Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12](O)=[O:13]>>[N:12]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: Oc1cccc2cccnc12
Reactant: O=NO
Product: O=Nc1ccc(O)c2ncccc12

Procedure:
The 8-hydroxyquinoline is reacted with nitrous acid to form 5-nitroso-8-hydroxyquinoline. The nitrous acid is generated in situ by the action of mineral acid, such as hydrochloric, sulfuric, and the like, on sodium nitrite usually under cold temperature conditions.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:39]([O-:41])=[O:40].Cl>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:39]([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)CC1
Agent: Cl
Solvent: CO
Product: Nc1nc(NCCNc2ncc(N3CCNCC3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of tert-butyl 4-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]piperazinecarboxylate was heated to 60° C. 3M HCl in MeOH for one hour and concentrated in vacuo to obtain {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-piperazinylpyrimidin-2-yl]amine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=4)(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(F)(F)F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[CH2:38][O:37]C(C)(C)[O:35]3)=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>CC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:35])[CH2:38][OH:37])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC3COC(C)(C)O3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC(O)CO)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 21 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyphenyl]ethoxycarbonyl)-1,4-dihydropyridine in 150 mL of acetone and 50 mL of water is treated with 10 mL of hydrochloric acid and the mixture heated at reflux for 6 h. Water (500 mL) is added and the mixture was extracted with ether. The ether layer is dried over Na2SO4 and evaporated to an oil which is purified by medium pressure chromatography on silica gel (90% ethyl acetate-hexane) to give 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine, m.p. 117-118° C., [α]D =-33.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1Cl.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(N(C)C)=O>[Cl:1][C:2]1[C:7]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)=[N:6][CH:5]=[C:4]([CH:9]=[O:10])[CH:3]=1
Reactant: O=Cc1cnc(Cl)c(Cl)c1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc(Oc2ncc(C=O)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Combine 5,6-dichloro-pyridine-3-carbaldehyde (1.37 g, 7.80 mmol), 4-hydroxy-benzamide (1.18 g, 8.58 mmol), potassium carbonate (1.62 g, 11.7 mmol) in toluene (10 mL) and DMA (30 mL). Stir the reaction mixture at 100° C. for 1 h. Pour the reaction mixture onto H2O (100 mL) and extract with Et2O (100 mL). Wash the organic layer with H2O (2× 100 mL), dry the organic phase extracts over magnesium sulfate, filter and concentrate to give the title compound (1.09 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)nc1
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)nc1

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and (4-isopropylphenyl)[(5-methoxypyridin-2-yl)methyl]amine (0.38 g) as starting materials, N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This is dissolved in ether, and 4 mol/L-hydrochloric acid/dioxane (0.40 mL) was added. The solvent was evaporated, and ether was added to the residue. The precipitated crystals were collected by filtration to give N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.54 g). melting point: 108-110° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1)(=[O:5])=[O:4].C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>CC#N>[F:15][C:2]([F:14])([F:1])[S:3]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:21](=[O:22])[NH:13][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Solvent: CC#N
Product: O=c1[nH]c2ccc(S(=O)(=O)C(F)(F)F)cc2[nH]1

Procedure:
Reflux 4-trifluoromethylsulfonyl-benzene-1,2-diamine (420 mg) and CDI (284 mg) for 16 hours in CH3CN (30 mL). Evaporate the solvent in vacuo. Purify by flash chromatography (1:1 hexanes/EtOAc) to obtain 5-trifluoromethylsulfonyl-1,3-dihydro-benzimidazol-2-one. F. 2-Chloro-5-trifluoromethylsulfonyl-1H-benzimidazole
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>>[CH:28]1([NH:31][C:18]2[S:19]/[C:15](=[CH:14]\[C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[N:7]=[CH:6][C:5]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:4]4[O:3][CH2:1][CH3:2])/[C:16](=[O:23])[N:17]=2)[CH2:30][CH2:29]1
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one (example 74e), cyclopropylamine, and DIEA (diisopropylethylamine) to give 2-cyclopropylamino-5-[1-(4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 418 (MH+).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:23]([CH:25]=[C:26]([NH:28]C(=O)C(F)(F)F)[N:27]=3)[CH:24]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Na+].O>C(O)C>[NH2:28][C:26]1[N:27]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:17]=[CH:16][CH:15]=3)=[CH:24][N:23]2[CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Temperature: 45 °C
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]benzamide (400 mg, 0.788 mmol) produced in Example A3(vii) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at 45° C. for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and fractions containing the object product was concentrated under reduced pressure to give the title compound (0.35 g, quantitative) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a slurry of Pd-C 10%, 170 mg) in MeOH (2 ml) was added a solution of the 3(R)-Benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) in MeOH (60 ml). The mixture was stirred under H2 (1 atm) for 8 hr. After being filtered through Celite, the filtrate was evaporated to give a light yellow oil (572 mg, 99%). 1H-NMR (300 MHz, CDCl3) δ 4.00-3.78 (m, 2H), 3.80 (m, 2H), 3.60 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.60-1.40 (m, 12H), 1.30 (m, 1H) ppm; IR (film) 3485, 3361, 3292, 2975, 22931, 2862, 1692, 1608, 1548, 1479, 1427, 1367, 1266, 1242, 1162 cm−1; LRMS (calculated for C10,H20N2O2) 200, found 200.
Reaction SMILES: [ClH:1].Cl.[NH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.[F:19][C:20]([F:53])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=O)[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]>ClCCl>[ClH:1].[ClH:1].[F:53][C:20]([F:19])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=[N:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]2([CH3:11])[CH3:10])[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]
Reactant: CC1(C)COCCN1N
Reactant: Cc1ccc(C[C@@H]2CN(CCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCC=NN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirred mixture of 4-amino-3,3-dimethylmorpholine dihydrochloride (122 mg) in dichloromethane (5 ml) was added triethylamine (61 mg) at ice bath temperature. A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-(2-formylethyl)piperazine (150 mg) in dichloromethane (2 ml) was added and the resulting mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent and the desired product was treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino-imino)propyl]piperazine dihydrochloride (122 mg).
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>CO>[CH2:18]([NH:19][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CO
Product: CCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (50 g.) and hexamethylenediamine (18.6 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxydecylamine] (I: R = CH3 (CH2)7, R' = H, X = (CH2)6, Z = H) (25.4 g., m.p. 118.0°-126.8° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][C:16]([F:30])([F:31])[F:15])=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 104.2 %

