Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH:9]1[O:14]CCCO1.[Li][CH2:16]CCC.CI>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:16])[C:3]=1[CH:9]=[O:14]
Reactant: Brc1cccc(Br)c1C1OCCCO1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cccc(Br)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1H NMR (500 MHz, CDCl3) δ [ppm] 7.55 (d, 3J=8.0 Hz 2H, ar), 7.00 (t, 3J=8.0 Hz 1H, ar), 6.19 (s, 1H, CH), 4.33-4.29 (m, 2H, CH2), 4.02-3.97 (m, 2H, CH2), 2.44-2.34 (m, 1H, CH2), 1.44-1.40 (m, 1H, CH2); 13C{1H} NMR (125.77 MHz, CDCl3) δ [ppm] 133.9, 132.5, 129.8, 122.9, 101.6, 66.7, 24.1. The acetal (10.1 g, 31.25 mmol) was dissolved in THF, abs. (200 ml). At −78° C. n-BuLi (15.1 ml, 2.5 M in hexane, 37.8 mmol) was added within 25 min, followed by 90 min additional stirring at that temperature. Then the reaction mixture was treated with methyliodide (5.99 g, 42.2 mmol) and stirred for 25 min at −78° C. Next the reaction mixture was allowed to warm to ambient temperature within 1.5 h. The resulting solution was quenched with HCl (290 ml of a 5 N solution) and stirred for 1.5 h at ambient temperature. The complete deprotection of the aldehyde was checked via GC analysis. Then the reaction mixture was subsequently extracted with diethylether (4×100 ml), the combined organic layers were washed with a 10% solution of sodium thiosulfate (100 ml), water (100 ml), dried over MgSO4, filtered and the volatiles removed in vacuo. The resulting slightly yellow solid was purified via Kugelrohr distillation to afford 50 (5.97 g, 96%) as white crystals. Rf 0.56 (cyclohexane:ethylacetate 10:1).
Reaction SMILES: [BrH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC>CO.[Pd]>[BrH:1].[BrH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Br
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc(OCCN2CCCCC2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.4 %

Procedure:
A mixture of 2-benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide (500 mg, 1.19 mmol) and Pd/C (10%, 50 mg, Aldrich) in MeOH (25 mL) was shaken under H2 (20-30 psi, Parr) for 2 h at 25° C. The catalyst was removed by filtration (Celite). The resulting solution was acidified with a dilute solution of HBr in MeOH (pH paper to red). The MeOH was removed in vacuo (rotoevaporator, 35-40° C.) to give a syrup. Ether (45 mL) was added and the resulting mixture was vigorously stirred at 25° C. for 24 h. A yellow suspension was obtained. The solid was collected, washed with ether (3×2 mL) and dried in vacuo (0.005 Torr, 56° C.) to give a beige powder (358 mg, 64%): mp 130° C.; 1H NMR (DMSO-d6) 1.28-1.95 (m, 6H), 2.69-3.95 (m, 7H), 4.60-4.55 (m, 2H), 7.08-7.42 (m, 9H), 9.60-10.25 (m, 4H); HRMS Calcd for C20H26N20: 310.2045. Found: 310.2040.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])(=[O:4])=[O:3].ClC1C=C(S(C)(=O)=O)C=CC=1O[CH2:17][C:18]1[C:23](C)=[CH:22][C:21]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:20][N:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:20][N:19]=2)=[CH:7][C:6]=1[CH3:12])(=[O:3])=[O:4]
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)cnc1COc1ccc(S(C)(=O)=O)cc1Cl
Reactant: Cc1cc(O)ccc1S(C)(=O)=O
Product: Cc1cc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)ccc1S(C)(=O)=O
Yield: 35 %

Procedure:
The title compound was prepared from tert-butyl 4-[(2-hydroxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1(2)) (64 mg, 0.219 mmol) and 4-methanesulfonyl-3-methylphenol (41 mg, 0.219 mmol) following a procedure analogous to that in Example 1(3) and (4) as a pale yellow amorphous (35 mg, yield 35%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([O:16][CH3:17])[CH:12]=[C:13](F)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:23].[OH-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:23])[CH:12]=[C:11]([O:16][CH3:17])[C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)cc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 3-benzyloxy-5-fluoro-2-nitroanisole(0.75 g), dimethylsulphoxide(5 mL) and 5N aqueous sodium hydroxide(2 mL) was stirred at 70° C. for 3 h. The mixture was diluted with water and acidified with concentrated hydrochloric acid, extracted with ethyl acetate and the extract was washed with water dried and evaporated to dryness to give the product (0.71 g), (m/e274, MH−).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32](Cl)=[O:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:32]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][N:26]=5)=[O:33])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4cnccn4)ccc32)n1)c1ccccc1
Yield: 55 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and pyrazine-2-carbonyl chloride (0.11 mmol) (prepared by reacting pyrazine-2-carboxylic acid with oxalyl chloride in dicloromethane at room temperature) furnished the product (24 mg, 55%) after chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)nn(CC(C)C)c1=O
Yield: 79.5 %

