Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc2c(c1)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A solution of indoline 1 (2.0 g, 16.78 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.68 g, 18.46 mmol) in dry 1,2-dichloroethane (30 mL) was treated with acetic acid (2.4 mL, 42.00 mmol) followed by NaBH(OAc)3 (5.34 g, 25.2 mmol) at 0° C. The resulting mixture was brought to room temperature and stirred for 3 h. The reaction was basified with 1 N NaOH solution (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 2 (5.0 g, 99%) as a syrup. 1H NMR (CDCl3) δ 7.05 (t, 2H, J=7.8 Hz), 6.62 (t, 1H, J=7.2 Hz), 6.43 (d, 11, J=7.5 Hz), 4.25-4.20 (m, 2H), 3.55-3.46 (m, 2H), 3.35 (t, 2H, J=8.4 Hz), 2.95 (t, 2H, J=8.4 Hz), 2.77 (t, 2H, J=12.3 Hz), 1.81-1.77 (m, 2H), 1.63-1.51 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %) 303 (MH+, 5), 247 (100).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Yield: 82 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) was converted, using 2-amino-2-methyl-propanol instead of ethanolamine, to the title compound (SiO2, heptane:ethyl acetate=95:5 to 50:50, 202 mg, 82%) which was obtained as a white foam. MS: m/e=383.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccccc1C=O

Procedure:
A mixture of 2-bromobenzaldehyde (10.05 mmoles), 1-dodecyne (12.03 mmoles), cuprous iodide (0.11 mmole) and bis(triphenylphosphine) palladium chloride (0.20 mmole) in freshly distilled triethylamine (30 ml.) was heated for one hour at reflux producing a white precipitate. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness at reduced pressure and then dissolved in diethyl ether (50 ml) and washed with brine (50.ml). After treatment with anhydrous magnesium sulfate and charcoal, the solution was evaporated to afford a dark oil, which was purified by flash chromatography (2% diethyl ether/hexane) to yield the desired product.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:18][C@@H:19]1[N:22]([S:23]([O-:26])(=[O:25])=[O:24])[C:21](=[O:27])[C@H:20]1[NH:28]C(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C[Si](C)(C)Cl>ClCCCl>[NH2:28][C@H:20]1[C@H:19]([CH3:18])[N:22]([S:23]([OH:26])(=[O:24])=[O:25])[C:21]1=[O:27]
Reactant: C[C@H]1[C@H](NC(=O)Oc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 0 °C
Yield: 65.5 %

Procedure:
A solution of 531 mg (0.001 mole) of (3S-trans)-4-methyl-2-oxo-3-(phenyloxycarbonylamino)-1-azetidinesulfonic acid, tetrabutylammonium salt in 10 ml of 1,2-dichloroethane is treated with 278 μl of triethylamine and 250 μl of trimethyl chlorosilane and the solution refluxed for 75 minutes. An aliquot of the reaction mixture shows intense IR absorption of 2270 cm-1 (indicative of the isocyanate group) and almost complete disappearance of the 1745 cm-1 band (for the urethane function) in addition to a strong absorption at 1770 cm-1 (β-lactam). The solution is refluxed for 20 hours (no change in IR), cooled to 0° C., and 2 ml of 88% formic acid is added. After 2.5 hours at room temperature the slurry is filtered to give 118 mg of (3S-trans)-3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid, inner salt.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].CO[C:11](=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[N:20]=[CH:21]N(C)C>C1COCC1>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[NH:20][CH:21]=[C:6]([C:7]#[N:8])[C:11]2=[O:25]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OC)c1N=CN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)c(C#N)c[nH]c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 35.0 mL of THF was added 26.6 mL (66.4 mmol ) of n-BuLi solution during 5 min at −78° C. To the stirred solution was added a solution of 3.55 mL (67.9 mmol) of CH3CN in 65 mL of THF during 10 min which time the solution became white suspension, and then continued to stir for 15 min at −78° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2-(Dimethylamino-methyleneamino)-3-methoxy-benzoic acid methyl ester in 45 mL of THF during 30 min, and then continued to stir 30 min at −78° C. during which time the mixture gradually became clear. The solution was quenched with 8.5 mL of HOAc. The resulting thick slurry was stirred and warmed to room temperature. After most of the solvent was evaporated, the residue was diluted with cold water. The separate solid was collected by filtration and washed with water. After drying in vacuo, this afforded 3.8 g of the product as an off white solid in 77.6% of yield, m.p. 270° C. (dec.), mass spectrum (electrospray, m/e): M+H 201.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][C:16]([F:15])([F:25])[F:26])=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccccc1OC(F)(F)F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1OC(F)(F)F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]([OH:19])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1)=[CH:8]2.[CH3:20][C:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[O:23][N:22]=1>>[CH3:20][C:21]1[C:25]([NH:26][C:17]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH:12]4[CH2:16][CH2:15][CH2:14][O:13]4)=[CH:8][C:7]=23)=[O:19])=[C:24]([CH3:27])[O:23][N:22]=1
Reactant: Cc1noc(C)c1N
Reactant: COc1ccc(C(=O)O)c2cc(C3CCCO3)oc12
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2cc(C3CCCO3)oc12
Yield: 66.8 %

