Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](COCC)[C:16]([NH:25][CH2:26][CH2:27]O)=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=O)C.S(Cl)([Cl:33])=O>>[OH:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][C:16]([NH:25][CH2:26][CH2:27][Cl:33])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CCOCn1c(NCCO)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(NCCCl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-(2-hydroxyethylamino)-3-methylxanthine (3.95 g, 9.3 mmol) and thionyl chloride (25 ml) was stirred at room temperature for 3 hours. After concentrating under reduced pressure to remove unreacted thionyl chloride, ethanol (100 ml) and a 1.0 M solution of hydrogen chloride in diethyl ether (10.0 ml) were added. After the mixture was stirred at 75-80° C. for 16 hours, concentrating under reduced pressure provided (R)-1-(5-hydroxyhexyl)-8-(2-chloroethylamino)-3-methylxanthine (2.2 g, 69% yield) as a white powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=3)=[O:11])[CH2:17][CH2:16]2)[CH:24]=1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cc1F
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of (3-fluoro-4-methylphenyl)(piperazin-1-yl)methanone hydrochloride (434 mg, 1.67 mmol), 4,6-dichloropyrimidine (250 mg, 1.67 mmol), and triethylamine (0.94 mL, 6.71 mmol) in dioxane (10 mL) was reflexed with stirring for 4 h. After cooling to rt, the mixture was poured onto water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-2:1) to give 400 mg (71% yield) of the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH:34]=[CH:35]/[C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH:34]=[CH:35]/[C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC/C(=C\C=C\C(O)(CC)CC)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\C=C\C(O)(CC)CC)c1cc(CCc2ccc(CO)c(CO)c2)cs1

Procedure:
In a manner similar to that of Example 7(f), by reaction of 440 mg (0.68 mmol) of (4E,6E)-7-(4-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}-2-thienyl)-3-ethylnona-4,6-dien-3-ol with 1.5 mL (1.5 mmol) of 1 M tetrabutylammonium fluoride solution, (4E,6E)-7-(4-{2-[3,4-bis-hydroxymethyl-phenyl]ethyl}-2-thienyl)-3-ethylnona-4,6-dien-3-ol is obtained in the form of a yellow oil (m=200 mg; Y=71%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:27][OH:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:27][OH:28])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: NC(CO)C(=O)Nc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(CO)C(=O)Nc1ccccc1

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-hydroxy-N-phenyl-propionamide to provide the title compound in good yield. LCMS m/z 386 (M+1).
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(C1C=CC(S(N)(=O)=O)=CC=1)=O)(C)(C)C.C(C1C(=O)N(S(C2C=C(C=CC=2)C(O)=O)(=O)=O)CC(=O)NC1)C1C=CC=CC=1.C(OC(C1C=C(S(N)(=O)=O)C=CC=1)=O)(C)(C)C.ClC1C=CC(S(N2C(=O)/C(=C/C3C=C(Cl)C=CC=3OC)/CNC(=O)C2)(=O)=O)=CC=1C(OC)=O>>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]([S:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([O:25][CH3:29])=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12][C:11](=[O:28])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C(=O)C(Cc2ccccc2)CN1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)OC(=O)c1cccc(S(N)(=O)=O)c1
Agent: COC(=O)c1cc(S(=O)(=O)N2CC(=O)NC/C(=C\c3cc(Cl)ccc3OC)C2=O)ccc1Cl
Agent: O=C1CN(S(=O)(=O)c2cccc(C(=O)O)c2)C(=O)C(Cc2ccccc2)CN1
Product: COC(=O)c1ccc(S(=O)(=O)N2CC(=O)NCC(Cc3ccccc3)C2=O)cc1

