass spectrometry (LC-MS): 3.7 min, 325 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[C:27](Cl)(=[O:29])[CH3:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH:6]1[CH2:7][CH2:8][N:9]([C:27](=[O:29])[CH3:28])[CH2:10][CH2:11]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)C(C(=O)OCC)C2CCNCC2)cc1
Reactant: CC(=O)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)OCC)C2CCN(C(C)=O)CC2)cc1
Yield: 89 %

Procedure:
Ethyl(1-acetyl-4-piperidinyl){[4-(2-butynyloxy)phenyl]sulfonyl}acetate was prepared according to the general method as outlined in example 116 (step 1), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}(4-piperidinyl)acetate (1.5 g, 3.61 mmol) and acetyl chloride (0.26 ml, 3.61 mmol); yellow oil (1.35 g). Yield 89%; MS: 422 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20].[NH3:23]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:23])=[CH:4][C:3]=1[S:19]([OH:22])(=[O:21])=[O:20]
Reactant: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: N
Solvent: O
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O

Procedure:
It must be described as extremely suprising that the reaction of 1-amino-4-bromo-anthraquinone-2-sulphonic acid with ammonia in water under the reaction conditions employed, under pressure, should take place so uniformly and smoothly to give 1,4-diamino-anthraquinone-2-sulphonic acid, without the formation of significant amounts of 1-amino-4-hydroxy-anthraquinone-2-sulphonic acid, as reported in German Patent Specification No. 1,142,174.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].C[CH2:16][N:17](C(C)C)[CH:18](C)C.CNC.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:12]
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C(=O)N(C)C)cc1C
Yield: 5.6 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added a 2M solution of dimethylamine in THF (0.10 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-[(dimethylamino)carbonyl]-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (br. s., 1H) 6.37 (d, 1H) 4.22 (q, 2H) 3.10 (br. s., 3H) 2.97 (br. s., 3H) 2.26 (s, 3H) 1.28 (t, 3H). MS: m/z 225.5 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:29].C(OCC)C>C(OCC)C.CO>[ClH:29].[Br:1][C:2]1[C:3]([C:25]([F:28])([F:27])[F:26])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n1C1CCNCC1
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-[6-bromo-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate (D68, 0.95 g, 2.0 mmol) in diethyl ether (50 ml) and methanol (10 ml) was treated at room temperature with 1M HCl/diethyl ether (10 ml, 10 mmol) and stirred for 20 hrs. The precipitate was filtered off, washed with diethyl ether and dried to afford the title compound as a beige solid (0.71 g, 87%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]2[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]12)=[O:4].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:11]1([C:8]2[N:7]3[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:30][CH2:31]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3)CC1)CC=C2c1ccccc1

Procedure:
A mixture of 3.8 g of 4-(chloroacetyl)-4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile, 2.5 ml of N-benzylpiperazine and 1.6 g of sodium carbonate in 165 ml of toluene was reacted as described in Example 146, giving 4 g of the desired product, mp 156-158.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:21][CH:19]1[CH2:20][N:17]([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:7]([F:6])([F:22])[F:23])=[N:9][N:10]=3)[N:13]=2)[CH2:18]1)(=[O:4])=[O:3]
Reactant: OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Methanesulfonyl chloride (0.929 mL, 12 mmol) was added dropwise to a stirred partial solution of 1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-ol (2.59 g, 10 mmol) and triethylamine (1.951 mL, 14 mmol) in DCM (17 mL) at 0° C. The solution was allowed to warm to ambient temperature and stirred for 30 minutes. The precipitate was collected by filtration, washed with a little DCM, a little ethanol and ether. It was dried under vacuum to afford 6-[3-(methanesulfonyloxy)azetidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.400 g, 71.2%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH3:16][NH:17][NH2:18]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:17]([CH3:16])[N:18]=2)=[CH:5][CH:4]=1
Reactant: CNN
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CC(C)O
Product: COc1ccc(C2=NN(C)C(=O)CC2)cc1