Procedure:
Starting from 7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid (262 mg) and 3,5-dimethylisoxazol-4-ylamine (120 mg). Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane afforded the title compound as an off-white solid (238 mg).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([CH3:33])[C:30](=O)[CH3:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][N:29]([CH3:33])[C:30](=[S:10])[CH3:31])=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(=S)N(C)Cc1ccc(F)cc1
Yield: 56.4 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([I:18])=[N:13][C:14]([I:17])=[CH:15][CH:16]=1)(C)(C)C.Cl.O1CCOCC1>ClCCl>[I:18][C:12]1[C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:15]=[C:14]([I:17])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(I)nc1I
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCOc1ccc(I)nc1I

Procedure:
To a solution of 4-2 (2.18 g, 4.45 mmol) in dichloromethane (5.0 mL) at room temperature under Ar was added 4.0 M HCl-dioxane solution (25 mL). A white precipitate formed immediately. After two hours the reaction was concentrated and dried to yield a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[O:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #32 (353 mg, 0.488 mmol, 1 eq.) in dichloromethane (10 mL, 0.04 M), amine #67 (271 mg, ≦0.588 mmol, 1.3 eq.), HATU (223 mg, 0.586 mmol, 1.2 eq.) and diisopropylethylamine (238 μL, 1.71 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane), affording #68 (404 mg, 88% over two steps) as a solid. LC-MS: m/z 940.7 [M+H+], 962.7 [M+Na+], retention time=1.04 minutes; HPLC (Protocol C): retention time=9.022 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.25 (br d, J=8 Hz) and 8.48 (br d, J=8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.31-7.36 (m, 2H), 7.14-7.24 (m, 5H), 4.43-4.69 (m, 3H), 4.17-4.26 (m, 3H), 3.91-3.99 (br m, 1H), 3.63 and 3.65 (2 s, total 3H), 3.19 and 3.24 (2 s, total 3H), 3.14 and 3.15 (2 s, total 3H), 2.90 and 2.99 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.6 Hz), total 3H].
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([C:7]([C:9]2SC=C(C)C=2C)=[O:8])[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:3]1[CH:2]=[CH:6][S:5][C:4]=1[C:7]([CH3:9])=[O:8]
Reactant: Cc1csc(C(=O)c2scc(C)c2C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1sccc1CBr
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of methyl 3-methyl-2-thienylketone (14 g., 0.10 mole), N-bromosuccinimide (18 g., 0.10 mole), α,α-azobisisobutyronitrile (AIBN, 0.3 g.), and carbon tetrachloride (300 ml.) was heated cautiously to reflux under a nitrogen atmosphere. After stirring 4 hours at reflux, the mixture was cooled, filtered to remove succinimide, washed first with sodium bicarbonate solution, then with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated at reduced pressure to obtain a pale yellow solid which was recrystallized from hexane to obtain 16 g. (73%) of the desired product as colorless crystals, M.P. 62°-64° C. 1H--NMR (CDCl3), ppm. (δ): 7.5 (d, J=5, aromatic-H), 7.2 (d, J=5, aromatic-H), 4.9 (s, CH2Br) and 2.55 (s, CH3). This compound is a strong irritant.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].C(O)(=O)C.[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][NH:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][N:39]([CH2:2][CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH2:40][C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21]
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccncc3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.21 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.42 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (0.47 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>C(Cl)Cl.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>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: C#CCCO
Reactant: COc1ccc(Br)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C#CCCO)cc1OC
Yield: 31.6 %

