Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2Br)[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:38]([O:45]CC)([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41]>>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:38]([O:42][CH2:43][CH3:44])([O:39][CH2:40][CH3:41])=[O:45])[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CCC12
Product: CCOP(=O)(OCC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Yield: 16 %

Procedure:
A solution of 3-bromo-7-[(phenoxyacetyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (784 mg, 1.4 mmol) in triethyl phosphite (4 mL) was refluxed under nitrogen for 90 minutes. After cooling, the reaction was poured into hexanes. The supernatant liquid was decanted from the resulting semi-solid which was then dissolved in ethyl acetate and purified by flash-chromatography on silica gel (50% ethyl acetate/hexanes to 100% ethyl acetate) to provide 7-[(phenoxyacetyl)amino]-8-oxo-3-(diethoxyphosphinyl)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl) ester (100 mg; 16%):
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][OH:2])=[CH:8][CH:7]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(N(c2ccccc2)c2ccc(CO)cc2)cc1

Procedure:
Bis(4-formylphenyl)phenylamine was reduced in ethanol with 2 equivalents of sodium borohydride to obtain bis(4-hydroxymethylphenyl)phenylamine. The bis(4-hydroxymethylphenyl)phenylamine was reacted with equimolar terephalic acid monomethyl chloride in a THF solvent to yield an intermediate compound having the structure represented by Formula (10).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:32])[CH2:11][NH:12][C:13](=[O:31])[C@@H:14]([NH:22][CH2:23]C(OC(C)(C)C)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:8][O:9][C:10](=[O:32])[CH2:11][NH:12][C:13](=[O:31])[C@@H:14]([NH:22][CH3:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CNC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](Cc1ccccc1)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (S)-N-(2-{N-[(1,1-dimethylethoxy)carbonyl]methylamino}-1-oxo-3-phenylpropyl)glycine methyl ester (Description 32, 2.28 g, 6.5 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated under reduced pressure, then toluene was added and evaporated under reduced pressure. Aqueous sodium carbonate (10%, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH (95:5), to give the title compound as a colorless oil (1.59 g, 98%). 1H NMR (250 MHz, CDCl3) δ7.71 (1H, br s), 7.61-7.21 (5H, m), 4.15 (1H, dd, J 18.3, 6.1 Hz), 4.02 (1H, dd, J 18.3, 5.5 Hz), 3.76 (3H, s), 3.25 (2H, m), 2.69 (1H, dd, J 14.7, 10.9 Hz), 2.31 (3H, s), and 1.30 (1H, br s). m/z (ES+) 251 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](NN)[CH2:9][N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:20]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:20][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C1=CNc2ccccc2C=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 50 parts by volume of acetic anhydride is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left standing at room temperature for 1 hour, poured in ice-water, neutralized with sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a]][1,4] benzodiazepine as colorless needles. Melting point: 224° C to 225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(C)=O.Br[CH:34]([CH3:36])[CH3:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:34]([CH3:36])[CH3:35])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C)c4=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 10 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one, prepared as described in Example XVII of U.S. Pat. No. 4,267,179, 1.5 parts of a sodium hydride dispersion 50% and 300 parts of dimethyl sulfoxide was stirred at 60° C. under nitrogen atmosphere till foaming had ceased. Then there were added 5.24 parts of 2-bromopropane and stirring was continued for 1 hour at 60° C. Another 1.5 parts of a sodium hydride dispersion 50% was added and stirring was continued till foaming had ceased. Then another 5.24 parts of 2-bromopropane was aded and the whole was stirred for 1 hour at 60° C. The reaction mixture was cooled and poured into water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 5.2 parts (47%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]- 2-(1-methylethyl)-3H-1,2,4-triazol-3-one; mp. 209.5° C. (intermediate 9).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][N:20]=1>CN(C=O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:18][C:19]3[N:23]=[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:21][N:20]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Reactant: ClCc1noc(-c2ccccc2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)nccc2n1Cc1noc(-c2ccccc2)n1
Yield: 63.2 %

Procedure:
To a solution of methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (500 mg, 2.374 mmole) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 123 mg, 3.09 mmole) portionwise at RT. After 30 min 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (601 mg, 3.09 mmole) was added all at once as a solid. After 6 hr the mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, O-20% EtOAc/hexanes) gave the title compound (553 mg, 63%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=6.0 Hz, 1 H); 8.05 (dd, J=7.8, 1.5 Hz, 2 H); 7.59-7.54 (m, 1 H); 7.54-7.44 (m, 3 H); 7.39-7.35 (m, 1 H); 6.03 (s, 2 H); 3.97 (s, 3 H).
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:6]2[S:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[C:5]=2[CH2:4][CH2:3]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH2:24][NH:25][CH3:26])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([OH:27])[CH2:24][N:25]([CH3:26])[S:10]([C:9]2[C:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[C:14](=[O:15])[C:6]=3[S:7][CH:8]=2)(=[O:12])=[O:11])=[CH:21][CH:22]=1
Reactant: CNCC(O)c1ccc(F)cc1
Reactant: CC1CCc2c(S(=O)(=O)Cl)csc2C1=O
Product: CC1CCc2c(S(=O)(=O)N(C)CC(O)c3ccc(F)cc3)csc2C1=O