Procedure:
Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 79.5%.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:13]([N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)CNCC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(CC(C)C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-Boc-glycine (1.0 g, 5.7 mmol) in DMF (10 ml) were added diisobutylamine (0.10 ml, 11.4 mmol), DIPEA (1.9 ml, 11.4 mmol) and TBTU (2.7 g, 8.5 mmol). The mixture was stirred for 1 hr at room temperature, quenched with saturated aqueous sodium bicarbonate (15 ml), and extracted with EtOAc (20 ml). The organic phase was washed with brine (15 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (30% EtOAc in hexanes) to provide tert-butyl 2-(diisobutylamino)-2-oxoethylcarbamate (1.6 g, 98%) as a colorless oil. [M+H]+ 287.3, HPLC purity: 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:26][CH3:27]>CN(C=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13]1)[CH3:27]
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 98 %

Procedure:
A solution of 13A (1 g, 3.67 mmol) in DMF (15 mL) was added with an. K2CO3 (1.5 mol eq, 0.76 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 0.45 ml) was added and the mixture was heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (60 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 14A as a pale yellow oil (1.1 g, 98% yield). 1HNMR (DMSO, 200 MHz) δ 1.095 (t, 3H, J=8), 4.43 (bs, 4H), 2.88 (s, 3H), 3.32 (m, 2H), 7.42 (t, 2H, J=8.2), 7.87 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](OC)=[O:6].[NH2:13][NH2:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: NN
Reactant: COC(=O)c1ccc(Cl)c(Br)c1
Solvent: CO
Product: NNC(=O)c1ccc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 25 %

Procedure:
Methyl 3-bromo-4-chlorobenzoate (120 mg, 0.481 mmol) was added to hydrazine (23.12 mg, 0.721 mmol) in methanol (8 mL) and refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography affording the title compound (30 mg). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=1.6 Hz), 7.60 (dd, 1H, J=2.0 & 8.0 Hz), 7.52 (d, 1H, J=8.0 Hz). ESI-MS: 250.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([N:25]=[C:26]=[S:27])(=[O:24])=[O:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([S:22]([NH:25][C:26]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)=[S:27])(=[O:23])=[O:24])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Yield: 77.9 %

Procedure:
77 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate prepared in accordance with Example 2 was suspended in 100 ml of toluene, and 37 ml of thionyl chloride was added to the suspension at 0° to 10° C. over the course of 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Distillation at reduced pressure gave 2-phenylbenzenesulfonyl isothiocyanate. On the other hand, 12.3 g of 2-amino-4,6-dimethylpyrimidine was suspended in 300 ml of dry toluene, and 27.5 g of 2-phenylbenzenesulfonyl isothiocyanate prepared as above was added. The mixture was heated under reduced pressure for 8 hours. After cooling, the resulting white precipitate was collected by filtration, and recrystallized from ethanol to give 31 g of the desired 1-(2-biphenylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)thiourea of the following formula, mp. 203°-204° C.: ##STR20##
Reaction SMILES: [F:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.O.Cl>C(#N)C>[CH3:34][O:33][C:31]1[N:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:17][S:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:2]([F:1])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5])(=[O:16])=[O:15])=[O:24])[N:32]=1
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Reactant: NS(=O)(=O)c1sccc1C(F)=C(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2sccc2C(F)=C(F)C(F)(F)F)nc(OC)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
According to steps (1) to (4) in Preparation Examples 1, 3-(1,2,3,3,3-pentafluoropropen-1-yl)-2-thiophenesulfonamide was prepared. A portion (0.3 g) of this substance and 0.311 g of phenyl-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate were dissolved in 4 ml of dry acetonitrile. To the solution, 0.175 g of 1,8-diazabicyclo-(5,4,0)-7-undecene was added dropwise, and the mixture was subjected to reaction under stirring for 2.5 hours at room temperature. After completion of the reaction, the resulting product was poured into water and acidified with hydrochloric acid. The precipitated crystals were filtered, washed with water and dried to obtain 0.47 g of the object compound having a melting point of 149° to 153° C.
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: BrBr
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5β-pregnan-20-one 3 g, 8.77 mmol) in MeOH (110 mL) was treated with two drops of HBr (48%), followed by bromine (0.5 mL, 10.8 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (3.2 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (4:1) gave 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (3.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[OH:11].[CH2:13](OB(C=C)OCCCC)[CH2:14]CC>C1COCC1.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:13]=[CH2:14])=[CH:6][C:5]=1[OH:11]
Reactant: C=CB(OCCCC)OCCCC
Reactant: COC(=O)c1ccc(I)cc1O
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(=O)OC)c(O)c1

