Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([O:12][CH3:17])=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(C(C)(C)C)cc(Br)cc1C(C)(C)C
Yield: 106.9 %

Procedure:
Under an argon atmosphere, to a solution of 4-bromo-2,6-di-tert-butylphenol (50 g, 0.175 moL) and potassium carbonate (96.7 g, 4.0 equivalents) in acetone (750 mL) was added dimethyl sulfate (38.6 g, 1.75 equivalents) at 22° C., and the mixture was stirred under reflux for 13 hrs. Insoluble materials were filtered off and the solvent was evaporated under reduced pressure. Ethylacetate (150 mL) and water (100 mL) were added, the mixture was partitioned, and the organic layer was washed successively with water (100 mL), 5% aqueous NaHCO3 solution (100 mL) and 5% aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure to give the title compound (56.1 g, brown oil). yield 95.2%
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C1C=C[NH+]=CC=1.[Br:16][Br-]Br>C(O)(=O)C>[Br:16][C:4]1[S:3][C:2]([Cl:1])=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: O=C(O)c1ccsc1Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)sc1Cl
Temperature: 40 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
A mixture of 2-chloro-3-thiophenecarboxylic acid (2.44 g), pyridinium bromide perbromide (5.33 g) and acetic acid (15 ml) was stirred at 40° C. for 4 hours and poured into ice-water. Precipitated crystals were collected by filtration, dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give 5-bromo-2-chloro-3-thiophenecarboxylic acid (2.81 g) as crystals.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][N:33]=3)=[CH:30][C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.05 g), 2-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.88 g), anhydrous iron (III) chloride (1.07 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.87 g of desired compound (melting point: 104.0°-108.0° C.).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([C:23]1[S:24][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:37])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:27][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cc2ccc(OC)cc2)s1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2ccc(C(NC(=O)C(CS)CCc3ccccc3)C(=O)O)s2)cc1

Procedure:
The title compound was prepared from 2-[5-(4-methoxybenzyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 66) by the procedure described in Example 24. vmax (CHCl3) 3423, 1724 and 1674 cm-1. m/z 469 (M+).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH2:9][OH:10])[CH2:2][CH3:3]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH2:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH:9]=[O:10])[CH2:2][CH3:3]
Reactant: CCCc1[nH]cnc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCc1[nH]cnc1C=O
Yield: 73.6 %

Procedure:
A mixture of 5-propyl-1H-imidazole-4-methanol (4.0 g) and manganese (IV) oxide (10.0 g) in 1,4-dioxan (150 ml) was heated at reflux under nitrogen for 1 h. The hot suspension was filtered (Hyflo), washed with hot 1,4-dioxan (100 ml) and evaporated to give the title compound (2.9 g) as a solid, m.p. 120°-124°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CO.[Pt](=O)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:19])(=[O:20])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(C(F)(F)F)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(C(F)(F)F)cc3)C2=N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.9 %

Procedure:
A mixture of 9-[4-(trifluoromethyl)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (250 mg) and platinum(IV) oxide (25.9 mg) in MeOH (10 mL) was stirred at room temperature under H2 for 20 hr. The reaction mixture was filtered by Celite and the filtrate was concentrated in vacuo. The residue was recrystallized from EtOAc-MeOH to give the title compound (68.0 mg) as a white solid.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:42]=[CH:41][C:9]([C:10]([CH:12]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:15]2=[O:40])[CH3:13])=[O:11])=[CH:8][CH:7]=1.[NH4+].[OH-]>ClCCl>[Cl:5][C:6]1[CH:42]=[CH:41][C:9]([C:10]([CH:12]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([C:32]5[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:15]2=[O:40])[CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4c(C)cn(C(C)C(=O)c5ccc(Cl)cc5)c4=O)cc3)CC2)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cn(C(C)C(=O)c2ccc(Cl)cc2)c(=O)n1-c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a mixture of 25 g of boron tribromide and 100 ml of dichloromethane was added dropwise a solution of 6.1 g of 1-[1-(4-chlorobenzoyl)ethyl]-1,3-dihydro-3-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4-methyl-2H-imidazol-2-one in 200 ml of dichloromethane (temp<10° C.). After stirring for 2 hours, the reaction mixture was poured into a mixture of NH4OH and ice. Then there were added 300 ml of dichloromethane and the whole was stirred for 1 hour. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was triturated in methanol. The product was filtered off and dried, yielding 4.3 g (72.3%) of 1-[1-(4-chlorobenzoyl)ethyl]-1,3-dihydro-3-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-4-methyl-2H-imidazol-2-one; mp. 229.7° C. (comp. 30).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:29])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH2:12][N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:29])[CH2:9][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1(CC=O)CC1
Reactant: CC(C)(C)OC(=O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN(CCC1(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
10.5 g (54.7 mmol, 1 eq.) 1-(2-oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester and 13.21 g (1.08 eq.) N-benzylglycine tert-butyl ester were dissolved in 140 ml toluene. 21 g (1.63 eq.) sodium triacetoxyborohydride were added (exotherm from 25° C. to 28° C.) and the reaction mixture was stirred 5 h at room temperature (IPC by GC). A solution of 2 ml (0.64 eq.) acetic acid in 15 ml toluene was added. After 30 min at room temperature, the reaction mixture was cooled to 0° C. and 100 ml sat. aq. sodium hydrogencarbonate solution was added over 40 min (foaming). 50 ml ethyl acetate were added. The mixture was stirred for 30 min at room temperature. The mixture was extracted with 200 ml and a second time with 50 ml ethyl acetate. The organic phases were washed with 50 ml sat. aq. sodium hydrogencarbonate solution followed by 50 ml sat. aq. sodium chloride solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 21.5 g of the title compound as an oil (ca. 95% yield, corrected for ca 3% residual toluene and 3% amine starting material).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:17][O:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CI
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccccc2cc1C(=O)O

