Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][P:13]([O:20][CH2:21][C:22]1[CH:76]=[CH:75][C:25]([C:26]([O:28][C:29]2[C:33]([O:34][C:35](=[O:56])[C:36]3[CH:41]=[CH:40][C:39]([CH2:42][O:43][P:44]([O:51]C(C)(C)C)([O:46]C(C)(C)C)=[O:45])=[CH:38][CH:37]=3)=[C:32]([C:57](=[O:61])[N:58]([CH3:60])[CH3:59])[N:31]([C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[C:30]=2[C:70](=[O:74])[N:71]([CH3:73])[CH3:72])=[O:27])=[CH:24][CH:23]=1)([O:15]C(C)(C)C)=[O:14])(C)(C)C>C(Cl)Cl>[P:44]([O:43][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([O:34][C:33]2[C:29]([O:28][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([CH2:21][O:20][P:13]([OH:15])([OH:14])=[O:12])=[CH:76][CH:75]=3)=[C:30]([C:70](=[O:74])[N:71]([CH3:73])[CH3:72])[N:31]([C:62]3[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=3)[C:32]=2[C:57](=[O:61])[N:58]([CH3:60])[CH3:59])=[O:56])=[CH:41][CH:40]=1)([OH:51])([OH:46])=[O:45]
Reactant: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)c3ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc3)c(OC(=O)c3ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc3)c2C(=O)N(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)c3ccc(COP(=O)(O)O)cc3)c(OC(=O)c3ccc(COP(=O)(O)O)cc3)c2C(=O)N(C)C)cc1
Reaction time: 72 h

Procedure:
TFA (16 mL, 208 mmol) was added dropwise to a solution of 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(4-(((di-tert-butoxyphosphoryl)oxy)methyl)benzoate) (64) (88 mg, 0.09 mmol) in DCM (64 mL) the mixture was left to stand for 72 h, and then concentrated in vacuo to afford 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(4-((phosphonooxy)methyl)benzoate) (UL1-124) as a yellow oil: m/z 776 (M+H)+ (ES+); 774 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.00-7.98 (m, 4H), 7.54-7.52 (m, 4H), 7.20-7.18 (m, 2H), 7.00-6.98 (m, 2H), 4.98-4.96 (d, 4H), 3.79 (s, 3H), 2.89 (s, 6H), 2.74 (s, 6H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN([CH:17]=[O:18])C.[NH4+].[Cl-]>C(OCC)(=O)C.CCCCCC.C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(Br)n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A three necked 100 mL round-bottomed flask with magnetic stirring, an immersion thermometer, and an addition funnel was charged with THF (30 mL) and cooled to −78° C. n-butyllithium (1.35 g, 21.10 mmol) was carefully added to the reaction maintaining an internal temperature of −70° C. After the addition of 2,6-dibromopyridine (5.0 g, 21.10 mmol), the resulting dark green solution was stirred for 15 min, then neat DMF (2.31 g, 31.66 mmol) was added over a period of 30 seconds. The reaction mass was stirred for 15 min at −70° C. The progress of the reaction was monitored by TLC analysis on silica gel with ethyl acetate:hexane (3:7) as mobile phase. Reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 5.0 g of crude compound which was purified by chromatography. Product elute at 3% ethyl acetate in hexane to give 1.5 g of pure product (Yield 38.4%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([S:12](Cl)(=O)=O)[CH:3]=1.CN(C)C(=O)C.Cl[Si](Cl)(C)C>ClCCCl.[Zn]>[SH:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: Cc1cc(S(=O)(=O)Cl)cc2oc(=O)[nH]c12
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: Cc1cc(S)cc2oc(=O)[nH]c12
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere a solution of 1.40 g (5.60 mmol) 4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-sulphonic acid chloride and 1.60 g (16.8 mmol) N,N-dimethylacetamide in 1,2-dichloroethane was slowly added dropwise to 1.30 g (19.9 mmol) zinc and 2.40 mL (19.5 mmol) dichlorodimethylsilane in 20 mL of 1,2-dichloroethane. The reaction mixture was stirred for 2 h at 75° C. After cooling the mixture was filtered and the filtrate was evaporated down. The residue remaining was combined with MeOH, the precipitate formed was filtered and the filtrate was evaporated down. The residue was further reacted as the crude product.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH2:7][CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:10](O)=[O:11])#[N:6].[BH4-].[Na+]>O1CCCC1.C(O)C>[OH:11][CH2:10][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22])[CH2:8][CH2:7][C:5]#[N:6]
