Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:22])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]1O.C(N(S(F)(F)[F:29])CC)C>ClCCl>[F:29][C@@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:18]([CH2:17][CH2:16][C@:14]12[CH3:15])[C:19]1[CH:20]=[C:3]([O:2][CH3:1])[C:4]([OH:22])=[CH:5][C:6]=1[CH2:7][CH2:8]3
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](F)CC[C@@H]12
Temperature: -35 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
215 mg of 2-methoxy-estra-1,3,5(10)-triene-3,17β-diol was dissolved in 20 ml of absolute dichloromethane and cooled to −35° C. Then, 280 μl of diethylamino sulfur trifluoride was added, and the cold bath was removed. After 1 hour, it was poured into aqueous sodium bicarbonate solution and extracted with dichloromethane (3×). The combined organic phases were dried and concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate=10:1) yielded 49% crude product, which was purified by means of HPLC (Chiracel OD-H 250×4.6 mm; n-heptane/2-propanol=95/5). 46 mg (21%) of 17α-fluoro-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene was obtained as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)cc3Cl)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 8 %

Procedure:
4-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (24 mg, 8%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,4′-dichloroacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.57-7.78 (m, 4H), 7.43 (t, J=8.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=[O:8])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH:7]([C:9]([F:11])([F:12])[F:10])[OH:8])[CH3:2]
Reactant: CCOC(=O)CCC(=O)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 30 mmole of 4-trifluoromethyl-4-oxobutyric acid ethyl ester in 20 ml of ethanol cooled to 0° C. is added 30 mmole of sodium borohydride. The reaction mixture is stirred at 0° C. for 4 hours then acidified with M HCl to a pH of 1. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester. A mixture of 20 mmole of 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester, 22 mmole of triphenylphosphine, 20 mmole of phthalimide and 22 mmole of diethyl azodicarboxylate in 60 ml of tetrahydrofuran is heated at reflux temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure, and the residue chromatographed on silica gel to give 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester. A suspension of 30 mmole of 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester in 20 ml of concentrated HCl is heated at reflux temperature for 24 hours. The solid which separates on cooling is filtered, and the filtrate concentrated under reduced pressure. The residue is dissolved in the minimum quantity of water, and the pH of the solution adjusted to 5 by the addition of sodium hydroxide. Acetone is added, and the precipitated 4-amino-4-trifluoromethylbutyric acid collected by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[O:15]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CC1c1ccc(OCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 79 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), (3-phenoxyphenyl)methanol (0.150 g, 0.747 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 60 hr. Hexane (15 mL) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.221 g, yield 72%) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: II
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved into 80 mL of tetrahydrofuran (abbr.: THF) and cooled to −78° C., and then 7.5 mL (12.0 mmol) of n-BuLi (1.6 mol/L) was dropped into the reaction solution using a dropping funnel and stirred for 1 hour. A solution in which 5 g (20.0 mmol) of iodine was dissolved in 20 mL of THF was dropped and further stirred for 2 hours at −78° C. After the reaction, an aqueous sodium thiosulfate solution was added to stop the reaction. An organic layer was washed with an aqueous sodium thiosulfate solution and a saturated sodium chloride solution and dried with magnesium sulfate. After natural filtration, the filtrate was concentrated, and the obtained solid was recrystallized with ethanol, thereby obtaining 3.1 g of objective 9-iodo-10-phenylanthracene as a light-yellow solid with a yield of 83%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[CH:21](O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:25][OH:26])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a solution of 9B (3.86 g, 11.3 mmol) in methanol:water (2:1, 50 mL) was added hydroxylamine hydrochloride salt (3.0 g) followed by pyridine (5.0 mL). The reaction was stirred at rt for 18 hr. Extract product into EtOAc, washing once with sat. aqueous NaHCO3 and once with water. Back extract the aqueous washings with EtOAc and combine this with the initial extract. Dry organic extract over MgSO4, filter and concentrate. Dilute residue in toluene and remove solvent under vacuum to provide the title compound as a white solid (2.9 g). MS (ES) m/z 359.30 [M+H]+
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1.N1C=CC=CC=1>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Cl:3])=[CH:10][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: c1ccncc1
Product: ClCc1ccc(Cl)nc1