Procedure:
From 6-methyl-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 13) (140 mg) and 1-(4-fluorophenyl)-2-methylamino ethanol (the compound of Preparation Example 17) (108 mg), the title compound (orange oily substance) (155 mg) was obtained as a mixture of diastereomers, in the same way as Preparation Example 41.
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(NCC2C=CC(OCCN3CCCCC3)=CC=2)C=1.C[O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([O:70]C)=[CH:66][CH:65]=2)=[C:42]([N:44]([CH3:61])[CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[CH:48][CH:47]=2)[CH:43]=1>>[OH:70][C:67]1[CH:68]=[CH:69][C:64]([CH2:63][CH2:62][C:41]2[CH:40]=[CH:39][C:38]([OH:37])=[CH:43][C:42]=2[N:44]([CH3:61])[CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][N:55]3[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]3)=[CH:48][CH:47]=2)=[CH:65][CH:66]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2N(C)Cc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2NCc2ccc(OCCN3CCCCC3)cc2)cc1
Product: CN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(O)ccc1CCc1ccc(O)cc1
Yield: 88.2 %

Procedure:
Synthesized from {5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl}[4-(2-piperidin-1-ylethoxy)benzyl]amine (780 mg) according to an analogous synthetic method to Preparation Example 18, {5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenyl}methyl[4-(2-piperidin-1-ylethoxy)benzyl]amine (380 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (316 mg).
Reaction SMILES: [CH:1]1([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.Cl[Si:39]([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]2([C:12]3[C:24]4[CH2:23][C:22]5[C:17](=[CH:18][C:19]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:20][CH:21]=5)[C:16]=4[CH:15]=[C:14]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC([Si](C)(C)C)=C4)CCCCC3)c1C2
Yield: 45.8 %

Procedure:
In a 30 ml Schlenk flask purged with nitrogen, 0.86 g (2.02 mmol, 1 eq) of 1-(cyclopentadienyl)-1-(3,6-di-tert-butylfluorenyl)cyclohexane was placed at room temperature. Then, 12 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 1.4 ml (2.28 mmol, 1.13 eq) of n-BuLi (hexane solution) was dropwise added. Then, the ice bath was removed, and the solution was stirred at room temperature for 19 hours. The solution was cooled with an ice bath, and to the solution, 1.6 ml (12.6 mmol, 6.24 eq) of chlorotrimethylsilane was dropwise added by a syringe. The ice bath was removed, and the solution was stirred at room temperature for 4 hours. The resulting yellow solution was poured into 50 ml of a diluted hydrochloric acid solution-to perform quenching. After the soluble component was extracted with 70 ml of diethyl ether, the organic phase was washed with 50 ml of a saturated saline solution. The organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a yellow amorphous product. The amorphous product was purified by silica gel column chromatography (developing solution: hexane) to obtain 0.46 g a white amorphous product (yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:16]=2)[NH:4][N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37]([NH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:16]=2)[NH:4][N:3]=1)(=[O:39])=[O:38]
Reactant: Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
3-Amino-4-(2-pyridyl)-5-(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole (0.39 g, 0.99 mmol) was dissolved in 5 ml of pyridine. Commercial 2,6-dichlorobenzenesulfonyl chloride (0.26 g, 1.04 mmol) was added and the red solution was stirred overnight at room temperature. The reaction mixture was poured into 50 ml of water and was extracted twice with 100 ml portions of ethyl acetate. The organic layers were washed with water and brine, combined, dried over MgSO4 and concentrated. The crude product was slurried in cold ethyl acetate and the solid was filtered off and washed with small portions of cold ethyl acetate and cold diethyl ether and dried under vacuum to afford 0.32 g (53% yield) of the final compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1)[C:9](=[O:22])[CH2:8][CH2:7][C:6]2([CH3:24])[CH3:23])#[CH:2].[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]#[C:1][C:3]2[CH:12]=[C:11]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:10]3[C:9](=[O:22])[CH2:8][CH2:7][C:6]([CH3:24])([CH3:23])[C:5]=3[CH:4]=2)=[CH:33][CH:34]=1
Reactant: C#Cc1cc(OCOCC[Si](C)(C)C)c2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OCOCC[Si](C)(C)C)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-4,4-dimethyl-8-(2-trimethylsilanyl-ethoxymethoxy)-3,4-dihydro-2H-naphthalen-1-one (Intermediate 73, 1.28 g, 3.7 mmol), 4-iodo phenyl acetic acid methyl ester (1.02 g, 3.7 mmol), triethyl amine (30 mL), copper(I)iodide (0.095 g, 0.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.35 g, 0.5 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow oil (1.61 g, 88%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1CN(C)[CH2:7][NH:6][C:5]1=[N:11][N+:12]([O-:14])=[O:13].O(C[CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1)S(C(F)(F)F)(=O)=O.Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[O:25]1[CH2:26][CH2:27][CH:28]([CH2:7][NH:6][C:5]([NH:4][CH3:3])=[N:11][N+:12]([O-:14])=[O:13])[CH2:24]1
Reactant: O=S(=O)(OCC1CCCO1)C(F)(F)F
Reactant: CN1CNC(=N[N+](=O)[O-])N(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Temperature: 25 °C