Procedure:
Five grams of 2-hydroxy-3-naphthoic acid was dissolved in 220 ml of dimethyl formamide, 3.74 grams of sodium hydride was added thereto little by little with ice cooling and stirring, then 11.0 grams of methyl iodide was added, and the mixture was stirred at room temperature for twelve hours. The reaction solution was partitioned between benzene and water, the benzene layer was collected, dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom, and the residue was dried. To this were added 10 ml of water, 90 ml of methyl cellosolve and 5.0 grams of potassium hydroxide, the mixture was heated to reflux for forty minutes with stirring, the reaction solution was poured over ice water, the mixture was acidified with diluted hydrochloric acid, and the separated mass was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, the solvent was evaporated therefrom, and the residue was crystallized from n-hexane to afford 2-methoxy-3-naphthoic acid. The yield was 4.62 grams.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[N:9]2[C:10](=[O:13])[C:11]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])c1nc2scc(C(F)(F)F)n2c(=O)c1Br
Reactant: OB(O)c1cccc(F)c1
Product: CC(N=[N+]=[N-])c1nc2scc(C(F)(F)F)n2c(=O)c1-c1cccc(F)c1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example 8, step 5, using 7-(1-azidoethyl)-6-bromo-3-(trifluoromethyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one and (3-fluorophenyl)boronic acid as the starting materials in 29% yield. LCMS for C15H10F4N5OS (M+H)+: m/z=383.9.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=O>>[C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: CCCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Pure azelaic acid is obtained by working up a reaction mixture containing C1-18 monocarboxylic acids, mainly pelargonic acid, and C4-16 dicarboxylic acids, mainly azelaic acid, obtained from the ozonolysis of oleic acid or a starting mixture containing oleic acid. All but <2% by weight of the monocarboxylic acids and part of the dicarboxylic acids with a chain length of <C9 and >C9 are separated off to obtain a prepurified product containing more than 75% by weight of oleic acid and the prepurified product is concentrated to more than 90% by weight of oleic acid in several process steps. In a first process step (1), the dicarboxylic acids with chain lengths of <C9 present in the prepurified product are removed as first runnings by fractional distillation. In a second process step (2), the bottom product obtained is reacted with water to split carboxylic anhydrides present in the bottom product. In a third process step (3), the reaction mixture is subjected to overhead distillation. The third process step (3) is carried out after or at the same time as the second process step (2). The product yield is improved. The process is particularly suitable for working on an industrial scale.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:16])[CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[OH:20][CH2:17][C:18]#[C:19][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:16])[CH:3]=1
Reactant: C#CCO
Reactant: Cc1cc(Br)ccc1C(=O)N1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C#CCO)ccc1C(=O)N1CCOCC1

Procedure:
Prepared analogously to Example 1g from N-(4-bromo-2-methyl-benzoyl)-morpholine, propargyl alcohol, tetrakis(triphenylphosphine)palladium(0), copper(I)iodide and triethylamine in acetonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([C@@H:12]([CH3:14])[OH:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[C@@H:12]([CH3:14])[OH:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C[C@@H](O)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@@H](O)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-threoninamide (981 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1764 mg) in 2-propanol (10 mL) was added piperidinium acetate (755 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (560 mg).
Reaction SMILES: [OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([NH:5][CH3:6])=O.B.O1CCCC1.CO>O1CCCC1>[N:16]1([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:2]([OH:1])[CH2:3][NH:5][CH3:6])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: CNC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CNCC(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropanamide (900 mg, 2.8 mmol) in anhydrous tetrahydrofuran (50 mL) at room temperature under nitrogen was added dropwise a solution of borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 13.9 mL, 13.9 mmol) and the mixture heated to reflux for 3 hours. The reaction mixture was then cooled to 50° C., methanol (20 mL) was added, and the mixture stirred at 50° C. for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure to afford a white solid. Purification by flash chromatography (silica, 15% methanol/dichloromethane) afforded 272 mg (32%) of (1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol as a yellow syrup. The product was dissolved in absolute ethanol (4 mL), a solution of hydrogen chloride (4 M in 1,4-dioxane, 0.28 mL, 1.12 mmol) added, the solution stirred for 10 minutes then concentrated under reduced pressure to afford a white foam. Crystallization from 1: 1: 1 v/v absolute ethanol : diethyl ether: hexane (12 mL) at −35° C. afforded 81.3 mg (8%) of (1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol hydrochloride as a hygroscopic white solid. MS (ES) m/z 311.3 ([M+H]+); HRMS: calcd for C19H22N2O2+H+, 311.17540; found (ESI, [M+H]+), 311.176.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1>ClCCl>[Br:21][C:20]([Br:24])=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A flask was charged with triphenylphosphine (477 g, 1.82 mol) and dichloromethane (2,500 ml) was cooled to 0° C. A solution of carbon tetrabromide (302 g, 910 mmol) in dichloromethane (300 ml) was added dropwise, followed by the dropwise addition of a solution of tert-butyl 3-(2-oxoethyl)pyrrolidine-1-carboxylate (97 g, 455.40 mmol, 1.00 equiv) in dichloromethane (200 ml). The resulting solution was allowed stir for 1.5 hours at 0° C. The reaction mixture was washed with 4,000 ml of petroleum ether, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl 3-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=O)[NH:10][CH2:11][CH2:12][CH2:13][C:14]=3[O:15][C:4]=2[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]=3[O:15][C:4]=2[CH:3]=1
Reactant: O=C1NCCCc2oc3cc(Br)ccc3c21
Agent: B
Solvent: C1CCOC1
Product: Brc1ccc2c3c(oc2c1)CCCNC3
Temperature: 65 °C
Yield: 45.3 %

