Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:4][O:5][CH2:6][C:7]([OH:9])=O)[CH3:3].S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2](=[N:4][O:5][CH2:6][C:7]([Cl:12])=[O:9])[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)=NOCC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)=NOCC(=O)Cl

Procedure:
To {[(1-methylethylidene)amino]oxy}acetic acid (286 g, 2.18 mol) was added 600 ml of toluene. Thionyl chloride (364 g, 3.06 mol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was heated to reflux for 10 hours. Toluene and thionyl chloride were evaporated under vacuum and the residue was distilled to afford the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:21])[C:9]([C:22]([O:24]CC)=[O:23])=[CH:8]1)(=O)C.Cl>C(O)(=O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]1
Reactant: CCOC(=O)c1cn(CCOC(C)=O)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2CCO
Yield: 85.9 %

Procedure:
Employing ethyl 1-(2-acetyloxyethyl)-5-methyl-6,7,8-trifluoro-l,4-dihydro-4-oxoquinoline-3-carboxylate (5.80 g) and conc. hydrochloric acid: 90% acetic acid (1:4) (100 ml), the procedure of Reference Example 23 is repeated to give 1-(2-hydroxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.04 g), as pale yellow flakes (recrystallized from ethanol), m.p. 244.5°-247° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH-].[Na+].CN(C)[CH:25]=[O:26]>O>[CH3:6][N:7]([CH3:20])[S:8]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:25]=[O:26])=[CH:16][NH:17]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)c1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc2c(C=O)c[nH]c2c1
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Phosphorus oxychloride (0.76 ml, 0.008 mol) was slowly added at 0° C. under nitrogen atmosphere to anhydrous N,N-dimethyl formamide (3.8 ml), 0.05 mol). The mixture was stirred for 15 minutes and a solution of 6-(N,N-dimethyl aminosulfonyl)indole (1.74 g, 0.0078 mol) in anhydrous N,N-dimethylformamide (4 ml) was added dropwise below 2° C. The reaction mixture was allowed to stand at room temperature for 20 h and diluted with water (10 ml). The solution was neutralized (pH 8) with 10% aqueous solution of sodium hydroxide. The mixture was cooled and the precipitated solid was collected by filtration and was recrystallized from ethanol to yield 1.05 g (54%) of the entitled product (mp 250–252° C.).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][C:30]1[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:33]5[N:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: Clc1ccc(Cl)nn1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Cl)nn4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 3,6-dichloropyridazine. Mass spectrum (ESI) 427.9 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[CH:28]3)O1.N>>[F:37][C:34]([F:35])([F:36])[C:29]1[NH:30][C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)=[CH:4][CH:3]=1)=[CH:33][CH:32]=2
Reactant: CC1(C)OB(c2ccc3[nH]c(C(F)(F)F)cc3c2)OC1(C)C
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Agent: N
Product: FC(F)(F)c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 9A (198 mg, 0.826 mmol) was coupled with the product of Example 48A (345 mg, 1.11 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™ RP-18, 5 μm, 30×100 mm; eluting solvent, NH4HCO3—NH4OH/H2O (PH=10), (v. 90/10 to 10/90 over 20 min.); flow rate, 40 mL/min.; uv, 254 nm) to provide a solid (79.7 mg, yield, 24.8%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.93 (m, 3H) 1.99-2.15 (m, 1H) 2.29-2.37 (m, 1H) 2.78-3.05 (m, 5H) 3.49 (ddd, J=14.83, 8.39, 1.86 Hz, 1H) 5.27-5.36 (m, 1H) 7.01 (s, 1H) 7.27 (d, J=9.49 Hz, 1H) 7.59 (d, J=8.81 Hz, 1H) 7.94 (dd, J=8.81, 1.70 Hz, 1H) 8.11 (d, J=9.15 Hz, 1H) 8.24 (s, 1H) ppm. MS (DCI/NH3) m/z 389 (M+H)+. Anal. Calculated for C20H19F3N4O: C, 61.85; H, 4.93; N, 14.43. Found: C, 61.62; H, 4.56; N, 13.89.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].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.Cl.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([C:76]2([CH2:79][F:80])[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[F:80][CH2:79][C:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C@H:21]([CH3:29])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:74])=[O:75])[CH2:77][CH2:78]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.7 g, 13.82 mmol) in dichloromethane (60 mL) was added HATU (5.78 g, 15.2 mmole) followed by DIPEA (7.13 mL, 41.4 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(1-(fluoromethyl)cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (4.34 g, 16.58 mmole) was added to the reaction mass and stirred at room temperature for 6 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (5% methanol in chloroform) to get 6.6 g (73%) of desired product as white solid. MS: MS m/z 658.3 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:11]2[OH:26])=[CH:6][CH:5]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:11]2[O:26][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:8][CH:9]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
37 mg (0.85 mmol) of sodium hydride (55% dispersion in refined oil) were added to a solution of 200 mg (0.56 mmol) of tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate and 188 mg (0.85 mmol) of 2-bromomethylnaphthalene in 10 ml of dimethylformamide and the reaction mixture was stirred at room temperature for 5 hours. For the working-up, the reaction mixture was evaporated in an oil pump vacuum, the residue was partitioned between water and ether and thereafter the separated aqueous phase was extracted five times with 50 ml of ether each time. The combined ether extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 96:4 mixture of toluene and ethyl acetate as the eluent. There were obtained 215 mg (77% of theory) of tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine-1-carboxylate as a colourless oil; MS: 494 (M+H)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19]>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])=[O:19]
Reactant: CON(C)C(=O)C=Cc1ccccc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(2-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (16 g) as an oil.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](O)=[C:29]([Br:36])[CH:28]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:29]([Br:36])[CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Trifluoromethanesulfonic acid t-butyldimethylsilyl ester (0.159 mL, 0.690 mmol) and triethylamine (0.120 mL, 0.863 mmol) were added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid methyl ester (158 mg, 0.574 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (203 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[C:11]1([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:19]2[CH2:20][CH2:21][O:22][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: c1ccc(C2CNCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
429 mg of 4-Bromobenzaldehyde was dissolved in 6 mL of THF and 386 mg of the HCl salt of 2-Phenylmorpholine (Array) and 1.15 g of MP-BH(OAc)3 (2.77 mmol/g) was added. The reaction was agitated on an orbital shaker overnight at room temperature. The reaction was filtered and the resin washed several times with dichloromethane. The filtrate was concentrated and purified by flash chromatography. Yield: 281 mg.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[C:17]1([S:23]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 84 %