Procedure:
85 ml of thionyl chloride are added cautiously to 14.4 g (0.1 mol) of 6-chloro-pyridine-3-methanol. 8.1 g (0.1 mol) of pyridine are then added dropwise and the mixture is heated under reflux until gas evolution is complete. Excess thionyl chloride is removed in vacuo and the residue is poured onto ice. The precipitate is filtered off with suction and dried. Yield 10.6 g (65.5% of theory), m.p.: 38°-40° C. The crude product can be used further without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8](=[O:15])[NH:7][C:6]1=[O:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>C1COCC1>[F:13][C:11]([F:12])([F:14])[C:9]1[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH:10]=1
Reactant: O=c1[nH]c(=O)n(CCCO)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
1-(3-Hydroxy-propyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione (Prep20, 100 mg, 0.42 mmol) was dissolved in dry THF (5 mL), the solution was then cooled to 0° C. and Dess-Martin periodinane (300 mg, 0.71 mmol) was added. The mixture was stirred at 0° C. for 1.5 hours. Et2O was added and the mixture washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to give 50 mg of title compound (68% yield).
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(F)cc2)CC1
Reaction time: 6.5 h
Yield: 53342.7 %

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzoyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 10:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide (738 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]4=[N:1][O:3][C:30]([C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=5)=[C:5]4[CH:6]=3)=[CH:11][CH:12]=[N:13]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(C(F)(F)F)cc4)c3c2)cc1

Procedure:
The title compound, yellow solid (41 mg, 27%), MS (ISP) m/z=420.2 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-trifluoromethyl-phenyl)-acetonitrile.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.35 g (15.35 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.46 g (5.12 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 9A in 50 ml of dry pyridine at 0° C. and the mixture is stirred for 30 min at RT. Subsequently, 3.18 g (46.06 mmol) of 1,2,4-triazole are added, and the mixture is stirred for 3 h at 20° C. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]1)=O.[N-:15]=[N+:16]=[N-:17].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C@@H:5]2[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]2)=[N:17][N:16]=[N:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)[C@@H]1CCC[C@H](C(=O)OC)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2nnnn2C)C1
Temperature: 0 °C
Yield: 67.6 %

Procedure:
(±)-cis-Methyl 3-(methylcarbamoyl)cyclohexanecarboxylate (460 mg, 2.309 mmol) was dissolved in Acetonitrile (5 mL) at 25° C. under nitrogen with stirring, then sodium azide (150 mg, 2.309 mmol) was added. Cooled to 0° C. then added trifluoromethanesulfonic anhydride (0.390 mL, 2.309 mmol) dropwise over 2 minutes. The reaction was a colorless solution. Stirred for 20 hours then added sat'd sodium bicarbonate and stirred for 15 minutes, then added a little EtOAc and concentrated in vacuo the acetonitrile. Added more EtOAc and separated the layers. The EtOAc layer was rinsed again with sat'd sodium bicarbonate then 1 time with brine. The EtOAc layer was dried over sodium sulfate and stripped to give of a colorless oil. Obtained (±)-cis-methyl 3-(1-methyl-1H-tetrazol-5-yl)cyclohexanecarboxylate (350 mg, 1.561 mmol, 68% yield) as a colorless oil for product. MS found: (M+H)+=225.00.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:19]2[CH:24]=[CH:23][C:22](C)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:9]2
Reactant: Cc1ccc(-c2cc3cc([N+](=O)[O-])ccc3n2C2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)cc(-c1ccccc1)n2C1CCCCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of 1-cyclohexyl-2-(4-methylphenyl)-5-nitro-1H-indole (45 mg; 0.13 mmol) in absolute ethanol (5 ml) was added stannous chloride dihydrate (152 mg; 0.67 mmol) and the mixture was left under stirring at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and then poured into H2O and ice (20 ml), NaHCO3 (saturated solution) was added to pH 8 and the mixture was left under stirring for 20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]3[S:15][C:14]([NH:16][C:17](=O)[C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[N:13][N:12]=3)=[CH:10][C:3]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]3[S:15][C:14]([NH:16][CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)=[N:13][N:12]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C(F)(F)F)c1)C(=O)Nc1nnc(-c2cc3c(Cl)cncc3s2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2cc3c(Cl)cncc3s2)s1)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
tert-Butyl (S)-1-(5-(4-chlorothieno[2,3-c]pyridin-2-yl)-1,3,4-thiadiazol-2-ylamino)-1-oxo-3-(3-(trifluoromethyl)phenyl)propan-2-ylcarbamate was dissolved in 10 mL THF and cooled to 0° C. in a round bottom flask under nitrogen. To this flask was added 5 mL of a 1 N LiAlH4 THF solution dropwise. The resulting mixture was stirred from 0° C. to 20° C. in 2 hours and then at 20° C. for 3 hours. The reaction mixture was diluted with 20 mL THF and quenched with addition of 2 grams of Na2SO4.10H2O. After the mixture was stirred for 16 hours, it was filtered through a pad of celite. THF was removed under reduced pressure, and the remaining residue was subjected to a silica gel flash column chromatograph separation using 40% EtOAc in hexane as the eluant to yield the desired product (0.075 g, two steps y=13%) as a white solid. LCMS (API-ES) m/z (%): 570.2 (100%, M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8][C:7]([CH3:16])([CH3:15])[C:6]=2[CH:17]=1.Br[C:19]1[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=1>>[CH3:15][C:7]1([CH3:16])[C:6]2[CH:17]=[C:2]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[S:22][CH:23]=3)[CH:3]=[CH:4][C:5]=2[NH:10][CH:9]([C:11]([F:14])([F:13])[F:12])[O:8]1
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)cs1
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared using the coupling procedure for Example 13 starting with 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-thiophenecarbonitrile. A yellow solid: 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.19 (s, 1H), 7.54 (d, 1H, J=1.98 Hz), 7.46 (dd, 1H, J=8.33, 1.98 Hz), 6.90 (s, 1H), 6.83 (d, 1H, J=8.33 Hz), 5.35 (d, 1H, J=3.57 Hz), 1.59 (s, 3H), 1.57 (s, 3H); MS (ES) m/z 337 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].Br[C:32]1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.CC1C=CC=CC=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.28 mmol) and 2-methyl aniline (0.28 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24]>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.1 %