Procedure:
To a slurry of the product of step C (858 mg, 3.06 mmol) in anhydrous THF (6 mL) was added 1 M borane-THF complex (1 N in THF, 15.3 mL, 15.3 mmol) at ambient temperature. The reaction mixture was heated to 65° C. for 15 h. After cooling to ambient temperature, the reaction mixture was quenched with 1 M HCl and concentrated in vacuo. The residue was basified with 1 M NaOH and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude material which was purified by flash column chromatography (SiO2, 90:10 dichloromethane/methanol) to provide 8-bromo-2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepine (369 mg, 45%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.53 (d, J=1.8 Hz, 1H), 7.33-7.28 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 3.95 (s, 2H), 3.18 (td, J=3.9, 2.4 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 1.94-1.84 (m, 2H), 1.57 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:30])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[CH:23][CH:22]=1.C([O:33][CH:34]=[C:35]([C:41](OCC)=O)[C:36]([O:38][CH2:39][CH3:40])=[O:37])C>O1CCCC1.C(O)(=O)C>[C:28]([C:27]1[CH:41]=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34](=[O:33])[N:26]2[C:25]=1[CH:24]=[CH:23][CH:22]=[C:21]2[C:14]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH3:30])#[N:29]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(C)c(-c2cccc(CC#N)n2)c(C)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C#N)c2cccc(-c3c(C)cc(C)cc3C)n2c1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Diisopropylamine (1.6 mL, 11.6 mmol) in tetrahydrofuran (15 mL) was charged with n-butyllithium (2.5M, 4.6 mL, 11.6 mmol) at 0° C. The reaction stirred for 0.5 h. The solution was cooled to −20° C. and (6-mesitylpyridin-2-yl)acetonitrile (2.49 g, 10.5 mmol) was added drop wise (as a solution in 5 mL tetrahydrofuran). After 0.5 h, the solution was cooled to −78° C. and diethyl ethoxymethylenemalonate (2.1 mL, 10.5 mmol) was added. The reaction stirred for 0.5 h and was then cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an orange residue. The material was dissolved in acetic acid (20 mL) and heated at 100° C. for 4 h. The solution was cooled and poured into an Erlenmeyer flask and washed with water. The solution was neutralized with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (3 times), dried, and concentrated. Flash chromatography (25% ethyl acetate/hexanes) gave 3.19 g (84% yield) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]([C:11](=[O:21])[NH:12][C:13]1[CH:18]=[C:17](Br)[CH:16]=[C:15]([NH2:20])[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[B:23]1(B2OCC(C)(C)CO2)[O:28]CC(C)(C)C[O:24]1.CC([O-])=O.[K+].CS(C)=O>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:20][C:15]1[CH:16]=[C:17]([B:23]([OH:28])[OH:24])[CH:18]=[C:13]([NH:12][C:11](=[O:21])[CH:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH3:8])[CH3:10])[N:14]=1
Reactant: CC(C(=O)Nc1cc(Br)cc(N)n1)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C(=O)Nc1cc(B(O)O)cc(N)n1)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.41 g, 0.6 mmol) is added to a mixture of tert-butyl-N-{1-[(6-amino-4-bromopyridin-2-yl)carbamoyl]ethyl}-N-methyl-carbamate B1 (5.2 g, 11.2 mmol), bis(neopentyl glycolato)diboron (5.1 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol) and DMSO (20 ml) under argon atmosphere and the mixture is stirred at 80° C. for 5 h. The mixture is diluted with DCM and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 3.2 g (85%). HPLC-MS: M+H=339; tR=0.51 min (Method—2).