Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]>C(O)=O>[Cl:1][C:2]1[C:3]([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)=[C:4]2[C:18]3[CH2:19][CH2:20][S:21](=[O:23])[CH2:22][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Solvent: O=CO
Product: O=C(O)COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCS(=O)C4)cc1

Procedure:
A solution of the compound obtained in Example 113 (600 mg) in formic acid (7 ml) was stirred at room temperature for 6 hours and then concentrated under reduced pressure. The residue was diluted with methylene chloride and washed with water and dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain (4-{3-chloro-2-[(2,5-dioxo-1-pyrrolidinyl)methyl]-7-oxido-5,8-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-b]pyridin-4-yl}phenoxy)acetic acid from the fraction eluted with chloroform-ethyl acetate (7:1) and then chloroform-methanol (10:1) (476 mg, 88%). It was recrystallized from methanol-hexane. Colorless prisms. Melting point 205-206° C.
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C.N1C=CC=CC=1>[C:8]([C:3]1[C:2]([C:11]#[C:10][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:9]
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cccnc2C#N)cc1
Yield: 76.1 %

Procedure:
A mixture of 3-bromo-2-cyanopyridine (3.63 g, 19.8 mmol), 4-ethynylanisole (3.15 g, 1.2 equivalents), dichlorobis(triphenylphosphine)palladium (II) (0.28 g, 0.02 equivalent), copper (I) iodide (0.14 g), triethylamine (60 ml) and dry pyridine (6 ml) was heated under reflux in nitrogen atmosphere for 12.5 hr. After the mixture was cooled as it was, ethyl acetate and a 10% aqueous solution of sodium carbonate were added thereto. The resulting mixture was stirred, and the resulting insoluble matters were filtered off. The organic layer was separated and washed with water/brine (1:1(v/v)) and brine in this order, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/chloroform/methanol system). The resulting product was recrystallized from chloroform/n-hexane, to give the title compound as a pale yellow powder (3.53 g, yield; 81%).
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]1[CH2:20][CH:21]2[N:27]([CH:28]=1)[C:26](=[O:29])[C:25]1[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:24]=1[N:23](COCC[Si](C)(C)C)[CH2:22]2.C(O)C.C1COCC1>O>[CH3:37][O:36][C:31]1[C:32]([O:34][CH3:35])=[CH:33][C:24]2[N:23]=[CH:22][C@@H:21]3[CH2:20][C:19]([C:10]4[CH:11]=[CH:12][C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH:9]=4)=[CH:28][N:27]3[C:26](=[O:29])[C:25]=2[CH:30]=1
Reactant: COc1cc2c(cc1OC)N(COCC[Si](C)(C)C)CC1CC(c3ccc4ccccc4c3)=CN1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)N1C=C(c3ccc4ccccc4c3)C[C@H]1C=N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
Solid sodium tetraborohydride (654 mg, 17.2 mmol) was added in three portions at two hourly intervals to a stirred solution of 10 (971 mg, 1.8 mmol) in a mixture of anhydrous ethanol (19 mL) and anhydrous THF (37 mL) and left to stir at room temperature for 24 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were evaporated in vacuo. The crude product was treated with ethanol (50 mL), water (30 mL) and silica gel (18.3 g) and left to stir at room temperature for 24 hours. The reaction mixture was filtered and the product extracted with ethyl acetate (3×50 ). The organic layers were combined and washed with brine (20 mL) and dried over anhydrous magnesium sulphate. Filtration and evaporation in vacuo afforded the crude product, which was purified using flash column chromatography with a 70-50% hexane in ethyl acetate as eluent. Pure fractions were combined and evaporated in vacuo to afford the pure product 11 as a yellow powder (151 mg, 0.39 mmol, 22% yield).
Reaction SMILES: C[O-].[Na+].[CH:4]1([CH:7]=[O:8])[CH2:6][CH2:5]1.Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C>CO.O>[CH:4]1([CH:7]2[O:8][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: O=CC1CC1
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1OC1C1CC1
Temperature: -10 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
A 300-ml three-necked flask equipped with a thermometer and a stirrer was charged with 87 g (0.45 mole) of a 28% sodium methoxide solution in methanol and 21 g (0.30 mole) of cyclopropanecarbaldehyde and, after the contents had been cooled down to −10° C., 48.9 g (0.45 mole) of methyl chloroacetate was added dropwise over 3 hours. After completion of the addition, the reaction mixture was allowed to be warmed up to room temperature and was then stirred at room temperature for 5 hours. Thereafter, 12 g (0.20 mole) of acetic acid was added to neutralize remaining sodium methoxide and the resulting mixture was poured into 140 g of water. The reaction mixture thus obtained was extracted three times each with 50 ml of ethyl acetate and the extracts were washed with 50 ml of saturated salt water. The mixture thus washed was dried over anhydrous sodium sulfate and condensed. The residue was distilled under reduced pressure to yield, as distillates at 70 to 73° C. [6 mmHg (8.0 hPa)], 29.8 g (0.21 mole; yield: 70.0%) of methyl 3-cyclopropyl-2,3-epoxypropionate having the following properties.
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10]([OH:17])[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21](F)=[CH:20][C:19]=2[F:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:40]=[CH:39][C:32]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=1.[H-].[Na+]>CS(C)=O>[CH:1]1([C:8]2[N:13]3[N:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10]([OH:17])[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21]([O:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:40][CH:39]=3)=[CH:20][C:19]=2[F:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(COCCCO)cc1
Reactant: Oc1nc2ncnn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COCCCOc2cc(F)c(-c3c(O)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.3 %