Procedure:
A solution of 2-hydroxy-4-iodo-benzoic acid methyl ester (8.01 g, 0.0288 mol) in THF (184 ml) and H2O (46 ml) is treated with vinyl-boronic acid di-butyl ester (9.53 ml, 0.0432 mol, 1.5 eq.), NaCO3 (21.37 g, 0.201 mol, 7 eq.), and dichloro-bis(triphenyl-phosphine)palladium (1.01 g, 1.44 mmol, 5 mol %). The solution is purged with N2 (g) for 5 minutes and then heated to reflux for 2 hour. The reaction is concentrated in vacuo, diluted with EtOAc, and sequentially washed with H2O and saturated aqueous NaCl. The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (5% ethyl acetate in hexanes) to afford 2-hydroxy-4-vinyl-benzoic acid methyl ester: ESMS m/z 179.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1>[Pd].CO>[F:19][CH:2]([F:1])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[O:17][CH3:18])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(C(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
Step N (4): 10% Palladium on carbon (250 mg) was added under an atmosphere of nitrogen to a solution of 4-(difluoromethyl)-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (2.5 g, 92.9 mmol) in methanol (25 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to stir at rt for 2 h. The reaction vessel was purged with nitrogen gas. The crude reaction mixture was filtered through a short diatomaceous earth (Celite®) plug. Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. The crude product was purified using silica gel column chromatography (EtOAc/hexane) to afford 4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyaniline (1.8 g, 81% yield). LC-MS (M+H)+ 240.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (s, 1 H) 7.93 (s, 1 H) 7.47 (d, J=8.4 Hz, 1 H) 7.19-6.88 (m, 3 H) 3.81 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:17])=[C:7]([C:18]([F:21])([F:20])[F:19])[CH:6]=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([N:12]([CH2:31][CH3:32])[S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:17])=[C:7]([C:18]([F:21])([F:20])[F:19])[CH:6]=2
Reactant: CCI
Reactant: COc1nc2cc(C(F)(F)F)c(Cl)c(NS(C)(=O)=O)c2nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(c1c(Cl)c(C(F)(F)F)cc2nc(OC)c(N)nc12)S(C)(=O)=O
Reaction time: 4 h
Yield: 94 %

Procedure:
A mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide (Preparation 20, 73 mg, 0.2 mmol) and anhydrous potassium carbonate (33 mg, 0.24 mmol) in acetone was stirred under reflux for 20 mins. Iodoethane (32 μl, 0.4 mmol) was added, and the mixture was heated for a further 2 h. Additional iodoethane (32 μl, 0.4 mmol) was added, and heating was continued for a further 4 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic solution was dried (MgSO4), concentrated under reduced pressure, and the residue was purified by flash chromatography (gradient elution with dichloromethane/methanol) to give N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide (75 mg, 96%), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([OH:26])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCBr
Reactant: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(7-Hydroxy-6-methyl-quinolin-8-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.3 g, 3.8 mmol) and methyl 4-bromobutyrate (680 mg, 3.8 mmol) were dissolved in DMF (7.5 mL). To this solution was added Cs2CO3 (3.7 g, 11.3 mmol) and reaction was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was then dried over MgSO4, filtered, and concentrated to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=1[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(CC(=O)N3CCC(c4ccncc4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 33.7 %

Procedure:
With 290 mg of the compound obtained in Step 51-2 and, 202 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 150 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(C)c1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-dimethylphenyl)boronic acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 177 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][CH3:24])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (54 mg) was added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (6/4) to give 111 mg (yield 77%) of the title compound.