Procedure:
4-[(6-benzyl-3,7-dioxo-1,4-diazepan-1-yl)sulfonyl]benzoic acid, synthesized by using 4-(tert-butoxycarbonyl)benzenesulfonamide instead of the starting material compound of Example 198, that is, 3-(tert-butoxycarbonyl)benzenesulfonamide for the similar procedure as in Example 198, was used instead of the starting material of Example 208, that is, the compound 196, for the similar procedure as with Example 208 to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5](Br)=[CH:4][C:3]=1[F:12].[CH2:13]([C:25]1[CH:26]=[C:27]([Sn](C)(C)C)[S:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:13]([C:25]1[CH:26]=[C:27]([C:2]2[C:7]3=[N:8][S:9][N:10]=[C:6]3[C:5]([C:27]3[S:28][CH:29]=[C:25]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:26]=3)=[CH:4][C:3]=2[F:12])[S:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Fc1cc(Br)c2nsnc2c1Br
Reactant: CCCCCCCCCCCCc1csc([Sn](C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCc1csc(-c2cc(F)c(-c3cc(CCCCCCCCCCCC)cs3)c3nsnc23)c1
Temperature: 105 °C
Yield: 47 %

Procedure:
4,7-Dibromo-5-fluoro-benzo[1,2,5]thiadiazole (0.82 g, 2.63 mmol), (4-dodecyl-thiophen-2-yl)-trimethyl-stannane (2.72 g, 6.57 mmol), and Pd(PPh3)4 (50 mg) were combined into a 100-mL Schlenk flask. The system was vacuumed and backfilled with argon for three cycles before 50 mL of anhydrous toluene was added. The mixture was heated at 105° C. for 3 days. After the reaction was cooled down, the solvent was removed by rotary evaporation. The product was further purified by silica gel column with dichloromethane/hexane (v/v, 1/4) as the eluent. Removal of the solvent offered the final product (0.81 g, 47.0% yield) as a red powder after being dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 8.03 (d, 1H, J=1.0 Hz), δ 7.92 (d, 1H, J=1.0 Hz), δ 7.67 (d, 1H, J=15.0 Hz), δ 7.08 (d, 1H, J=1.0 Hz), δ 7.02 (d, 1H, J=1.0 Hz), δ 2.63 (m, 4H), δ 1.63 (m, 4H), δ 1.26 (m, 18H), δ 0.81 (t, 6H, 7.0 Hz).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]([CH2:18][CH2:19][NH:20][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])([O:16][CH2:14][CH3:15])=[O:21]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chlorosulfonylbenzoic acid (3-1) (Maybridge Chemicals) (1.10 g, 5 mmoles) and β-alanine ethyl ester (0.85 g, 5.5 mmoles) in CHCl3 (20 ml) at room temperature was added triethylamine (1.52 g, 15 mmoles). After stirring for 3 hrs the solvent was removed, the residue was taken up in EtOAc, washed with H2O, 10% KHSO4 solution, H2O, brine and dried (Na2SO4). Solvent removal gave a residue that was purified by flash chromatography on silica gel eluting with CHCl3 (97)/MeOH(3) to give pure 3-2.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(C)=O>O>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13]([N:35]3[CH2:36][CH2:37][N:32]([C:30]4[S:29][N:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:31]=4)[CH2:33][CH2:34]3)=[O:20])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cc(-c2ccccc2)no1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 71.7 %

Procedure:
A solution of 2,2,2-trichloroethyl (3-phenylisoxazol-5-yl)carbamate (336 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol) diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration. This was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (310 mg, 71.8%) as a solid.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:10]([O:12]N1C(=O)CCC1=O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:30][C@H:31]([C:41]([OH:43])=[O:42])[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:10]([NH:30][C@H:31]([C:41]([OH:43])=[O:42])[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Yield: 64 %

