Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:24]([C:21]3([CH3:20])[CH2:23][CH2:22]3)=[O:25])=[CH:9][C:8]=2[C:14]([F:15])([F:16])[F:17])=[CH:18][CH:19]=1
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2ccc(Oc3ccc(Cl)cc3)c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of 5.75 g (0.02 mole) of the amine prepared under (b) above in 40 ml of tetrahydrofuran was added dropwise 2.4 g (0.02 mole) of 1-methylcyclopropylcarboxylic chloride. The mixture was stirred and heated at 60° C. for 0.5 hour, poured into ice water and filtered. The filter cake was recrystallized from ether-hexane (1:3) to give 6.5 g (88%) of product, m.p. 115°-117° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(O)C>[C:1]([NH:4][C:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCCCCCCCCCCCCOC1CCCCO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCCCCCCCOC1CCCCO1)(NC(C)=O)C(=O)OCC
Yield: 39.2 %

Procedure:
Diethyl acetamidomalonate (6.996 g) and 3.189 g of sodium ethoxide were dissolved in 130 ml of dry ethanol and a solution of 10.698 g of 1-bromo-12-tetrahydropyranyloxydodecane in 200 ml of dry ethanol was added thereto. The mixture was refluxed under heating for 8 hours. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography to give 5.837 g of diethyl 2-acetamido-2-(12-tetrahydropyranyloxydodecyl)malonate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[CH:6]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:20]1([S:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH2:14][C:15]3[NH:19][CH:18]=[CH:17][N:16]=3)=[CH:6]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCn1cc(Cc2ncc[nH]2)c2ccccc21
Solvent: c1ccncc1
Product: O=S(=O)(NCCCn1cc(Cc2ncc[nH]2)c2ccccc21)c1ccccc1
Yield: 29.5 %

Procedure:
A mixture of 1-(3-aminopropyl)-3-(1-imidazolylmethyl)indole (1.27 g) and benzenesulphonyl chloride (0.88 g) in pyridine (15 ml) was heated on a steam bath for 2 hours and then evaporated to dryness. The residue was treated with an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. The column was first eluted with chloroform to remove a small amount of impurity and then the product was eluted with a mixture of chloroform and methanol (20:1). Evaporation of the product containing fractions gave an oil which crystallised on standing. The product was recrystallised from ethyl acetate containing a trace of methanol to give 1-(3-benzenesulphonylaminopropyl)-3-(1-imidazolylmethyl)indole (0.58 g), m.p. 130°-131° C. Found: C, 63.71; H, 5.58; N, 14.03. C21H22N4O2S requires: C, 63.93; H, 5.62; N, 14.20.
Reaction SMILES: [N:1]1([C:5](=[O:16])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][C:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)=[O:16])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CC(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
1-(Azetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.27 mmol) was taken in methanol (20 ml) and at 0° C., Pd—C (10%, 0.05 g) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.34 gm).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])C.[OH-].[Na+]>C(O)C>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([OH:28])=[O:3])=[CH:21][CH:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: CCCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 27 g of α-[p-(1-cyclohexenyl)-phenoxy]-undecanoic acid ethyl ester in 150 ml of ethanol are added 100 ml of 2N sodium hydroxide solution and the mixture stirred for 2 hours at room temperature. The ethanol is stripped off in vacuo and the residue partitioned between 2N hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness. Distillation of the residue at 0.04 mm yields in the fraction boiling at 185°-190° C the α-[p-(1-cyclohexenyl)-phenoxy]-undecanoic acid of the formula ##STR20## (m.P. 70°-73° C).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[N:11]([O-])=O.[Na+].[F:15][P-:16]([F:21])([F:20])([F:19])([F:18])[F:17].[NH4+]>O>[F:15][P-:16]([F:21])([F:20])([F:19])([F:18])[F:17].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]#[N:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: O
Product: COc1ccc([N+]#N)cc1
Temperature: -5 °C