Procedure:
A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.5 g of trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of dichloromethane was stirred for an hour at room temperature. Water was poured into the reaction solution to separate the organic layer, which was washed with 1 N hydrochloric acid, water and a saturated saline solution, dried, and concentrated to obtain 20 g of 3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride were added to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and 60 ml of DMF at room temperature, followed by stirring for an hour. 20.0 g of the 3 tetrahydrofuranylmethyl triflate were added thereto, and the mixture was stirred at 50° C. for 2 hours. After cooling the mixture to room temperature, 50 ml of 2N hydrochloric acid were added thereto, followed by stirring at 50° C. for 2 hours. The resultant mixture was neutralized with sodium bicarbonate and extracted with dichloromethane, and the extract was dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain 7.8 g of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran).
Reaction SMILES: C([O:4][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:6])(C)C.[OH-].[Na+]>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:5]([OH:6])=[O:4])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN1S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred solution of 2.06 g (6.5 mmol) of 1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid isopropyl ester ( ) in 10 mL of methanol was added 2.3 mL (13 mmol) of 5N NaOH. After 2 hours, the solvent was removed in vacuo and the aqueous residue was acidified with 1N HCl and then extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1.69 g of the title compound as a white solid; mp 145-148° C.; 1H NMR (DMSO) δ 1.56-1.63 (m, 1H), 1.78-2.05 (m, 4H), 3.13-3.21 (m, 1H), 4.10-4.15 (m, 1H), 7.42-7.50 (m, 2H), 7.88-7.95 (m, 2H), 12.75 (bs, 1H); MS (ES) m/z 271.9 (MH−); HRMS for C11H12N2FO4S: 274.0543 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:10]([CH3:13])([CH3:11])[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][C:26]([C@@H:24]([N:20]3[CH2:19][CH2:18][C@:17]([CH2:16][C:15]([OH:14])([CH3:47])[CH3:48])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:22][C:21]3=[O:23])[CH3:25])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(O)COc1ccc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccc(OCC(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (30 mg, 0.122 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under nitrogen. The mixture was stirred for 1 h at rt. A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (58.4 mg, 0.122 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated, and purified by preparative TLC (1:1 PE/EtOAc) and HPLC to afford the title compound (7.6 mg, 12.1%). 1H NMR (CDCl3): δ 8.23 (d, 1H), 7.72 (q, 1H), 7.74-6.68 (m, 10H), 5.70 (m, 1H), 4.24 (s, 2H), 3.43 (s, 1H), 2.85 (m, 1H), 2.40 (m, 1H), 2.27-2.14 (m, 5H), 1.54 (d, 3H), 1.33-1.29 (d, 3H), 1.18-1.12 (d, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH3:12].Br[C:14]1C(OC)=CC=C2[C:15]=1C=CN2>>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:5]([CH:14]=[CH:15][NH:8]2)=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Reactant: COc1ccc2[nH]ccc2c1Br
Product: COc1c(Br)ccc2cc[nH]c12
Yield: 14 %

Procedure:
6-Bromo-7-methoxy-1H-indole CXXXVII (14% yield) was prepared from 2-bromo-6-nitro-anisole using the procedure described above for preparation of 4-bromo-5-methoxyindole XLVI (Example 12).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>O1CCCC1.O.O.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>[CH3:9][O:8][C:7]1[C:3]([CH2:2][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([C:29]([F:46])([F:45])[F:28])[CH:35]=2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccnc(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Step D, 0.525 g, 66 weight %, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.42 g, 1.5 mmol). The mixture was heated to reflux and stirred for 17 h. The reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (25 mL, 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford the title compound (0.12 g) as a pale yellow solid.