Procedure:
Condensation of ZPheOSu (6.96 g.) and HLDap(Boc)OH (6.0 g.) by the salt coupling method gave ZPhe-LDap(Boc)OH in 64% yield. Condensation of ZPhe-LDap(Boc)OH (4.85 g.) and HLeuOMe (2.73 g.) by the mixed anhydride method using diphenylphosphinic chloride gave ZPhe-LDap(Boc)-LeuOMe in 69% yield. Debenzyloxycarbonylation of ZPhe-LDap(Boc)-LeuOMe (4.15 g.) by hydrogenation with palladium catalyst gave HPhe-LDap(Boc)-LeuOMe in 100% yield. Condensation of BocPro-PheOH (1.09 g.) and HPhe-LDap(Boc)-LeuOMe (1.44 g.) using dicyclohexylcarbodiimide and N-hydroxynorbornenedicarboximide gave BocPro-Phe-Phe-LDap(Boc)-LeuOMe in 75% yield. Hydrazinolysis of BocPro-Phe-Phe-LDap(Boc)-LeuOMe (1.69 g.) gave BocPro-Phe-Phe-LDap(Boc)- LeuNHNH2 in 36% yield.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C@@H:13]([NH2:15])[CH3:14].C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([C:47](O)=[O:48])=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C@@H:13]([NH:15][C:47]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:48])[CH3:14]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cc(C(F)(F)F)ccc1C(F)(F)F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cc(C(F)(F)F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 639 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]12[BH:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH2:8][CH2:7][CH2:6]2>C1COCC1>[CH3:4][CH:2]([CH3:3])[CH2:1][B:13]1[CH:5]2[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6]2
Reactant: B1C2CCCC1CCC2
Reactant: C=C(C)C
Solvent: C1CCOC1
Product: CC(C)CB1C2CCCC1CCC2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of isobutylene (4.40 g, 78.45 mmol) in 11 ml THF at -78° C., 9-Borabicyclo[3.3.1]nonane (9-BBN) (0.5 M in THF, 157 ml, 78.45 mmol) was added. The mixture was stirred at -78° C. for 3 hours, and then warmed to room temperature and stirred overnight to form 9-(2-Methylpropyl)-9-borabicyclo[3.3.1]nonane (9-isobutyl BBN). In a separate flask, to a solution of 3-bromobenzylalcohol (13.34 g, 71.32 mmol) in 36 ml THF, tetrakis(triphenylphosphine)palladium(0) (2.47 g, 2.14 mmol) and 60 ml 3M NaOH were added. The 9-isobutyl BBN prepared above was then transferred into the flask under argon and the mixture was refluxed for 21 hours. The mixture was cooled with an external ice bath and 18 ml 30% hydrogen peroxide was added. The mixture was stirred for 30 minutes, concentrated to about 100 ml and partitioned between 200 ml each of water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with 60 ml brine, dried and concentrated. The residue was chromatographed on silica gel using 9:1 hexane/ethyl acetate to afford compound A (8.16 g, 70%) as a liquid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>>[N+:21]([C:19]1[CH:20]=[C:15]([O:13][CH2:12][C@@H:9]2[CH2:10][CH2:11][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:16]=[N:17][CH:18]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: O=[N+]([O-])c1cncc(O)c1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
1-BOC-2-(S)-azetidinylmethanol (868 mg, 4.64 mmol) and 3-hydroxy-5-nitropyridine from Example 132d (500 mg, 3.57 mmol) were coupled according the procedure of Example 17a. Solvent was removed, and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to afford the title compound (800 mg, 73%). 1H NMR (CHCl3, 300 MHz) δ 1.45 (s, 9H), 2.56 (m, 2H), 4.52 (m, 4H), 4.82 (m, 1H), 8.25 (t, J=3 Hz, 1H), 8.65 (d, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H). MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11]O)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CCOCC>C1COCC1.ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[CH:17][CH:18]=3)[C:9]([CH3:11])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(CO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
A suspension of N-{4-[4-amino-6-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (423 mg, 0.930 mmol) in THF 5 (mL) and 1,2-dichloroethane (5 mL) was treated with thionyl chloride (148 μL, 2.05 mmol) at rt. After 10 min the reaction appeared complete by RP-HPLC. After 30 min the reaction was concentrated under vacuum. The residue was suspended in 1,2-dichloroethane and sonicated briefly, then concentrated again under vacuum (2×). The resulting solid (412 mg, 0.86 mmol) was suspended in THF (20 mL) and cooled to −45° C. This suspension was treated with 1.0 M L-Selectride in THF (8.6 mL, 8.6 mmol). After 15 min the reaction was complete by HPLC. The reaction mixture was removed from the ice bath and quenched with MeOH (1 mL), then treated with 1 M sodium hydroxide (2 mL) and 30% hydrogen peroxide (2 mL). After 15 min stirring, the mixture was diluted with EtOAc (200 mL) and water (200 mL). The organic layer was washed with brine and dried with sodium sulfate. Concentration of the organic layer and trituration with ether:hexanes gave the title compound as an white powder (323 mg, 0.73 mmol, 84% yield). 1H-NMR (CD3OD-d6) δ 8.61 (d, J=8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=9 Hz, 2H), 7.48 to 7.50 (m, 1H), 7.35 (d, J=9 Hz, 2H), 7.31 to 7.36 (m, 2H), 2.14 (s, 3H); MS [M+H]+=445.1; LCMS RT=2.80.
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>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].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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)=[CH:26][CH:25]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CCCC3=O)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCCc2cc(Sc3ccc(F)cc3)ccc21
Yield: 77.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (5.0 g, 17.0 mmol) in dioxane (75 mL) was added 4-fluorothiophenol (2.6 g, 20.4 mmol), Pd2(dba)3 (392 mg, 0.43 mmol), Xantphos (492 mg, 0.85 mmol) and DIEA (4.4 g, 34.0 mmol). The mixture was heated to reflux overnight under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=20:1 to 5:1) to give 3.6 g (77%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 2.08-2.13 (m, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 6.94 (br s, 1H), 6.98 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.10-7.14 (m, 2H), 7.49-7.53 (m, 2H), 7.88 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C16H13FOS, 273. Found, 273.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[N+:11]([C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].I[CH3:26].[Cl-].[NH4+]>C1COCC1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]([CH3:26])[C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: CI
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of lithium hexamethyldisilazide (1M, hexane, 1.0 eq., 21.5 ml) was added dropwise to a stirred solution of methyl (3-nitrophenyl)acetate (4.2 g) in THF (30 ml) at −30□ C. The mixture was warmed to 0□ C. and re-cooled to −30□ C. then iodomethane (1.0 equiv., 3.0 g.) was added. The solution was warmed to room temperature and poured into aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The crude was purified using chromatography (SiO2, SPE) using cyclohexane/ethyl acetate (80/20) as eluent to afford the title compound as yellow liquid (1.50 g, 30% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)cnc1Cl
Yield: 49.4 %