Procedure:
1440 cc. of 5N aqueous hydrochloric acid was charged into a 3000 cc. capacity vessel equipped with a stirrer, thermometer, condenser and addition funnel. 184.5 g. (1.5M) of p-anisidine was added and the mixture stirred at room temperature until complete conversion to the ammonium salt was achieved. The solution was cooled in an ice-methanol bath to -5° C. Diazotization was achieved by adding 184.5 g. (1.52M) of sodium nitrite in 300 ml of water dropwise over a 30-minute period while maintaining the temperature between 0°-5° C. A solution of 244.5 g. (1.5M) of ammonium hexafluorophosphate in 300 ml of water was added to precipitate the hexafluorophosphate salt. The salt was filtered, washed chloride-free and vacuum-dried at 25° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(Cl)(Cl)=O.[CH3:16][NH:17][CH3:18].O>C(Cl)Cl.CN(C=O)C>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:17]([CH3:18])[CH3:16])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: CNC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a suspension of 4-formylbenzoic acid (4.00 g, 26.7 mmol) in dry DCM (8 mL) were added thionyl chloride (2.92 g, 40.0 mmol) and DMF (0.6 mL) dropwise at ambient temperature under nitrogen. The reaction mixture was refluxed for 2 h. After cooling, this mixture was added to 33% dimethylamine in water (10.5 mL, 72 mmol) dropwise over 15 min in an ice-water bath, and the reaction mixture stirred for 1 h at the same temperature. The solvent was evaporated in vacuums. The residue was purified by chromatography on silica gel to give the title compound (2.5 g, yield 53%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.86 (s, 3H), 3.30 (s, 3H), 7.60 (d, J=7.6 Hz, 2H), 7.95 (d, J=7.6 Hz, 2H), 10.04 (s, 1H); LC-MS (ESI) m/z: 178 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])[CH2:6][CH2:7]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2Cl)CC1)c1ccccc1
Yield: 78.2 %

Procedure:
0.14 g (0.00062 mol) of 1-(2-chloro-benzyl)-piperidin-4-ol and 0.17 ml (0.00123 mol) of triethylamine were dissolved in 6.2 ml of toluene, treated with 0.09 ml (0.000776 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1→1:2). 0.16 g (78%) of 1-(2-chloro-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[S:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[S:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ncns2)cc1F
Yield: 77.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (146 mg, 0.236 mmol) prepared in Example 9b, triethylsilane (0.3 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (86.0 mg, 78%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]1[N:12]([CH3:31])[C:13](=[O:30])[C:14]([O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=1.N1C=CC=CC=1.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>ClCCl.CN(C1C=CN=CC=1)C>[C:22]([O:21][C:14]1[C:13](=[O:30])[N:12]([CH3:31])[C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]2[C:45]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=2)=[O:46])=[N:16][C:15]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)c2ccccn2)n(C)c(=O)c1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
The residue of Step 1 was dissolved in dichloromethane. Pyridine, picolinoyl chloride hydrochloride and a catalytic amount of DMAP were added. A further addition of the reactants was made after two hours. After evaporation of the solvent, the residue was diluted with EtOAc, the organic phase washed with water, dried (Na2SO4) and evaporated to afford the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]([CH2:58][NH2:59])[OH:57]>>[OH:57][CH2:56][CH2:58][NH:59][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][C:15]([CH3:31])([CH3:30])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([CH3:19])([CH3:20])[CH2:18]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound, a colorless glass, is prepared from the reaction of 2-chloro-4,6-bis[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and ethanolamine according to the procedure of Example 1.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][OH:35])[C:30](=[O:33])[O:31][CH3:32])=[C:25]([CH3:36])[CH:24]=1.O>C(Cl)Cl>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:34][O:35][C:7](=[O:10])[CH2:8][CH3:9])[C:30](=[O:33])[O:31][CH3:32])=[C:25]([CH3:36])[CH:24]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)N(CO)c1ccc(OCc2nc3ccccc3s2)cc1C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OCN(C(=O)OC)c1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
0.1 ml of pyridine and 0.1 ml of propionyl chloride were added to a solution of 121 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N-hydroxymethylcarbamate (prepared as described in Example 19 above) in 2 ml of methylene chloride cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude residue which was purified by column chromatography through silica gel using a 5:1 by volume mixture of hexane and ethyl acetate to give 133 mg (yield 94%) of the title compound as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[C:56]([C:61]#[N:62])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:51][CH:50]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[C:56]([C:61]#[N:62])=[N:57][CH:58]=[CH:59][CH:60]=4)=[CH:51][CH:50]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: N#Cc1ncccc1-c1ccc(O)cc1
Product: N#Cc1ncccc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
The title compound 58 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 58A in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.84 (dd, J=4.6, 1.53 Hz, 1H), 7.98 (dd, J=7.98, 1.53 Hz, 1H), 7.95 (d, J=7.67 Hz, 1H), 7.27-7.7 (m, 9H), 7.01-7.03 (m, 2H), 4.77 (s, 2H), 4.01 (t, J=6.29 Hz, 2H), 3.66 (t, J=5.98 Hz, 2H), 3.12-3.16 (m, 2H), 2.97 (t, J=5.98 Hz, 2H), 1.95-2.02 (m, 2H). ESI (+)/MS: 673 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:28]C(=O)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Yield: 98.5 %