Procedure:
To a solution of 7-cycloheptyl-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol (362 mg, 1.0 mmol) and 3-[(4-methoxybenzyl)oxy]-1-propanol (490 mg, 2.5 mmol) in 4.0 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol). The mixture is stirred at room temperature for 3 h, and partitioned between ethyl acetate and 1.0 N hydrochloric acid. The organic solution is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 66% ethyl acetate in hexanes to 5% methyl alcohol in ethyl acetate. Concentration provides 7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidin-5-ol as a yellow oil (820 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.Cl[C:30]1[CH:31]=[CH:32][N:33]=[C:34]2[C:39]=1[N:38]=[CH:37][C:36]([O:40][CH3:41])=[CH:35]2.CCCCO>[OH-].[Na+]>[CH3:41][O:40][C:36]1[CH:35]=[C:34]2[C:39]([C:30]([N:2]([CH3:1])[C:3]3[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=3)=[CH:31][CH:32]=[N:33]2)=[N:38][CH:37]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1cnc2c(N(C)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a resealable pressure vessel was added n-methyl-4-nitroaniline (0.911 ml, 7.19 mmol), pyridinium p-toluenesulfonate (1.81 g, 7.19 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (1.000 g, 5.14 mmol), and n-BuOH (15 mL). The vessel was sealed and heated to 100° C. After 4 h, the mixture was cooled to RT, diluted with 1 N NaOH, and extracted with EtOAc. The organic fraction was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography using 50-100% Hexanes:EtOAc to afford 7-methoxy-N-methyl-N-(4-nitrophenyl)-1,5-naphthyridin-4-amine as a yellow solid. MH+=311.2@1.51 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[O:9][C:8](=[O:13])[CH2:7]2.[C:14](OCC)(OCC)([O:16][CH2:17][CH3:18])[CH3:15]>>[CH2:14]([O:16]/[C:17](=[C:7]1/[C:8](=[O:13])[O:9][C:10](=[O:12])[C:11]2[C:6]/1=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])/[CH3:18])[CH3:15]
Reactant: CCOC(C)(OCC)OCC
Reactant: O=C1Cc2cccc(F)c2C(=O)O1
Product: CCO/C(C)=C1/C(=O)OC(=O)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
A suspension of 8-fluoro-isochroman-1,3-dione (7.125 g, 39.55 mmol) and triethyl orthoacetate (50.0 mL, 273 mmol) was heated to a gentle reflux during 5 min and reflux continued for 10 min. It was allowed to cool to r.t. with formation of crystalline product. It was cooled further on dry ice-EtOH bath, filtered, washed with cold ethanol (3×15 ml) and dried in vacuo (50° C., 30 min) to give 4.600 g of the title compound as a pink solid. The supernatant was evaporated and the purple oil residue was quenched with ethanol (20 ml) with formation of crystalline product, separated by filtration to give 693 mg more of the title product, total yield 53.5%. LC-MS (m/z) 251.2 (MH+), tR=1.05. 1H NMR (500 MHz, DMSO-d6): 1.41 (t, J=7.0 Hz, 3H, Me of Et), 2.68 (s, 3H, Me), 4.46 (q, J=7.0 Hz, 2H, CH2 of Et), 7.21 (dd, J=8.5 Hz, 10.7 Hz, 1H, C (7)-H), 7.72 (dt, J (d)=5.9 Hz, J (t)=8.3 Hz, 1H, C (6)-H), 8.08 (d, J=8.3 Hz, 1H, C (5)-H). 19F NMR (470.59 MHz): −110.2 ppm (dd, J=5.9 Hz, 10.7 Hz). 13C APT (125.76 MHz, DMSO-d6=39.89 ppm): 14.8 (CH3 of Et), 17.97 (CH3), 66.79 (CH2), 99.71 (C4), 109.04 (d, J=7.9 Hz, C9), 114.04 (d, J=20.6 Hz, CH, C7), 123.43 (d, J=3.3 Hz, CH, C5), 136.28 (d, J=10.5 Hz, CH, C6), 137.43 (s, C3=O), 157.22 (d, J=4.3 Hz, C1=O), 161.77 (C), 162.19 (d, J=262 Hz, C8), 178.45 (═C—OEt).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C([O-])([O-])=O.[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(OC(C)C)ccc1Br
Temperature: 25 °C

