Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].C1COCC1.C[O:9][C:10](=O)[CH:11]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13]>C(O)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:17]([N:16]([CH3:31])[CH:11]([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:1][OH:2])=[O:9])=[O:18])=[CH:24][CH:23]=1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: NO
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A 50% aqueous solution (0.20 mL) of hydroxylamine was added to a THF (0.25 mL)-ethanol (0.20 mL) solution of 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (30 mg) as obtained in Example 1-(1), and the mixture was stirred for 4 hours at room temperature. The solvents were distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=8/1). Upon addition of IPE, the precipitated solid was separated by filtration, and dried to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 1, light yellow solid) (17 mg, 59%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4](=[CH2:6])[CH3:5].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)(=O)C>[CH2:8]([O:7][CH2:3][C:4]([CH3:6])=[CH2:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(C)CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Under nitrogen stream, 50 % sodium hydride (5.28 g; 0.11 mole) was added to dry tetrahydrofuran (50 ml), and a solution of methallyl alcohol (7.2 g;0.1 mole) in dry tetrahydrofuran (20 ml) was portionwise added thereto with ice-cooling, followed by stirring for 30 minutes. A solution of benzyl bromide (17.1 g; 0.1 mole) in dry tetrahydrofuran (20 ml) was added thereto to quench the reaction. The reaction mixture was diluted with ethyl acetate and washed successively with lN hydrochloric acid, water and an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 1-benzyloxy-2-methyl-2-propene.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20]Cl)=[C:13]([Cl:22])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH2:24]>C(O)C>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][NH:24][CH3:23])=[C:13]([Cl:22])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=c1c(NCCCCl)c(Cl)cnn1COCc1ccccc1
Solvent: CCO
Product: CNCCCNc1c(Cl)cnn(COCc2ccccc2)c1=O
Reaction time: 5 h
Yield: 80 %

Procedure:
5.35 g (15.63 mmoles) of 2-benzyloxymethyl-5-chloro-4-[N-(3-chloropropyl)-amino]-3(2H)-pyridazinone [which can be prepared according to method 3.ii)] are dissolved in 40 ml of ethanol containing 33% of methylamine. The solution is kept at 100° C. for 5 hours in a pressure-tight steel tube. The solvent is evaporated and the residue is subjected to chromatography on a silica gel column. Thus 4.19 g (80%) of the desired compound are obtained. Rf =0.35.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[C:4]([CH3:11])=[N:3]1.[Li]CCCC.[I:17]I>O1CCCC1.CCCCC>[I:17][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:11])[C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cn(C)nc1C
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nn(C)c1I
Temperature: -45 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of methyl 1,3-dimethyl-1H-pyrazole-4-carboxylate (154 mg, 1 mmol) in dry tetrahydrofuran (10 mL) at −78° C., 2 M solution of BuLi (0.550 mL, 1.100 mmol) in pentane was added dropwise. The reaction mixture was then warmed to −45° C. and stirred for 1 h. It was then cooled to −78° C. and a solution of IODINE (279 mg, 1.100 mmol) in THF (2 mL) was added. The reaction mixture was warmed to RT and stirred for 1 h. It was then quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine, dried over MgSO4, and then concentrated in vacuo. The crude product was obtained as a brown thick oil. This material was then purified by preparative HPLC using CH3CN/H2O/TFA as solvent system. Homogeneous fractions were combined and concentrated in vacuo. The concentrate was then extracted with ethyl acetate and the extracts combined and dried over MgSO4. The suspension was then filtered and the filter and evaporated under reduced pressure to give the title compound as a white solid, (137 mg, 0.460 mmol, 46.0% yield). MS m/z 281 (MH+), Retention time: 1.107 min. (basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3H) 3.84 (s, 3H) 3.91 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:26]4[CH:27]=[CH:22][CH:23]=[C:24]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][O:37][CH2:38][CH2:39]6)[CH2:32][CH2:33]5)[CH:25]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(N2CCC(N3CCOCC3)CC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCC(N6CCOCC6)CC5)c4)nc23)cc1

