Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:7][NH:6][CH2:5]1)#[N:3].N1CCCC1.[C:13]([NH:20][C@@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15]C(C)(C)C)=O.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:42]([N:44]1[CH:48]=[C:47]([C:49]2[N:54]=[C:53]3[C:55](C(O)=O)=[CH:56][N:57](COCC[Si](C)(C)C)[C:52]3=[N:51][CH:50]=2)[CH:46]=[N:45]1)[CH3:43].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[C:2]([CH:4]1[CH2:7][N:6]([C:23](=[O:25])[C@H:21]([NH:20][C:13]([C:55]2[C:53]3[C:52](=[N:51][CH:50]=[C:49]([C:47]4[CH:46]=[N:45][N:44]([CH2:42][CH3:43])[CH:48]=4)[N:54]=3)[NH:57][CH:56]=2)=[O:15])[CH3:22])[CH2:5]1)#[N:3]
Reactant: N#CC1CNC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3-cyanoazetidine hydrochloride for pyrrolidine, Boc-D-alanine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used in place of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=393.
Reaction SMILES: C1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]4[O:20]C[O:22][C:16]=4[CH:15]=3)O)=O)=[CH:4][C:3]=2[O:2]1>CO.[OH-].[OH-].[Pd+2]>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:12][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(CCc2ccc(O)c(O)c2)cc1O
Yield: 74899.8 %

Procedure:
A solution of the tetrahydroxybenzil (see Example 1) (70 mg) in methanol (10 ml) with palladium hydroxide on carbon (20%, 10 mg) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite, and the solvents removed in vacuo to give an orange gum. Separation by column chromatography over silica gel eluting with 20% ethyl acetate in dichloromethane gave DC-0004 as an off white gum (43 g, 68%).
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.Cl.C1(C)C=CC(NN)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:26][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Reactant: Cc1ccc(NN)cc1
Agent: Br
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(N2N=C3c4ccncc4CCC3CC2=O)cc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
Methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide (1.2 g) (Wu et al, Synthetic Communications 24, 273 (1994)) 4-tolylhydrazine (0.5 g) and 4-tolylhydrazine hydrochloride (0.19 g) in xylene (20 ml) were heated under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and the volatiles removed. The residue was dissolved in dichloromethane-methanol, washed with sodium hydrogen carbonate solution twice and then brine. The organic phase was dried, filtered and concentrated to a dark oil. The crude product was adsorbed onto silica and chromatographed eluting with 7:3 dichloromethane:ethyl acetate. The resultant oil was triturated with ether and recrystallised from isopropanol to give the title compound (0.3 g).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([O:17]CC)=O)=[N:12][N:11]=2)=[CH:6][CH:5]=1.[NH:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:39]=[CH:38][C:29]([CH2:30][N:31]3[CH2:37][C:33]4([CH2:36][O:35][CH2:34]4)[CH2:32]3)=[CH:28][CH:27]=2)[CH2:22]1>>[CH2:36]1[C:33]2([CH2:32][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][CH:23]4[CH2:22][N:21]([C:15]([C:13]5[O:14][C:10]([C:7]6[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:20])=[CH:9][CH:8]=6)=[N:11][N:12]=5)=[O:17])[CH2:24]4)=[CH:39][CH:38]=3)[CH2:37]2)[CH2:34][O:35]1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC(F)F)cc2)o1
Reactant: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Product: O=C(c1nnc(-c2ccc(OC(F)F)cc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Yield: 68.6 %

Procedure:
Using a similar protocol as described in Example 6 but employing 7A (60 mg, 0.21 mmol) and 3B (50 mg, 0.19 mmol) as starting materials afforded 65 mg (68%) of 7 as a solid. 1H NMR (500 MHz, CDCl3): δ 3.0-4.2 (m, 6H), 4.34 (m, 1H), 4.66 (m, 1H), 4.76 (m, 5H), 5.10 (m, 2H), 6.62 (t, 1H), 6.76 (m, 2H), 7.27 (m, 4H), 8.18 (d, 2H), MS (APCI+) m/z 499 [M+H]+, LC purity: 96%.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[S:9]([C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 42.3 %