Reactant: N#CCCC(C(=O)O)c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: N#CCCC(CO)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Thionyl chloride (8.25 mL) was added to 4-cyano-2-(2-trifluoromethylphenyl)butanoic acid (2.9 g), and the mixture was heated under reflux. After one hour, concentration under reduced pressure gave an oil. The oil was dissolved in tetrahydrofuran (50 mL) and ethanol (20 mL), and sodium borohydride (855 mg) was added at 0° C. After stirring at room temperature for one hour, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine and dried over magnesium sulfate. Concentration under reduced pressure gave a pale yellow oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (2.14 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: Clc1nccc(I)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
To a solution of crude 3-bromo-2-chloro-4-iodopyridine (10.0 g, 31.41 mmol) in toluene (120 mL) at room temperature under argon was added 4-chlorophenylboronic acid (5.8 g, 37.1 mmol), tetrakis(triphenylphosphine)palladium (2.2 g, 1.9 mmol), and a solution of Na2CO3 (6.6 g, 62.3 mmol) in water (20 mL). The resulting suspension was stirred and heated at 100° C. under argon for 2.5 h. After the reaction mixture was cooled to room temperature, water (120 mL) and EtOAc (150 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column eluting with 7% ethyl acetate-hexanes) to isolate 3.7 g of the title compound as a white solid. HPLC/MS: retention time=3.78 min, [M+H]+=302. 1H NMR (CDCl3, 500 MHz): δ 8.35 (d, J=5.0 Hz, 1H), 7.46 (d, J=10.0 Hz, 2H), 7.34 (d, J=10.0 Hz, 2H), 7.14 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(Cl)cc(=O)n(C)c2=O)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (16.2 g, 101 mmol), p-methoxybenzyl chloride (16.5 mL, 122 mmol) and potassium carbonate (7.0 g, 50.7 mmol) in anhydrous DMF (200 mL) is heated at 60° C. for 3 hours. Additional potassium carbonate (3.0 g, 21.7 mmol) is added, and the reaction mixture heated at 60° C. for another 3 hours. After hot filtration, the filtrate is evaporated to dryness under reduced pressure. The obtained oil is directly used for the synthesis in the next step. A small amount of product is further purified by silica-gel flash chromatography to give pure product as crystals. 1H NMR (400 MHz, MeOH-d4) δ3.37 (s, 3H), 3.83 (s, 3H), 5.24 (s, 2H), 5.96 (s, 1H), 6.91 and 7.32 (AB, 4H, J=6.8 Hz). MS (FAB) m/z 281.23 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[NH2:8][CH2:9][CH2:10][CH2:11]O.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)=[C:18]([CH:22]=1)[C:19]([OH:21])=O>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)=[C:18]([CH:22]=1)[C:19]([N:8]1[CH2:9][CH2:10][CH2:11][O:3][CH:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:21]
Reactant: CCOC(=O)C=O
Reactant: NCCCO
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1OCCCN1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using ethyl glyoxylate (polymer type, a solution of 47% toluene) (4.3 mL, 20.4 mol), 3-aminopropan-1-ol (1.6 mL, 20.4 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.0 g, 4.9 mmol), the same procedure as in Reference Example 1 was carried out to obtain the title compound (1.3 g) (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1.[S].C1[S:23](=O)(=O)CCC1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([SH:23])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2nc[nH]c2-c2cccs2)cc1
Reactant: O=S1(=O)CCCC1
Agent: [S]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc(-c2ccc(Cl)cc2)c(-c2cccs2)[nH]1
Temperature: 200 °C

Procedure:
A mixture of 9.4 g of 4-(4-chlorophenyl)-5-(2-thienyl)-1H-imidazole, 2 g of sulfur, and 50 ml of tetramethylene sulfone was stirred under nitrogen and heated to 200° C. for 8 hrs. It was cooled, poured into water, filtered and washed well with water to give 11.5 g. This was dissolved in dimethylformamide and chromatographed on a column 6 cm diameter by 125 cm long of alumina (Woelm neutral activity grade 1) using dimethylformamide to elute. A yield of 5.6 g was obtained as the dimethylformamide adduct. A sample was dried by heating under a high vacuum, m.p. 274.5°-276° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1>ClCCl.N1C=CC=CC=1.