Procedure:
4-[1-(3-Bromo-phenyl)-piperidin-4-yl]-morpholine was prepared from 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol) and 3-bromophenylboronic acid (0.50 g, 2.5 mmol) in a manner analogous to Step 49a. The reaction product was isolated as a tan resin (0.238 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.08 (t, J=7.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.75-3.68 (m, 6H), 2.79-2.70 (m, 2H), 2.60-2.55 (m, 4H), 2.37-2.28 (m, 1H), 1.97-1.89 (m, 2H), 1.68-1.56 (m, 2H). MS=325, 327 (MH)+. 57b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-[1-(3-bromo-phenyl)-piperidin-4-yl]-morpholine (100.0 mg, 0.3075 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.035 g, 25%). MP=230-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.4 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.08 (d, J=7.1 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.24-7.18 (m, 1H), 7.01 (d, J=6.7 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.84 (s, 1H), 6.60 (d, J=8.4 Hz, 1H), 3.81 (d, J=11.7 Hz, 2H), 3.77-3.72 (m, 4H), 3.10 (s, 3H), 2.78 (t, J=11.8 Hz, 2H), 2.63-2.58 (m, 4H), 2.40-2.30 (m, 1H), 1.97 (d, J=12.7 Hz, 2H), 1.74-1.62 (m, 2H). MS=533 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([CH3:35])[CH:29]=1>>[CH3:35][C:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[C:32]([CH3:34])[N:31]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine in Step 4. LC-MS Method tR=1.228, m/z=445; 1H NMR (CDCl3) 1.32 (m, 1H) 1.51 (d, 3H), 1.60-1.72 (m, 1H), 1.86-2.02 (m, 2H), 2.19 (m, 1H), 2.25-2.39 (m, 2H), 2.79 (s, 6H), 2.93 (m, 1H), 3.50 (t, 2H), 5.64 (m, 1H), 7.00 (d, 2H), 7.21 (m, 2H), 7.29 (m, 2H), 7.32 (m, 3H), 7.40 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]=[CH:15][CH:16]([OH:21])[CH2:17][C:18](=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([O:21][CH:16]([CH:15]=[CH:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(=O)CBr
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Bromoacetyl bromide (1.1 ml, 13.2 mmole) was added dropwise to a stirred solution of 6-(2,4-dichlorophenyl)-4-hydroxy-5-hexene-2-one (3.4 g, 13.1 mmole) and pyridine (1.07 ml, 13.2 mmole) in ether (100 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with H2O (100 ml). The organic layer was separated and washed with 1 N HCl (100 ml), H2O (2×100 ml) and brine, dried over MgSO4, filtered and evaporated. The residual oil was chromatographed on a 60 mm column with 15 cm of silica gel (230-400 mesh) Elution with methylene chloride-acetone (99:1; v:v; 1.9 L) provided the title compound (2.8 g, 56%); pmr (CDCl3) δ2.2 (3H, s), 2.92 (2H, t), 3.85 (2H, s), 5.9 (H, m), 6.15 (H, m) 6.95-7.5 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[C:7]1[C:14]([O:16][CH3:17])=[O:15])[CH3:31]
Reactant: CCI
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (7.5 g) in N,N-dimethylformamide (100 ml) was added oily sodium hydride (60%, 1.6 g) and the mixture was stirred for 30 minutes at room temperature. After dropwise addition of ethyl iodide (4.8 ml), the reaction mixture was further stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethyl ether to give methyl 1-ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (6.38 g, 77%) as pale red prisms.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ncccc1CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccnc1[N+](=O)[O-]

Procedure:
Methane sulfonyl chloride (0.16 mL, 2.14 mmol) was added to a solution of 3-(2-hydroxyethyl)-2-nitropyridine (0.300 g, 1.78 mmol) and triethylamine (0.37 mL, 2.67 mmol) in methylene chloride (5 mL) at 0° C. under argon. After 1 h the reaction was worked up with saturated sodium bicarbonate and methylene chloride, and the organic phase dried over sodium sulfate and concentrated to give the title compound MS 247 (M+1).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH:31]([CH3:35])[C:32](=O)[CH3:33]>C(O)C>[CH3:35][C:31]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]4)=[N:8][CH:9]=2)[S:3][C:32]=1[CH3:33]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C)c(C)s4)cn3)ccc21
