Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:42]([NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:44])[CH3:43]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccccc1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-isopropylaniline (135 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), then quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-isopropyl-N-phenylamide. MS m/z 576.0 (M+H); 544.0 (M+H-MeOH).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][NH:27][CH2:26]1>>[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: CC(C)(C)ON=C1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Product: CC(C)(C)ON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Yield: 67.3 %

Procedure:
141 mg (0.5 mmole) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 143 mg (0.55 mmole) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were refluxed for 2.5 hours under heating according to the same manner as Example 89 and cooled down to room temperature. Then, the resulting product was then separated and purified with preparative HPLC to obtain. 151 mg (Yield: 67%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:53][CH2:52][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[C:48]([F:51])[C:49]=4[CH:50]=[C:42]3[C:41]=2[N:54]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:51][C:48]1[C:49]2[CH:50]=[C:42]3[C:41]4[N:54]=[C:37]([C:18]5[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][C:10]6[O:9][C:8]([C:5]7[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=7)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=6[CH:17]=5)[CH:38]=[CH:39][C:40]=4[O:53][CH2:52][N:43]3[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (56 mg, 0.199 mmol) and K3PO4.3H2O (159 mg, 0.597 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80° C. for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether/EtOAc=1:1.5) to provide the pure product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H-NMR (CDCl3, 400 MHz) δ: 7.99 (s, 1H), 7.93˜7.96 (m, 2H), 7.65 (s, 1H), 7.45˜7.50 (m, 2H), 7.17˜7.21 (m, 4H), 7.10 (d, J=8.0 Hz, 1H), 6.81˜6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:26]([CH3:25])(=[O:28])=[O:27])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2H), 7.14 (m, 3H), 6.98 (d, 1H), 6.73 (d, 1H), 4.57 (t, 2H), 4.29 (s, 4H), 4.24 (s, 2H), 3.66 (s, 3H), 3.19 (t, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 2.61 (t, 2H).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[C:1]([O:14][CH:11]([CH3:13])[CH3:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CC(C)O
Product: CC(C)OC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), Chloronil (22.5 mmol), isopropanol (10 mL) is taken in a round bottom flask and catalytic amount of silica gel (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Isopropyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C3H8) is isolated in 49% yield. 1H-NMR (CDCl3, 300 MHz) δ7.59 (1H, d, J=16.55 Hz), 7.41 (2H, m), 7.27 (3H, m), 6.34 (1H, d, J=16.55 Hz), 5.07 (1H, m), 1.18 (6H, d); 13C-NMR (CDCl3, 75.4 MHz) δ166.4, 144.3, 134.5, 130.1, 128.6, 128.0, 118.8, 67.7, 21.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.52 g, 2.59 mmol) in anhydrous CH2Cl2 (5 mL) under argon were added acetic anhydride (0.37 mL, 3.89 mmol) and Pyridine (0.31 mL, 3.89 mmol). The resulting solution was stirred at 25° C. for 3 hrs. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (80% EtOAc in hexanes) to give the product (0.62 g, 100%) as a white solid. 1H NMR (CDCl3) δ: 1.46 (d, J=7.0 Hz, 3H), 1.99 (s, 3H), 5.03-5.12 (m, 1H), 5.68 (brs, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H). ESIMS (MNa+): 264.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:12][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)(C)C(O)/C=C/Br
Product: CCCCC(C)(C)C(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 1.88 g. (8 moles) of 1-bromo-4,4-dimethyl-trans-1-octen-3-ol (Example 1174) with 2.58 g. (8 moles) of triphenylmethyl bromide in 20 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: CN1CCC(CO)CC1
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(COc2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methylpiperidin-4-yl)methanol (0.500 g, 3.87 mmol) was dissolved in dry DMF (8 mL), cooled (<0° C.), NaH (0.232 g, 5.80 mmol, 55% in oil) added and stirred for 30 minutes. 3-fluorobenzonitrile (0.492 g, 4.06 mmol) was added and the reaction mixture allowed to warm to r.t. over 1 hour. Due to excessive foaming the reaction mixture was diluted with dry DMF to 20 mL and stirred over night at r.t. The reaction was quenched by addition of water portionwise, and the mixture was extracted with EtOAc. The organics were dried (MgSO4) and concentrated in vacuo. The product was purified by flash chromatography using a step gradient of EtOAc:MeOH:TEA (100:10:2) in EtOAc to give the title compound as an oil. Yield: 0.417 g (44%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.35 (m, 1H), 7.19 (m, 1H), 7.05-7.10 (m, 2H), 3.78 (d, 2H, J=6.1 Hz), 2.83-2.90 (m, 2H), 2.26 (s, 3H), 1.89-1.98 (m, 2H), 1.70-1.84 (m, 3H), 1.33-1.46 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[C:18]([Cu])#[N:19].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:18]#[N:19])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: N#C[Cu]
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
A solution of 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 from Example 12 (0.2 g, 0.5 mmol) and CuCN (50 mg, 0.6 mmol) in pyridine (1 mL) was heated at 115° C. for 2 h then cooled to room temperature and stirred 18 h. The reaction was poured into 1 M HCl and ice and the aqueous layer was extracted with CH2Cl2. The product was purified by silica gel chromatography (0-75% EtOAc in hexane) to provide 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbonitrile (35 mg).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:40])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH3:38])[C:35](=[O:39])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].O.[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>>[C:8]([O:12][C:13](=[O:40])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:39])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH3:38])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CN
Reactant: Cc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Agent: Oc1ccccn1
Solvent: O
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCC(C)(C)C)CC1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
6.8 mg of 2-hydroxypyridine (0.072 mmol) was added to a solution of 165 mg of {(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (85b) (0.36 mmol) in (2,2-dimethylpropyl)amine (1.5 ml), and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 167 mg of the title compound (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([O:41][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: COc1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Product: COc1ccccc1OC(CCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1F