Procedure:
A solution of 1-[3-(trifluoromethyl)-2-pyridyl]piperazine (60 mg, 0.26 mmol), and Benzene sulfonyl chloride (0.043 mL, 0.31 mmol) in DCM (4 mL) and saturated sodium bicarbonate (2 mL) was stirred at room temperature for 12 hours. The mixture was diluted with DCM (5 mL) and water (5 mL). The organic layer was collected and washed two times with water, dried with magnesium sulfate, and concentrated. The product was purified using column chromatography (20% Ethyl Acetate in Hexanes) to produce 1-(phenylsulfonyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine (81.1 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1cc(F)cc(F)c1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 3,5-difluorobenzyl chloroformate.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br.CC(O)=[O:17]>>[OH:17][C:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: CC(=O)O
Agent: Br
Product: Oc1cccc2sc3ccccc3c12
Temperature: 130 °C

Procedure:
To a stirred solution of the dibenzothiophene (0.040 g, 0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40% HBr (0.65 mL, 5.6 mmoles) under N2. The reaction was heated to 130° C. for 20 hrs. The resulting green solution was partitioned between EtOAc and ice/brine. The organic layer was washed with sat. NaHCO3 (2X) and brine. The EtOAc extract was dried over Na2SO4 and concentrated in vacuo to give an off-white solid (0.0366 g). Purification by plate layer chromatography with 1:1 hexane/CH2Cl2 afforded the desired phenol as a white solid (0.0294 g).
Reaction SMILES: [CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:28])[NH:8][C:9]3[C:10]([N:16]([CH2:18][CH2:19][O:20]CC4C=CC=CC=4)[CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2].CO.[OH-].[Na+]>[Pd]>[CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:28])[NH:8][C:9]3[C:10]([N:16]([CH2:18][CH2:19][OH:20])[CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncc2c(=O)[nH]c3c(N(C)CCOCc4ccccc4)ncnc3n12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ncc2c(=O)[nH]c3c(N(C)CCO)ncnc3n12