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of ethyl [(1 S)-5-(3-{[5-(aminocarbonothioyl)2-pyridinyl]oxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 259, 90 mg, 0.22 mmol) and 3-bromo-2-butanone (40 mg, 0.26 mmol) in ethanol (9 mL) was heated under argon at 80° C. for 18 h, and then concentrated under reduced pressure. The product (85 mg, 84%) was isolated after purification by silica gel chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.54 (dd, 1H), 8.05 (dd, 1H), 7.02 (d, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.69 (dd, 1H), 4.51 (t, 2H), 4.18-4.10 (m, 4H), 3.48 (qt, 1H), 2.92-2.75 (m, 2H), 2.69 (dd, 1H), 2.42-2.30 (m, 8H), 2.29-2.20 (m, 2H), 1.80-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([O:16][CH3:17])=[C:6]([C:12](OC)=[O:13])[C:7]=1[C:8](OC)=[O:9].O.[NH2:20][NH2:21]>CO>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:21][NH:20][C:12](=[O:13])[C:6]=2[C:5]([O:16][CH3:17])=[N:4][C:3]=1[CH3:18]
Reactant: COC(=O)c1c(OC)nc(C)c(N)c1C(=O)OC
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1nc(C)c(N)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 8 ml of methanol was dissolved 280 mg of 3-amino-4,5-dimethoxycarbonyl-6-methoxy-2-methylpyridine, and then 0.54 ml (10 eq.) of hydrazine monohydrate was added to the solution. The mixture was refluxed. The resulting crystals were collected by filtration and washed with methanol. The crystals were suspended in water, and the suspension was acidified with hydrochloric acid. The crystals were collected by filtration and washed with water.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[S:14](N)([NH2:17])(=[O:16])=[O:15]>N1C=CC=CC=1>[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:14](=[O:16])(=[O:15])[N:17]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1c(C=O)ccc2cccnc12
Solvent: c1ccncc1
Product: O=S1(=O)N=Cc2ccc3cccnc3c2N1
Yield: 82.1 %

Procedure:
8-Amino-quinoline-7-carbaldehyde 404 (100 mg, 0.58 mmol) and sulfamide (558 mg, 5.81 mmol) in pyridine (2 ml) was heated in a microwave at 140° C. for 2 h. After cooling, the mixture was concentrated in vacuo. The crude residue was dissolved in DCM and neutralised with citric acid. The resulting precipitate was collected by filtration and dried to give the title compound (111 mg, 82%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31]([O:33][CH3:34])=[O:32].CO>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:30]([C:31]([O:33][CH3:34])=[O:32])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A solution of 200 mg (0.52 mmol) of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl) -4H-1,2,4-triazole (from Step A) in 2 ml of dry DMF was treated with 21 mg (0.52 mmol) of sodium hydride (60% in oil), and the mixture was stirred under N2 at room temperature for a few minutes until H2 evolution had ceased and a clear solution had resulted. To this was added 119 mg (0.52 mmol) of methyl α-bromophenylacetate, and stirring was continued under N2 at room temperature for 10 minutes and then at 65° C. for 6 hours. The cooled mixture was treated with 1 ml of MeOH and then concentrated in vacuo. The residue was partitioned between 25 ml of EtOAC and 30 ml of H2O. The EtOAc phase was washed with 2×25 ml of H2O and then with 25 ml of saturated NaCl. The organic solution was dried over MgSO4, filtered, and concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.75-1.2% MeOH in CH2Cl2) yielded 191 mg (69%) of the title compound as a glass; homogeneous by TLC in 97:3 CH2Cl2 -MeOH.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:17])[F:16])[CH:12]=3)[C:7]([C:18]#[N:19])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:18]([C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[CH:10][CH:9]=2)[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[C:6]=1[B:20]([OH:25])[OH:21])#[N:19]