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:9]([NH:11][CH:12]2[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Agent: [Cr+3]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2CCC(=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of 8.0 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS,5RS)-2-(3,4-dimethoxyphenyl)-5-hydroxycyclohexyl]benzamide (compound D1) in 80 ml of dichloromethane is added dropwise to a suspension of 10 g of chromium (III) oxide in 160 ml of dichloromethane and 16 ml of pyridine. After stirring for 2 h at room temperature, the reaction mixture is extracted with 6 N sodium hydroxide solution, 2 N hydrochloric acid and finally water. The organic phase is dried using sodium sulfate and concentrated. 7.3 g of the title compound of m.p. 150-151.5° C. are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH2:28][CH3:29])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C

Procedure:
4-Acetylaminobenzenesulphonyl chloride (7.3g, 0.03 mole) was added portionwise to a well stirred mixture of aqueous sodium carbonate (21.2 g. in 250 ml of water) and 2-aminomethyl-1-ethylpyrrolidine (4.0 g. 0.03 mole) in chloroform (250 ml) at about 10°. The ice bath used for cooling was removed. After 2 hours the chloroform layer was separated, dried (MgSO4) and then evaporated under reduced pressure to give a gum, which slowly crystallised (11.6 g). Recrystallisation from cold ethanol, followed by recrystallisation from water gave the pure title compound m.p. 94°-96° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([C:15]#[C:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)[S:13][CH:14]=2)[C:5]([C:26]#[N:27])=[C:4]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][OH:18])[S:13][CH:14]=2)[C:5]([C:26]#[N:27])=[C:4]([S:28][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[S:33][CH:34]=2)[N:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1nc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(CCCO)n1

Procedure:
Under argon, 220 mg of the mixture from Example 22A were initially charged in 10 ml of ethyl acetate, 110 mg of palladium (10% on activated carbon) were added and the mixture was hydrogenated at atmospheric hydrogen pressure and room temperature overnight. The catalyst was filtered off through Celite, the filter cake was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by preparative HPLC. This gave 31 mg (17% of theory) of the target compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]=[C:12]2[CH:15]2[CH2:17][CH2:16]2)=[C:7]([O:18][CH3:19])[CH:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH:15]1([C:12]2[C:13]3[C:8](=[C:7]([O:18][CH3:19])[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=3)[CH:9]=[CH:10][N:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1cc(OC)c2ccnc(C3CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-Cyclopropyl-5-methoxy-isoquinoline-7-carboxylic acid methyl ester (4.87 g, 18.9 mmol) was dissolved in THF (50 ml) and MeOH (50 ml), and 5N NaOH aq. (18.9 ml) was added thereto. After stirred at 60° C. for 2 h, the mixture was concentrated in vacuo. The residue was triturated with H2O and 5N HCl aq. (18.9 ml) and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH3:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CCOCC.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])[CH3:18])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
5.5 g (0.0149 g) of N-benzyloxycarbonyl-L-alanyl-L-alanine anilide were dissolved in 30 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. A white solid separated out and was allowed to settle. The solution was decanted off and the solid washed with two 150 ml portions of ether. Recrystallisation of the solid from methanol/ethyl acetate yielded 4.1 g (88%) of L-alanyl-L-alanine anilide hydrobromide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:18])[CH3:17])[CH2:12]2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:25])[C:3]=1[C:26]#[N:27]>O.O.O.O.O.O.[Fe](Cl)Cl.[Zn].CN(C)C=O>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:17])[CH3:18])[CH2:12]2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:25])[C:3]=1[C:26]#[N:27]
Reactant: Cc1c(C#N)c(N)c([N+](=O)[O-])c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Agent: Cl[Fe]Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C#N)c(N)c(N)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