Procedure:
Benzyl 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-1a) (517 mg, 1 mmol) was stirred a 10/1/2 solution of 6N NaOH(aq)/THF/MeOH (27 mL) at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 (ca. 50 mL), and the aqueous phase was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (15 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient: 25 minutes) in three 5 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in 15 mL of absolute ethanol and evaporated on the rotovap (4×) to provide pure 4-(N-benzyl-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (174 mg, 42%) as a white solid. M.p 161-163° C. 1H NMR (CDCl3, 400 MHz): 8, 3.78 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 709-7.07 (m, 2H), 7.27-7.24 (m, 3H), 7.93 (d, J=8.8 Hz, 2H), 8.24 (d, J=8 Hz, 2H). MS 412 (MH+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.C(Cl)Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[Na+]>O>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]3=1
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
15,75 g of 5-hydrazino-3-methylbenzothiophene hydrochloride are suspended in 500 ml of water, a layer of methylene chloride is introduced under the suspension and 10.5 g of 1-methyl-4-piperidone are added at about 0° C. The mixture is then adjusted to pH 9.5 with N NaOH and is stirred for 30 minutes. The organic phase is separated off and washed with saturated NaCl solution, dried and mixed with 500 ml of ethylene glycol and the methylene chloride is distilled off under a vacuum of 12 mm. Some of the glycol is then distilled off under 0.01 mm and at 100° C. and the concentrated solution is heated to 200° C. (bath temperature) in an N2 atmosphere for 1/2 hour. The crystals which precipitate on cooling the mixture are filtered off, washed and recrystallised from ethyl acetate. Melting point: 224°-227° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[O:20]
Reactant: NCc1ccccn1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.00 g, 5.50 mmol), 2-(aminomethyl)pyridine (0.710 g, 6.57 mmol), triethylamine (0.610 g, 6.03 mmol) and benzene (40 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-pyridyl)methyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.410 g, 54.2% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:12])=[CH:5]2.C([O:15][B:16](OCC)[O:17]CC)C.C([Li])CCC>C1COCC1>[F:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([B:16]([OH:17])[OH:15])=[CH:11][CH:10]=2
Reactant: CCOB(OCC)OCC
Reactant: Fc1cc2cc(Br)ccc2cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2cnc(F)cc2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of 6-bromo-3-fluoroisoquinoline (9.10 g, 40.3 mmol) and triethylborate (11.8 g, 80.5 mmol) in THF (100 mL) was cooled to −78° C. Butyllithium (1.6 M in hexanes 50.3 mL, 80.5 mmol) was added dropwise over 45 minutes. Over the course of the addition, the solution changed color from colorless to a light tan. The solution was stirred at −78° C. for 3 hours. The mixture was quenched with HCl (5 N, 120 mL) while in the cold bath at −78° C., diluted with water (100 mL), and then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The solid residue was triturated with DCM (200 mL), and the solid was recovered by filtration to provide the title compound (6.0 g, 78%). LCMS (API-ES) m/z: 192 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])(=[O:35])[CH3:34]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 1 h

Procedure:
Sodium hydride (12.5 mg of a 60% dispersion in mineral oil, 0.31 mmol) was added to a stirred suspension of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (102 mg, 0.25 mmol) in THF (5.0 mL) under a nitrogen atmosphere. This resulted in degassing and the formation of a yellow solution. Acetyl chloride (0.022 mL, 0.5 mmol) was added and the mixture was stirred for 1 h then left to stand for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic phase was dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (2 g Si II SPE eluted with DCM then 10% EtOAc in DCM). Concentration of the appropriate fractions in vacua gave the title compound which was freeze-dried from acetonitrile/water to afford a fluffy white solid (56 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 33.3 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.1 mg, 0.12 mmol) in dichloromethane (1 mL) was added ethanesulfonyl chloride (32 mg, 0.24 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 26.4 mg (33%) of the title compound as off white solid. MS (ES) m/e 661.2 [M+H]+.
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13](I)[N:12]=[CH:11]1)C1C=CC=CC=1.C([Mg]Br)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:26]=[CH:25]2.[Cl-].[NH4+]>ClCCl.C1COCC1.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]=[C:27]([C@@:34]([C:14]1[N:10]=[CH:11][NH:12][CH:13]=1)([OH:38])[CH:35]([CH3:36])[CH3:37])[CH:26]=[CH:25]2
Reactant: COc1cc2ccc(C(=O)C(C)C)cc2cc1OC
Reactant: Ic1cn(COCc2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2ccc([C@](O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Reaction time: 1 h
Yield: 71.5 %