Reactant: N#Cc1cn(C2CCC2)c2cc(OC(F)F)ccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)n(C2CCC2)c2cc(OC(F)F)ccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 1-cyclobutyl-6-(difluoromethoxy)-1H-indole-3-carbonitrile (1.5 g, 5.7 mmol) and triisopropyl borate (2.4 mL, 10.3 mmol) in THF (25 mL) at −78° C. was added LDA (1.5 M in cyclohexane, 5.0 mL, 7.5 mmol). The mixture was stirred at −78° C. for 30 min and then quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with 2 N aq. HCl to pH 5 and extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-cyano-1-cyclobutyl-6-(difluoromethoxy)-1H-indol-2-ylboronic acid as a solid (1.8 g, 60% pure by LCMS) that was used in the next step without further purification.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.[C:36]([O:40][C:41]([NH:43][C@@H:44]([C:53](O)=[O:54])[CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([NH:25][C:53](=[O:54])[C@@H:44]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])[CH:27]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 73.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (829 mg) and N,N-diisopropylethylamine (1.13 mL) were added to a solution of 3-aminoquinoline (391 mg) and N-tert-butoxycarbonyl-D-homophenylalanine (1.13 g) in dichloromethane (15 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 19 hr, the solvent was removed in vacuo. The residue was diluted with 10% citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform: methanol=50:1, v/v) to afford the title compound (813 mg) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.00-2.10 (m, 1H), 2.27-2.39 (m, 1H), 2.80 (t, J=7.8 Hz, 2H), 4.20-4.29 (m, 1H), 4.98-5.07 (m, 1H), 7.19-7.33 (m, 5H), 7.51-7.55 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), and 8.68-8.80 (m, 3H).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]>C1COCC1.CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8](=[O:17])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1ccccc1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of vinylmagnesium bromide (220 mL, 1.0 M, 220 mmol) in 100 mL THF, was added dropwise under nitrogen atmosphere at 0° C. a solution of 2-(2-methylphenyl)-N-methoxy-N-methylacetamide (Step A, 21 g, 106.6 mmol) in ˜150 mL dry ether. The reaction mixture was stirred at 0° C. for 0.5 hr then poured slowly into an ice/2N aq HCl (300 mL) mixture. The resulting mixture was diluted with ether, transferred to a separation funnel. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to give 14.2 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.15-7.25 (4H, m), 6.47 (1H, dd, J1=14.2 Hz, J2=11 Hz), 6.35 (1H, d, J=14.2 Hz), 5.86 (1H, d, J=11 Hz), 3.83 (2H, s), 2.28 (3H, s).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22].C(O)CCC>O>[F:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Solvent: O
Solvent: CCCCO
Product: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20.1 %

Procedure:
A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine, 60 ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs. The reaction was poured into 11 of water, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. Recrystallization of the residue from isopropanol-water and then from isopropanol yielded 3.3 g (20.1%) of product, mp 214°-216° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:13]>CC(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([I:12])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:13])[C:6]=12
Reactant: Clc1nccn2c(I)nc(Br)c12
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: Nc1nccn2c(I)nc(Br)c12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-8-chloro-3-iodo-imidazo[1,5-a]pyrazine (250.00 mg, 0.696 mmol) in i-PrOH (8 mL) in a Parr bomb was added 7 mL ammonia in water (35%). The resulting solution was stirred at 95° C. overnight. The solvent was removed under reduced pressure and the crude material was passed through a short silica gel column (5% MeOH in DCM as eluent). The fractions were collected and combined, solvent was removed under reduced pressure to give a residue which was used in next step without further purification. MS (ES+): m/z: 338.80, 340.81 [MH+]. HPLC: tR=1.64 min (OpenLynx: polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of compound 4-bromo-2-nitrophenol (1 g, 4.59 mmol) and SnCl2 (5.2 g, 22.9 mmol) in ethanol (10 mL) was stirred at 70° C. for 2 h. After cooled down, the mixture was diluted with water (100 mL), adjusted to pH 7 with saturated aqueous NaHCO3 and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated to give 2-amino-4-bromophenol (770 mg, 89%) as a grey solid. LCMS: 188 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 4.79 (s, 2H), 6.48 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 9.26 (s, 1H).