An aqueous solution (14 ml) of iron chloride hexahydrate (0.83 g, 3.06 mmol) and zinc (5.01 g, 76.6 mmol) were added to an N,N-dimethylformamide (35 ml) solution of 4-amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-methyl-5-nitrobiphenyl-3-carbonitrile (I-268) (1.40 g, 3.83 mmol), followed by stirring at room temperature for 1 hour. The insoluble matter was removed by filtration under suction, then the filtrate was diluted with ethyl acetate, washed with aqueous saturated sodium carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, followed by drying with a vacuum pump to obtain the entitled compound (1.25 g, 97%) as a dark brown solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:6][CH2:7][C:8]#[C:9][Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCOC1CCCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 18.8 mL, 30 mmole) was added in a stream over 2 min to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (4.7 mL, 30 mmole) in dry THF (60 mL) at 0° C. under argon. After 0.5 hr, tributyltin chloride (8.1 mL, 30 mmole) was added all at once, and the reaction was warmed to RT. After 3 hr, the reaction was diluted with hexanes (300 mL) and washed sequentially with H2O (2×60 mL), 10% KF (2×30 mL), and saturated brine (60 mL). Drying (Na2SO4), concentration, and silica gel chromatography (3% EtOAc/hexanes) gave the title compound (3.58 g, 27%) as a nearly colorless oil: TLC (5% EtOAc/hexanes) Rf 0.37; 1H NMR (400 MHz, CDCl3) δ 4.66 (narrow t, 1 H), 3.75-3.96 (m, 2 H), 3.49-3.62 (m, 2 H), 2.56 (app t, 2 H), 1.76-1.91 (m, 1 H), 1.65-1.78 (m, 1H), 1.42-1.65 (m, 10 H), 1.22-1.41 (m, 6 H), 0.82-1.08 (m, 15 H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[O:15][CH3:16].C([BH3-])#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][NH:12]2)=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(cc1OCCN(C)C)NCC2
Yield: 74.6 %

Procedure:
A stirred solution of 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D16, 0.50 g, 2.1 mmole) in glacial acetic acid (10 ml) at room temperature was treated portionwise over 15 minutes with sodium cyanoborohydride (0.25 g, 4 mmole). After 2 hours the solution was diluted with water (50 ml), basified by addition of Na2CO3 and then extracted with ethyl acetate (2×50 ml). The combined extract was dried (Na2SO4), and concentrated in vacuo to leave the title compound as a brown oil (0.37 g, 73%).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.N([O-])=O.[Na+].[BrH:18]>O.[Cu]Br>[Br:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: Br
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the cooled and vigorously stirred suspension of 4-amino-2-(trifluoromethyl)benzonitrile (5.00 g, 26.8 mmol) in 25 ml of concentrated hydrogen bromide a solution of sodium nitrite (1.85 g, 26.8 mmol) in 10 ml of water was added dropwise while keeping the temperature below 5° C. during the addition. This mixture was then poured into a solution of copper(I)bromide (3.85 g, 26.8 mmol) in 30 ml of concentrated hydrogen bromide and stirred at RT for two hours. The reaction mixture was then poured into an ice-water (300 ml) mixture and extracted four times with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and water, dried and evaporated to dryness. Combiflash purification using heptane/ethyl acetate as eluent system afforded 5.1 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 8.13 (d, 1H), 8.18 (d, 1H), 8.27 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[C:14]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])(=[O:16])[CH3:15].C(Cl)Cl.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[C:14]([N:17]1[CH2:21][CH2:20][N:19]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[C:18]1=[O:22])(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCNC1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C(C)=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a mixture of p-(methoxycarbonyl)phenylboronic acid (2.45 g), 1-acetylimidazolidin-2-one (870 mg) and copper(II) acetate (1.23 g) were added methylene chloride (20 mL) and triethylamine (1.9 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the insoluble material was collected by filtration. The filtrate was extracted with chloroform, and the solvent was evaporated from the organic layer. The obtained residue was purified by column chromatography (chloroform) to give the title compound (292 mg).