Procedure:
A mixture of 10 g (46 mmol) of 1-bromo-3,4-dimethoxybenzene, 3.4 g (48 mmol) of 3-butyn-1-ol and 8 mL (58 mmol) of triethylamine in 20 mL of methylene chloride was stirred and flushed with argon. To the mixture there was added 0.12 g (0.06 mmol) of cuprous iodide and 0.30 g (0.43 mmol) of bis(triphenylphosphine)palladium dichloride. The reaction mixture was stirred at room temperature for 4 hours and at reflux for 16 hours. After filtration, the filtrate was washed with water, dried and concentrated. The crude product was purified by HPLC using 30% ethyl acetate-toluene to give 3.0 g (32% yield) of 4-(3,4-dimethoxyphenyl)-3-butyn-1-ol.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.N([O-])=O.[Na+].C(N)CN.[BrH:21]>[Cu]Br>[N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9]([Br:21])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: Br
Reactant: Nc1ccc(-n2ncnn2)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: NCCN
Product: Brc1ccc(-n2ncnn2)cc1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
4-(Tetrazol-2-yl)aniline (450 mg, 2.8 mmol) in 48% HBr (10 ml) at -5° C. was stiired while sodium nitrite (193 mg, 2.8 mmol) was added portionwise over 5 minutes. The brown sludge was left stirring for 15 minutes and then added portionwise over 5 minutes to a refluxing mixture of copper (I) bromide (401 mg, 2.8 mmol) in 48% HBr (2 ml). The mixture was then heated at reflux for 1 minute, allowed to cool slightly, and poured into 10% ethylene diamine solution (20 ml). The aqueous solution was extracted with ethyl acetate, dried (Na2SO4), and evaporated to dryness under reduced pressure. The resulting mixture was purified by column chromatography on silica eluting with n-pentanelethyl acetate (4-10%) to afford the title compound as a white solid (238 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)Cl.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(Br)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(Br)cc1

Procedure:
prepared by reaction of 3-(4-bromo-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=312.1.
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Reactant: CC(C)c1ccc(B(O)O)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C(C)C)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (0.3 g, 0.67 mmol) and 4-isopropyl-phenylboronic acid (0.24 g, 1.0 mmol) in toluene (16 mL) and EtOH (4 mL) is added 2 M K2CO3 (0.6 mL, 1.34 mmol). The mixture is purged with argon for 30 minutes. Pd(PPh3)4 (0.077 g, 0.067 mmol) is added and the mixture is heated at 100° C. overnight. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth. The filtrate is diluted with water (30 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with saturated brine solution (20 mL), dried over sodium sulphate, filtered, and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash using 24 g redisep column) eluting with 45% EtOAc/hexane to give the title compound as a brown liquid (0.22 g, 68.75%). LCMS m/z 481 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](=O)[CH3:19])=[CH:14][CH:13]=1)#[N:11]>CO>[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([NH2:7])[CH3:19])=[CH:14][CH:13]=1)#[N:11]
Reactant: CC(=O)COc1ccc(C#N)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)COc1ccc(C#N)cc1
Yield: 27.8 %

Procedure:
293 g of ammonium acetate and 16.7 g of sodium cyanoborohydride were added to a solution containing 66.5 g of 4-cyanophenoxyacetone dissolved in 1500 mL of methanol, and the resultant mixture was stirred for 30 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and acidified with concentrated hydrochloric acid. 500 mL of diethyl ether and 300 mL of water were then added thereto. Subsequently, the resultant water layer was made basic with a 5% aqueous solution of sodium hydroxide, the solution was extracted with 1000 mL of diethyl ether, and then washed with water. The organic layer was then dried over anhydrous sodium sulfate, and the diethyl ether was removed under reduced pressure. The obtained residue was distilled under reduced pressure to yield 13.0 g of the desired product (19%). Boiling point: 132° C./0.26 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].O>C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc(CNCCOc2ccc(Cl)cc2Cl)c1

Procedure:
2.70 Grams (10.0 mmol) of 2-(2,4-dichlorophenoxy)ethyl bromide was dissolved in 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 3-chlorobenzylamine. The mixture was refluxed for 6 hours on an oil bath. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).