Procedure:
To a stirred suspension of 4-bromo-3-methoxyphenol (2.03 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in 2-butanone (70 mL) at ambient temperature under argon is added dropwise isopropyl iodide (2.21 g, 13.3 mmol). The resulting mixture is heated and stirred under reflux for 17 hours. The mixture is allowed to cool to ambient temperature then is filtered and concentrated by evaporation of the solvent. The residue is partitioned between Et2O and H2O. The Et2O layer is extracted with 5% NaOH (2×50 mL), washed with brine, and dried over MgSO4. The solvent is evaporated and the resulting residue is purified by flash chromatography (5% EtOAc/hexane) to afford the desired compound as a pale yellow oil. 2.13 g (87%).
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]#[CH:10])/[C:4](=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)/[S:3]1.[ClH:25].C(OCC)(=O)C>>[ClH:25].[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12](/[CH:11]=[C:4]2/[C:5]([NH:7][CH2:8][C:9]#[CH:10])=[N:6][C:2](=[O:1])[S:3]/2)[CH2:13][CH2:14]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1

Procedure:
A mixed solution of tert-butyl 4-{(Z)-[2-oxo-4-(prop-2-yn-1-ylamino)-1,3-thiazol-5(2H)-ylidene]methyl}piperidine-1-carboxylate (14.0 g) and 4M hydrogen chloride/ethyl acetate solution (80 mL) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (12.7 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>C(#N)C>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CSCCN1
Solvent: CC#N
Product: N#Cc1ccc(N2CCSCC2)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 53.3 %

Procedure:
4-fluorobenzonitrile (500 mg, 4.13 mmol) and thiomorpholine (1.18 ml, 12.4 mmol) was dissolved in acetonitrile (2 ml) and stirred at 100° C. for 40 hours. The reaction was cooled, evaporated and purified by flash chromatography using pet.ether/EtOAc (4:1) as eluent to give 450 mg (53%) of the title compound as pale solids.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C@H:16]2[C@@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C1CC1
Yield: 93.6 %

Procedure:
To 76G (2.9 g) in methanol (60 mL) was added 10% Pd/C (990 mg). The mixture was hydrogenated with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 76I (2.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.83-0.93 (m, 5H) 0.95-1.04 (m, 2H) 1.13-1.24 (m, 11H) 2.02-2.07 (m, 1H) 2.09-2.16 (m, 1H) 2.73-2.79 (m, 1H) 3.48-3.56 (m, 1H) 3.63-3.74 (m, 4H) 5.79 (d, J=7.70 Hz, 1H) 6.48-6.54 (m, 2H) 7.40 (d, J=8.79 Hz, 1H), LC-MS 439 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:10][CH:11]([C:13]#[CH:14])[CH3:12].[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[C:19]=[O:20]>C(Cl)Cl>[CH3:12][CH:11]([N:10]([CH2:9][C:8]1[CH:15]=[CH:16][CH:17]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)[C:19]([NH:18][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=1)=[O:20])[C:13]#[CH:14]
Reactant: C#CC(C)NCc1cccc(-c2nccs2)c1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: C#CC(C)N(Cc1cccc(-c2nccs2)c1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the crude N-[3-(1,3-thiazol-2-yl)benzyl]but-3-yn-2-amine (25 mg, 0.10 mmol) in 1 mL CH2Cl2 was added 1-isocyanato-4-(trifluoromethoxy)benzene (31 mg, 0.16 mmol). The reaction was allowed to stir at ambient temperature for 5 min, concentrated, and purified on a Waters reverse phase preparatory instrument to give 1-(1-methylprop-2-yn-1-yl)-1-[3-(1,3-thiazol-2-yl)benzyl]-3-[4-(trifluoromethoxy)phenyl]urea. 1H NMR (399 MHz, CD3 OD): δ 7.96 (s, 1 H); 7.84 (d, J=10.5 Hz, 2 H); 7.60 (d, J=3.5 Hz, 1 H); 7.47 (d, J=4.9 Hz, 2H); 7.38 (d, J=8.8 Hz, 2 H); 7.14 (d, J=8.6 Hz, 2 H); 5.39 (d, J=7.7 Hz, 1 H); 4.94-4.76 (m, 2 H) 2.83-2.81 (m, 1 H); 1.42 (d, J=7.1 Hz, 3 H). LCMS [M+H]+=446.2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.C([O-])(O)=[O:24].[Na+]>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:24])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: Cc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(C(N)=O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Yield: 34 %