Procedure:
To acetic acid 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (2.7 g, 5.4 mmol) in tetrahydrofuran (88 mL) and methanol (30 mL) at room temperature was added dropwise an aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h the reaction mixture was concentrated under reduced pressure. The resulting residue was combined with water (200 mL) and acidified with 10% aqueous hydrochloric acid to a pH of 1. The solution was extracted with diethyl ether (300 mL) and the diethyl ether layer was washed twice with water and dried (Na2SO4). Concentration under reduced pressure gave the title compound as a white solid (2.4 g, 100%): (DMSO-d6): δ 9.54 (s, 1H), 8.16 (d, 1H), 7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.03 (s, 1H), 6.93 (m, 2H), 3.32 (m, 1H), 2.41 (s, 3H), 1.94 (m, 2H), 1.58 (s, 3H), 1.72-1.42 (m, 6H); MS(EI): [M+], 1 bromine isotope pattern, 450/452; Anal. Calc. for C25H23BrOS: C, 66.52, H, 5.13, N, 0.00. Found: C, 67.17, H, 5.25, N, 0.04.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cccc(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D starting from 3-Trifluoromethyl-phenol and 2-Fluoro-5-formyl-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C.C1CCCCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A suspension of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2, 1 g, 2.427 mmol) and (3S,4S)-pyrrolidine-3,4-diol (0.3 g, 2.91 mmol) in a mixture of DIPEA (1.272 mL, 7.28 mmol) and iPrOH (3.24 mL) was subjected to MW irradiation at 140° C. for 1 h. The RM was treated with 0.5 M HCl (40 mL) and extracted with EtOAc. The combined extracts were washed with water, sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was suspended in a mixture of cyclohexane EtOAc. The resulting solid was filtered-off, washed with cyclohexane and dried to afford the title product as an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=477.9 [M+H]+, m/z=475.8 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.55 (d, J=11.13 Hz, 2H) 3.91-4.09 (m, 4H) 5.18 (d, J=2.81 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.80-7.93 (m, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.67 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 95 °C

Procedure:
A solution of the 3,5-dibromo-pyridine (12.8 g, 68.8 mmol) and piperazine-1-carboxylic acid tert butyl ester (10 g, 42.4 mmol) in 200 mL of dioxane was treated with Pd2(dba)3 (5 g, 5.5 mmol), 2-(di-tbutyl-phosphino)biphenyl (4 g, 13.4 mmol), and sodium t-butoxide (7.2 g, 75 mmol). The reaction was heated to 95° C. for 8 h then cooled and filtered through celite. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of 1:4 ethyl acetate/hexane to 100% ethyl acetate. Recovered 2.9 g of product (20%). MS (ESI) m/z 344 (M+H)+.
Reaction SMILES: C[C@@H:2]1[CH2:7][N:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.F[C:32](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:32][C@@H:5]1[CH2:4][NH:3][CH2:2][CH2:7][N:6]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:10][N:9]=1
Reactant: C[C@@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(R)-tert-butyl 2-methyl-4-(4-phenylphthalazin-1-yl)piperazine-1-carboxylate (495 mg, 1.22 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (2.36 mL) was added and the reaction stirred at rt for 1.5 hours. The reaction was added to saturated NaHCO3 (30 mL) and neutralized by the portion wise addition of solid NaHCO3. The layers were separated and extracted twice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow foam. MS (M+H)+=305.4.
Reaction SMILES: CN(C)[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[C:15]=1[F:25].CC[OH:30]>[OH-].[Na+]>[CH2:11]([C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[C:15]=2[F:25])=[C:5]([CH2:4][C:3]([OH:26])=[O:30])[CH:10]=1)[CH3:12]
Reactant: CCO
Reactant: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)O)c1
Temperature: 80 °C

Procedure:
A solution of the above 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide described in Example 3 (0.9 g, 2.4 mmol) in EtOH (25 mL) and 4N NaOH (12 mL) is heated to 80° C. overnight. After cooling, the reaction is concentrated under reduced pressure and diluted with ice cold EtOAc. The pH of the aqueous layer is adjusted to 1-2 with ice cold 2.5 N HCl. The separated organic layer is dried with Na2SO4 and concentrated to a solid. The solid is purified by trituration with an Et2O/hexane mixture to give the title acid, 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>CCO>[F:1][CH:2]([F:8])[C:3]1[NH:11][N:10]=[C:5]([NH2:6])[CH:4]=1
Reactant: NN
Reactant: N#CCC(=O)C(F)F
Solvent: CCO
Solvent: O
Product: Nc1cc(C(F)F)[nH]n1
Temperature: 25 °C
Yield: 27 %

Procedure:
To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+.