Procedure:
Prepared by Procedure A and Scheme AN using 2-methoxyphenol and N-(3-[1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 547.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](O)(=[O:15])C.C1N2CN3CN(C2)CN1C3>O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
6-Nitroindole (1.0 g, 6.2 mmol) was successively added with acetic acid (2.5 mL), water (5.0 mL), and hexamethylenetetramine (1.2 g, 8.4 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration, and then dried to obtain 6-nitro-1H-indole-3-carboxaldehyde (0.91 g, 77%).
Reaction SMILES: [Cl:1][C:2](Cl)([Cl:6])C([O-])=O.[Na+].[C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:11])[CH3:10].O>COCCOCCOC>[C:9]([O:12][CH2:13][C@H:14]1[C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1([Cl:6])[Cl:1])(=[O:11])[CH3:10]
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: CC(=O)OC/C=C/c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of sodium trichloroacetate (27.8 g, 150 mmol) in diglyme (20 ml) was added dropwise over 1 hour to a solution of trans-cinnamyl acetate (8.81 g, 50 mmol) in diglyme (80 ml) at 120° C. to 135° C. and the reaction mixture was heated at 120° C. to 125° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into water (300 ml), extracted with n-hexane (300 ml+3×50 ml) and dried over MgSO4. The solvent was removed and the residue was distilled under vacuum affording the title compound (11.0 g, 76% yield, b.p. 104-105° C. (0.15 mmHg)).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][C@H:21](O)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[C:2]1([O:1][C@@H:23]2[CH2:22][CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Oc1nccc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2nccc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-hydroxyisoquinoline (1.00 g, 6.9 mmol), (S)-1-BOC-3-hydroxypiperidine (4.17 g, 20.7 mmol), Ph3P (7.23 g, 27.6 mmol) in THF (40 mL) was stirred at RT into a clear solution. DIAD (5.43 mL, 27.6 mmol) was added dropwise. The mixture was stirred at RT for 1 h and then at 50° C. for overnight. The mixture was diluted with EtOAc, washed with water ×3, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0% to 15% EtOAc in DCM to afford (R)-tert-butyl 3-(isoquinolin-1-yloxy)piperidine-1-carboxylate (53).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:11][C:12]1[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=1[O:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=2[O:29][C:30]2[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN2CCN(C(C)=O)CC2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 92.5 %

Procedure:
N-Acetylpiperazine (42 mg, 0.330 mmol) in N,N-dimethylformamide (1 ml) was added to a stirred solution of the bromide of Example 137 (148 mg, 0.300 mmol) and diisopropylethylamine (57 μL, 0.330 mmol) in N,N-dimethylformamide (2 ml) at room temperature. The reaction was stirred for 5 hours and the mixture was concentrated under reduced pressure. A solution of the residue in dichloromethane (30 ml) was washed with 1M aqueous potassium carbonate solution (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (150 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CC(C)([O-])C.[K+].O>CN(C=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([CH:15]=1)[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoroaniline (1.813 mL, 18.86 mmol) and 2,4-difluoro-1-nitrobenzene (1.723 mL, 15.71 mmol) in DMF (26.2 mL) was added potassium tert-butoxide (3.53 g, 31.4 mmol) under argon gas. The solution was stirred overnight at rt poured into water and extracted with DCM. The combined organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give an orange solid that was triturated in EtOAc:hexane (1:1) and filtered to give 5-fluoro-N-(3-fluorophenyl)-2-nitroaniline as an orange solid: LC-MS (ESI), m/z 251.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28].Cl>ClCCl>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)=[O:41])([CH3:28])[CH3:29]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: c1ccc(CN[C@H]2CC[C@@H](c3ccccc3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccccc1)[C@H]1CC[C@@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 400 mg of cis-N-benzyl-N-(4-phenylcyclohexyl)amine in 20 ml of dichloromethane were added 2 ml of pyridine and then a solution of 310 mg of 2,6-diisopropylphenylisocyanate in 5 ml of dichloromethane dropwise. The mixture was stirred at room temperature, poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 460 mg of cis-N-(2,6-diisopropylphenyl)-N'-benzyl-N'-(4-phenylcyclohexyl)urea, melting at 153°-154° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])([O-:3])=[O:2].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
2-nitrobenzenamine (5.0 g, 36.2 mmol) was dissolved in 100 mL of THF under N2 atmosphere, 60% NaH (1.7 g, 43.4 mmol) was added at 0° C., and the mixture was stirred for 30 min at room temperature. (Bromomethyl)benzene (7.4 g, 43.4 mmol) was added at 0° C. and the reaction was stirred at 80° C. overnight. The solvent was evaporated in vacuo and the residue was purified by combi-flash (PE:EA=2:1) to give N-benzyl-2-nitroaniline as a yellow solid (2.92 g, 36%). 1H NMR (300 MHz, CD3OD): δ 4.65 (d, J=6 Hz, 2H), 6.69 (t, J=7.2 Hz, 1H), 6.94 (d, J=9 Hz, 1H), 7.25-7.50 (m, 5H), 8.09 (d, J=8.4 Hz, 1H), 8.62-8.68 (m, 1H).