Procedure:
Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoate (intermediate 179.3) (1.5 g, 3.68 mmol, 1.00 equiv) in neat 2,2,2-trifluoroacetic acid (TFA; 2.0 mL). The resulting solution was stirred for 40 min at ambient temperature. Excess TFA was removed under vacuum to afford a pale-yellow oil residue which was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:5˜1:2˜2:1) to yield 1.1 g (84%) of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([CH2:16]O)=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]=2)=[O:10])=[CH:4][CH:3]=1.CS([Cl:29])(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([CH2:16][Cl:29])=[CH:14][N:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(Br)nc1)c1nn(-c2ccc(Cl)cc2)cc1CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)nc1)c1nn(-c2ccc(Cl)cc2)cc1CCl
Temperature: 25 °C

Procedure:
To mixture of N-(6-bromopyridin-3-yl)-1-(4-chlorophenyl)-4-(hydroxymethyl)-1H-pyrazole-3-carboxamide (330 mg, 0.810 mmol) in CH2Cl2 (15 mL) at RT was added methanesulfonyl chloride (0.101 mL, 1.295 mmol) and DIEA (0.283 mL, 1.619 mmol). The resulting mixture was stirred at room temperature over a weekend. The reaction mixture was diluted with H2O, stirred for 5 min and subjected to filtration. The solid collected was dried under vacuum to give Example 17D (340 mg, (99%) as a beige solid. 1H NMR (CDCl3) δ 4.98 (s, 2H), 7.44-7.53 (m, 2H), 7.61-7.72 (m. 2H), 8.06 (s, 1H), 8.20-8.28 (s, 2H), 8.53 (s, 1H), 8.79 (s, 1H). LCMS, [M+H]+=426.9.
Reaction SMILES: Cl.[CH:2]1([CH2:5][NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]#[N:31])=[CH:27][C:21]=4[S:20](=[O:33])(=[O:32])[N:19]=3)[C:8]2=[O:34])[CH2:4][CH2:3]1.[CH3:35][OH:36]>>[CH:2]1([CH2:5][NH:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([OH:17])=[C:9]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30](=[NH:31])[O:36][CH3:35])=[CH:27][C:21]=4[S:20](=[O:33])(=[O:32])[N:19]=3)[C:8]2=[O:34])[CH2:3][CH2:4]1
Reactant: N#CCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CO
Agent: Cl
Product: COC(=N)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride gas was bubbled into a solution of the product of Example 392A (50 mg, 0.11 mmol) in methanol (10 mL) at 0° C. until saturation. The reaction was stirred at room temperature for 3 hours. The solution was evaporated under reduced pressure to give title compound (quantitative yield).