Procedure:
1-benzyloxymethyl-4-iodoimidazole (31.5 g) was dissolved in dichloromethane (500 mL) under argon atmosphere. A solution of ethylmagnesium bromide in THF (0.96M; 110 mL) was added dropwise to the solution with keeping the reaction temperature below 8° C. and the mixture was stirred for 1 h. A solution of 6,7-dimethoxy-2-isobutyrylnaphthalene (31 g) in dichloromethane (50 mL) was added to the mixture and stirred at room temperature for 24 h. Saturated ammonium chloride solution (150 mL) and water (350 mL) were added to the mixture, and organic layer was concentrated. The residue was dissolved in THF (200 mL)-ethyl acetate (1 L), washed with water and brine, dried over Na2SO4 and concentrated in vacuo to one tenth of initial volume. The crystals were collected and washed with ethyl acetate to give the titled compound (23.4 g) as colorless crystals. Second crystals (4.53 g) were recovered from the mother liquor.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]=O)=[C:29]([CH3:37])[CH:28]=1>C1COCC1.CCOC(C)=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:23]2[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]2)=[C:29]([CH3:37])[CH:28]=1
Reactant: Cc1cc(Br)ccc1CCC=O
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1CCCN1CCC(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.70 g (3.30 mmol) of sodium triacetoxyborohydride and 0.16 mL of glacial acetic acid were added to a solution of 0.32 mL (2.70 mmol) of 4-methylpiperidine and 0.60 g (2.64 mmol) of 3-(4-bromo-2-methylphenyl)propionaldehyde in 10 mL of THF and the mixture was stirred for 2 hours at RT. The reaction mixture was diluted with EtOAc, and the organic phase was washed with semisaturated aqueous sodium bicarbonate solution washed, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.65 (78% of theoretical); C16H24BrO (M=310.273); calc.: molpeak (M+H)+: 310/312 (Br); found: molpeak (M+H)+: 310/312 (Br); Rf value: 0.28 (silica gel, PE/EtOAc 3:2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]3)=[N:6][CH:7]=1.[C:25]([O:29][C:30]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](O)=[O:37])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:25]([O:29][C:30]([N:32]1[CH2:40][CH2:39][CH:35]([C:36](=[O:37])[NH:1][C:2]2[CH:7]=[N:6][C:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[O:15][CH:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12]4)=[CH:4][CH:3]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Oc3ccc4c(c3)CCC(c3ccccc3)O4)nc2)CC1