Procedure:
4.00 g (27.6 mmol) of 2-chloro-3-fluoro-5-methyl pyridine was dissolved in 80 ml of carbon tetrachloride, 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed overnight. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to obtain 3.06 g (yield 51%) of 5-(bromomethyl)-2-chloro-3-fluoropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][C:3]=1[NH2:4].[C:10]([Si:14]([CH3:30])([CH3:29])[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](O)([CH3:27])[CH3:26])([CH3:13])([CH3:12])[CH3:11].COC1C=CC=CC=1C(O)(C)C.[Cl:43][C:44]1[CH:50]=[CH:49][C:48]([S:51][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[O:61][CH2:62][CH2:63][OH:64])([CH3:54])[CH3:53])=[CH:47][C:45]=1[NH2:46].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C=O.O>[Cl:43][C:44]1[CH:50]=[CH:49][C:48]([S:51][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[O:61][CH2:62][CH2:63][OH:64])([CH3:54])[CH3:53])=[CH:47][C:45]=1[NH2:46].[Si:14]([O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([CH3:27])([S:9][C:6]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH:5]=1)[NH2:4])[CH3:26])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:29])[CH3:30]
Reactant: Nc1cc(S)ccc1Cl
Reactant: CC(C)(O)c1ccccc1OCCO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(Sc1ccc(Cl)c(N)c1)c1ccccc1OCCO
Agent: COc1ccccc1C(C)(C)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Sc1ccc(Cl)c(N)c1)c1ccccc1OCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-5-{1-[2-(2-hydroxyethoxy)phenyl]-1-methylethylthio}aniline was prepared in a similar manner to that described in Reference Example 52 using 2-chloro-5-mercaptoaniline and 2-{2-[2-(tert-butyldimethyl silyloxy)ethoxy]phenyl}-2-propanol instead of 2-chloro-5-mercapto-4-methoxyaniline and 2-(2-methoxyphenyl)-2-propanol, respectively. To the solution of the obtained 2-chloro-5-{1-[2-(2-hydroxyethoxy)-phenyl]-1-methylethylthio}aniline (0.55 g) and imidazole (0.14 g) in N,N-dimethylformamide (3 mL) was added tert-butyldimethylsilyl chloride (0.24 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (0.66 g).