Procedure:
Prepared by hydrogenation of the product of Example 24 with palladium on carbon in methanol containing 1.1 eq. NaOH at 50 psi for 8 hours.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[F:18][C:19]1[CH:31]=[C:30]([O:32][C:33]([F:34])([F:36])[F:35])[CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:26][CH2:27]1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: Fc1cc(OC(F)(F)F)ccc1OC1CCNCC1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)cc2F)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 50.9 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(2-fluoro-4-(trifluoromethoxy)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 128 mg title compound was generated and yield was 51%.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[Si:29]([O:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[Si:29]([O:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]3[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:4][CH:3]=2)=[CH:45][CH:44]=1)(=[O:42])=[O:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: CC(C)(C)[Si](C)(C)OCCNS(=O)(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cc1

Procedure:
Compound 2b was subjected to Suzuki coupling reaction conditions as described in Example 1, Step G, with (4-(N-(2-((tert-butyldimethylsilyl)oxy)ethyl)sulfamoyl)phenyl)boronic acid to obtain compound 33a. Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H42N6O4SSi: 671.3 (M+H). Found 671.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[S:20][C:21]([CH:25]=[O:26])=[C:22]([Cl:24])[N:23]=1>O1CCCC1>[Cl:24][C:22]1[N:23]=[C:19]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[S:20][C:21]=1[CH:25]=[O:26]
Reactant: NCc1ccncc1
Reactant: O=Cc1sc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1sc(NCc2ccncc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(aminomethyl)pyridine (516, 1.16 mL, 11.5 mmol) and N,N-diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 2.0 g, 11.0 mmol) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude compound 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517) was used for the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:13](=[O:15])[CH2:12][C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)Cc1nc(-c2ccccc2)ns1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1nc(-c2ccccc2)ns1

Procedure:
Following General Procedure I' above, and using (3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[NH:15][C:14]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:9][CH:8]=1.O>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([CH3:23])=[C:19]([CH3:22])[CH:20]=3)[NH:15][C:14]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:11][CH:12]=1
Reactant: COC(=O)c1[nH]c2cc(C)c(C)cc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(C)c(C)cc2c1-c1ccc(O)cc1
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of boron tribromide (BBr3) (0.18 ml) in dichloromethane (0.36 ml) was dropwise added to a solution of methyl 3-(4-methoxyphenyl)-5,6-dimethylindole-2-carboxylate (0.3 g) in dichloromethane (10 ml) at 0° C. The reaction mixture was stirred for 2 hours at the same temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from acetone to give methyl 3-(4-hydroxyphenyl)-5,6-dimethylindole-2-carboxylate (0.127 g, 44%) as colorless needles.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=2)=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:18][CH2:19][C:20]([C:23]1[S:24][C:25]([C:28]2[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=2)[NH2:34])=[CH:26][N:27]=1)([CH3:22])[CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc([N+](=O)[O-])c2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ncc(-c2cccc(N)c2)s1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of the product of Step 2 (461 mg, 0.892 mmol) in ethyl acetate (9 mL) was added Pd/C (10 wt %, 190 mg, 0.178 mmol), and the reaction vessel was charged with H2 (balloon) and stirred overnight, at which point LCMS analysis indicated complete conversion. Dichloromethane was added to deactivate the catalyst, and the mixture was filtered through a pad of Celite (ethyl acetate rinse) and concentrated in vacuo to provided 393 mg (0.807 mmol, 91%) of 3-[2-(1-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropan-2-yl)-1,3-thiazol-5-yl]aniline as a light yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[CH:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:31]2[CH:30]=[CH:29][N:28]=[C:27]3[NH:23][CH:24]=[CH:25][C:26]=23)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc3[nH]ccc23)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 400 (M+H). Calc'd. for C24H25N5O—399.50.