Procedure:
In a 500 mL round bottom flask, 4-(4-methoxyphenyl)-4-oxobutyric acid (27 g, 132 mmol) and methylhydrazine (7.3 g, 8.5 mL, 159 mmol) in 2-propanol (150 mL) were stirred at reflux 12 h. The solvent was concentrated to about 50 mL, ether was added (˜50 mL) and the product collected by filtration, washed 1× with ether and dried under house vacuum. Yield 27 g (94%, purity >95%), mp 133-135° C. 1H NMR (CDCl3) δ 2.57 (m, 2H), 2.9 (m, 2H), 3.4 (s, 3H), 3.8 (s, 3H), 6.9 (d, 2H), 7.6 (d, 2H). MS m/z=218 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[OH:16].[C:18]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[O:16][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl)quinolin-4-ol (Step 1, 3.54 g, 13.3 mmol, 1 eq.) in acetone (75 mL) was added anhydrous K2CO3 (3.88 g, 28.0 mmol, 2.1 eq.), followed by iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.). The resulting mixture was stirred at reflux for 1.5 hours. An additional aliquot of iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.) was added and reflux was continued for an additional 1 hour. The reaction was cooled to room temperature, poured onto ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give 3.72 g (100% yield) of the desired product as a yellow solid, which was used in subsequent reactions without further purification. An analytical sample was prepared by recrystallization from hexane/ethyl acetate; MP=198-200° C.; MS (ES) m/z (relative intensity): 280 (M+H)+ (100).
Reaction SMILES: [OH:1][C:2]1[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][C:3]=1[CH:19]([CH3:21])[CH3:20].Cl[C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:16]([C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([CH:19]([CH3:21])[CH3:20])[C:2]=1[O:1][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[N:25][N:24]=1)[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:17])[CH3:18]
Reactant: Clc1nnnn1-c1ccccc1
Reactant: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cc(C(C)C)c(Oc2nnnn2-c2ccccc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
11 g of Methyl 3-(4-hydroxy-3,5-diisopropylbenzoyl]propionate was dissolved in 200 ml of N,N-dimethylformamide, followed by the addition of 8.15 g of 5-chloro-1-phenyl-1H-tetrazol and 10.4 g of potassium carbonate. The obtained mixture was stirred for 1 hour under heating, cooled to room temperature by allowing to stand and poured onto ice-water. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel chromatography (developer: 20% ethyl acetate/n-hexane) to give 14.1 g of the title compound as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([OH:56])=O)(=[O:44])=[O:43])=[C:37]([CH3:57])[CH:36]=1.[N:58]1([CH2:63][CH2:64][O:65][C:66]2([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:81])([F:80])[F:79])[CH:73]=3)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:57])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([N:69]2[CH2:70][CH2:71][C:66]([O:65][CH2:64][CH2:63][N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:80])([F:79])[F:81])[CH:73]=3)[CH2:67][CH2:68]2)=[O:56])(=[O:43])=[O:44])=[C:39]([CH3:41])[CH:40]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: FC(F)(F)c1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3cccc(C(F)(F)F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Diisopropylethylamine (4 eq.), EDCl HCl (1.2 eq.) and HOBt (1 eq.) were added to a mixture of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (10 ml). A mixture of 4-(2-(pyrrolidin-1-yl)ethoxy)-4-(3-(trifluoromethyl)phenyl)piperidine [amine H] and DIPEA (2 eq.) in methylene chloride (3 ml) was added dropwise, while cooling with ice, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and with sat. sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 78%. MS, Rt=3.9 min, m/z=696.4 [MH]+
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[C:26](O)(=[O:28])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:26](=[O:28])[CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: CC(=O)O
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (84.0 mg, 0.208 mmol) was suspended in dichloromethane, and the suspension was added with triethylamine (0.090 mL, 0.648 mmol) and anhydrous acetic acid (0.031 mL, 0.324 mmol), followed by stirring at room temperature for 12 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(acetylamino)propoxy]-7-iodoisoindolinone (78.6 mg, yield 92%).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([C:27]1[C:35]2[N:34]=[C:33]([O:36]CC)[N:32](C(OC(C)(C)C)=O)[C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1)=[O:26]>C1COCC1>[F:22][C:23]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:24]=1[C:25]([OH:26])([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)[C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[C:29]([C:46]2[C:47]([CH3:52])=[N:48][O:49][C:50]=2[CH3:51])[CH:28]=1
Reactant: CCOc1nc2c(C(=O)c3c(F)cccc3F)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: c1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2cnccn2)c2c(F)cccc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
n-BuLi (0.21 mL, 0.33 mmol) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (0.06 mL, 0.33 mmol) in THF (0.7 mL) at 0° C. and was allowed to stir for 5 minutes. Pyrazine (24 mg, 0.3 mmol) in THF (0.4 mL) was added and the reaction was stirred for an additional 5 minutes and then cooled to −78° C. tert-butyl 4-(2,6-difluorobenzoyl)-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in THF (0.4 mL) was added, the solution was allowed to stir for 5 minutes and then quenched with water. Solution was extracted three times with EtOAc, washed once with brine and concentrated. Crude was purified by reverse-phase HPLC and then taken up in EtOH (3 mL) and HCl (0.1 mL) and heated to 65° C. for 2 hours. Reaction was cooled and concentrated to afford desired product as a pale brown powder.