Procedure:
6-Methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinonitrile (0.02 g, 0.066 mmol) in acetic acid (2 mL) and H2SO4 (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was subsequently poured into a conical flask containing ice and was carefully neutralized with NaHCO3 and extracted into DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with a gradient of 45-55% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as white solid (0.32 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 7.42 (d, J=1.26 Hz, 1H), 7.73 (br s, 1H), 7.90-8.08 (m, 3H), 8.14 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H11F3N4O, 321.1. found 321.2.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([Cl:11])=[C:5]([Cl:12])[C:4]=1[Cl:13])[CH3:2].[Cl:14]Cl>>[Cl:14][CH:1]([C:3]1[C:4]([Cl:13])=[C:5]([Cl:12])[C:6]([Cl:11])=[C:7]([Cl:10])[C:8]=1[Cl:9])[CH3:2]
Reactant: CCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCl
Product: CC(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In U.S. Pat. No. 2,193,823, a method is taught for low yield α-chlorination of ethylpentachlorobenzene by contacting the same in the liquid phase at elevated temperature with chlorine gas in the presence of the light of an ordinary electric light bulb to produce α-chloroethylpentachlorobenzene. The desired product must be separated from the reaction mixture by treating the mixture chemically to remove residual chlorine, followed by two vacuum distillation steps.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.O1CCCC1.Cl>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (5.00 g, 10.91 mmol), tetrahydrofuran (150 mL), and 1 M aqueous hydrochloric acid (50 mL); let stir overnight at room temperature. Dilute with ethyl acetate. Wash with excess 1M aqueous sodium hydroxide, followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow foam (3.84 g, 94%). MS (ES) m/z=376 [M]+.
Reaction SMILES: [C:1]([CH:5]1[C:9](=[O:10])[CH2:8][CH2:7][S:6]1)([O:3][CH3:4])=[O:2].[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[C:9]2([CH2:8][CH2:7][S:6][CH:5]2[C:1]([O:3][CH3:4])=[O:2])[O:10][CH2:11][CH2:12]1
Reactant: OCCO
Reactant: COC(=O)C1SCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1SCCC12OCCO2
Yield: 72.5 %

Procedure:
A solution of 1.60 g (10.0 mmol) of 2-carbomethoxy-2,3,4,5-tetrahydrothiophen-3-one (contained 15% of the 4-carbomethoxy isomer, Pfaltz and Bauer), 1.4 g (24.0 mmol) of ethylene glycol, and 0.02 g of p-toluenesulfonic acid dihydrate in 20 ml of benzene was heated at reflux in a flask equipped with a Dean-Stark trap for 40 hours. The cooled solution was washed with saturated sodium bicarbonate solution (10 ml), water (3×5 ml), and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.48 g of an oil. The oil was flash chromatographed on silica gel eluting with hexane:ether (3:1) to give 1.23 g (60%) product as an oil, a 5:1 mixture of the 6-carboxylate: 4-carboxylate; NMR (deuteriochloroform): δ 4.0 (m, 3H), 3.75 (S, 3H), 2.95 (m, 2H), 2.60 (d of d, 1H), 2.05 (d of d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:29][C:30]1[CH:31]=[N:32][N:33]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[CH:34]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([NH:29][C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)[CH:34]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1

Procedure:
A suspension of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), Cs2CO3 (0.291 g, 0.892 mmol) and tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.158 g, 0.595 mmol) in 1,4-dioxane (2 mL) was sonicated for 10 minutes. Xantphos (6.9 mg, 12 μmol) and Pd(II) acetate (1.3 mg, 5.9 μmol) were added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in cyclohexane then 0-10% MeOH in EtOAc) to give the title compound A20 as a brown solid (21 mg, 12%). LCMS-C: rt 5.54 min; m/z 565.9 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][C:16]=1[CH3:17]>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:15][C:16]=1[CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C(F)(F)F)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under ice-cooling, 4.0 ml (34.5 mmol) of benzoyl chloride was added dropwise to a mixture of 4.97 g (28.8 mmol) of 3-amino-4-methyl-benzotrifluoride and 10 ml of pyridine. After stirring the mixture at room temperature for 1 hour, the solvent was removed under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration and then washed with water and a 50% aqueous methanol solution to give 8.04 g of 3-benzoylamino-4-methyl-benzotrifluoride.