Procedure:
5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine (500 mg) and N-(tert-butoxycarbonyl)isonipecotic acid (541 mg) was dissolved in 40 ml of THF. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (451 mg) was added. The mixture was refluxed for few hours. Reaction was quenched with addition of water and extracted with ethyl acetate. Combined organic layers were washed with water, saturated sodium carbonate solution, dried with Na2SO4 and evaporated. 1H-NMR (300 MHz; d6-DMSO) δ: 10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.92 (d, 1H, J 8.8 Hz), 6.87-6.84 (m, 3H), 5.13 (dd, 1H, J 2.2, 10.1 Hz), 4.04-3.96 (m, 2H), 2.99-2.91 (m, 1H), 2.81-2.69 (m, 3H), 2.20-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.79-1.74 (m, 3H), 1.50-1.35 (m, 11H).
Reaction SMILES: [H-].[Na+].Br[CH:4]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]2[CH:12]=[CH:13][C:14]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:15][C:6]=2[CH:5]1O.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].CS(C)=[O:35]>>[CH3:10][C:9]1([CH3:11])[O:8][C:7]2[CH:12]=[CH:13][C:14]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:15][C:6]=2[C@@H:5]([N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])[C@@H:4]1[OH:35]
Reactant: O=C1CCCN1
Reactant: Cc1ccc(S(=O)(=O)c2ccc3c(c2)C(O)C(Br)C(C)(C)O3)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)c2ccc3c(c2)[C@@H](N2CCCC2=O)[C@H](O)C(C)(C)O3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.75 g (0.025 mol) of 80 % NaH is introduced into 8.2 g (0.02 mol) of 3-bromo-3,4-dihydro-2,2-dimethyl-6-(4'-methyl-phenylsulfonyl)-2H-benzo[b]pyran -4-ol in 30 ml of dimethyl of dimethyl sulfoxide. After stirring for one hour at 20°, a further 0.75 g (0.025 mol) of 80 % NaH and 1.9 ml (0.025 mol) of 2-pyrrolidone are added and the mixture is stirred for 45 minutes at 40° and for 6 hours at 20°. After the mixture has been introduced into ice water, the precipitate is filtered off with suction, dried and recrystallized several times from methanol. Crystals of melting point: 242-243°.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](F)[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:15][C:16]2[O:20][C:19]([F:22])([F:21])[O:18][C:17]=2[CH:23]=1.CCN(C(C)C)C(C)C.[Cl:40]CCl>CN(C1C=CN=CC=1)C.O1CCCC1.CO.[OH-].[Li+]>[Cl:40][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:14]2[C:13]([Cl:12])=[CH:23][C:17]3[O:18][C:19]([F:21])([F:22])[O:20][C:16]=3[CH:15]=2)=[CH:29][N:28]=1)=[O:5]
Reactant: ClCCl
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)O3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)O3)cn1)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Under an atmosphere of argon, acid 2,6-difluorobenzoyl chloride (16 mg, 92 μmol) was added to a stirred solution of 113 (25 mg, 88 μmol), Hünig's base (46 μl, 34 mg, 260 μmol), and DMAP (1.1 mg, 8.8 μmol) in dichloromethane (440 μL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (500 μL), methanol (200 μL) and 1.2 M lithium hydroxide solution (100 μL). The mixture was stirred and heated to 60° C. for 5 min then cooled to room temperature and diluted with dichloromethane and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 114 (21.6 mg, 58%) as a solid: LRESIMS m/z 423.3 [M+H]+, calcd. for C19H11Cl2F2N2O3 423.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1.[NH3:18]>CS(C)=O>[NH2:18][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[N:3]=1
Reactant: N
Reactant: Cc1nc(Cl)c(C#N)c(C)c1-c1ccccc1
Solvent: CS(C)=O
Product: Cc1nc(N)c(C#N)c(C)c1-c1ccccc1
Temperature: 0 °C

Procedure:
2-Chloro-4,6-dimethyl-5-phenyl-3-pyridinecarbonitrile (8.3 grams) was dissolved in 110 ml DMSO and treated with gaseous NH3 at a temperature of 100°-110° C. After about 66 hours of heating and treatment with NH3, the reaction mixture was cooled and poured into ice water. A solid precipitate formed which was collected, washed with water, and then dried in an oven desicator. The identity of the desired product was confirmed by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:16]=[C:17](SC)[NH:18]C(OC(C)(C)C)=O)=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH:31]([NH:34][NH2:35])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:34]([CH:31]([CH3:33])[CH3:32])[N:35]=[C:17]([NH2:18])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CSC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NC(=O)OC(C)(C)C
Reactant: CC(C)NN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 120 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a mixture of methyl N′-9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carbonyl-N-Boc-carbamimidothioate (1.2 g, 2.5 mmol) and isopropylhydrazine hydrochloride (0.55 g, 5 mmol) in DMF (50 mL), DIPEA (3.2 g, 25 mmol) was added. The resulting mixture was stirred at 120° C. overnight. The reaction mixture was concentrated, and MeOH (30 mL) was added. The solid was collected to give 5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (430 mg, 49%). 1H NMR (DMSO, 400 MHz) δ 8.28 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 5.69-5.66 (m, 1H), 5.35 (s, 1H), 4.49 (s, 4H), 4.10 (s, 1H), 3.14 (s, 2H), 1.37 (d, J=6.8 Hz, 6H)