Procedure:
Mixture of (R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (2.50 g, 11.5 mM) obtained in example 7 and 4-(4-trifluoromethoxyphenyl)piperazine (3.11 g, 12.6 mM) in N,N-dimethylformamide (25 ml) was stirred at 70° C. for 7 hours. The temperature of reaction mixture was turned back to a room temperature, water was added and extracted twice with ethyl acetate. The organic layers were combined, washed with water three times, dried on anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure, there was obtained (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (5.55 g, yield: 100%) of slightly yellow oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[S:16]([Cl:20])(=O)(=[O:18])[OH:17]>>[Cl:20][S:16]([C:5]1[CH:6]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Product: CCOC(=O)Cc1ccc(OCC)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
After addition of 208 mg(1.0 mmol) of ethyl 2-(4-ethoxyphenyl)acetate to 0.2 ml(3.0 mmol) of chlorosulfuric acid dropwise at 0° C., the mixture was warmed to room temperature and stirred for one hour, and then poured into ice water. After the resultant was extracted with ethyl acetate, the extracted ethyl acetate solution was washed with water three times. The solvent was removed under reduced pressure to give 110 mg of the title compound in a yield of 34%.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH:15]=[CH2:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33]OS(C)(=O)=O)[CH2:28]1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH3:21][O:22][C:23]1[CH:48]=[CH:47][C:46]([N:49]2[CH:53]=[N:52][N:51]=[N:50]2)=[CH:45][C:24]=1[C:25]([N:27]1[CH2:31][CH2:30][C@@:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([CH2:32][CH2:33][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH:15]=[CH2:16])[C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:28]1)=[O:26]
Reactant: C=Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide (0.70 g, 1.40 mmol), 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine (0.61 g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) and acetonitrile (18 mL) under argon for 48 hours. Cool and concentrate in vacuo. Thin layer analysis (silica gel, 10% methanol/0.1% ammonium hydroxide solution in acetonitrile) indicates a mixture with a major component Rf=0.40. Dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 solution (50 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions to afford a tan solid. Purify the solid (in three separate injections of 110 mg, 250 mg and 250 mg) by reverse phase chromatography (PrepPak 40×100 mm μBondapak C18, 10 μm, 125 A°, Waters 037684, flow rate 35 mL/minute using the following gradients: 5 minutes with 10% acetonitrile/90% water with 0.1% trifluoroacetic acid, increase over 30 minutes to 50/50 water/acetonitrile, hold 5 minutes at 50/50 water/acetonitrile, increase over 5 minutes to 100% acetonitrile, hold 15 minutes at 100% acetonitrile). Combine the desired fractions to afford 0.17 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[Cl-].[NH4+]>CCOCC>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(C=O)c1
Reactant: BrCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(C(O)CCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
19.1 ml (0.14 mole) of 2-phenylethyl bromide were dissolved in 100 ml of ether and added dropwise to a suspension of 3.4 g (0.14 mole) of magnesium in 300 ml of ether. The reaction solution was next stirred for one hour at 40° C. and then cooled to 0° C. 20.4 g (0.15 mole) of 3-methoxybenzaldehyde in 100 ml of ether were added while cooling with ice and the reaction solution was stirred overnight at 20° C. 150 ml of a 20% ammonium chloride solution was then added at 0° C. to the reaction solution. The reaction solution was extracted three times with 200 ml of ether each time and the combined ether extracts were dried over sodium sulfate. The solvent was removed in vacuo. After drying, 28.5 g (98%) of 1-(3-methoxyphenyl)-3-phenylpropan-1-ol were obtained as a grey oil.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([OH:40])=[O:39])=[CH:13][C:12]=2[C:41]([F:44])([F:43])[F:42])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].Cl[C:46](Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:18]4[C:27]5[CH:26]=[C:25]([C:28]6[CH:29]=[N:30][C:31]7[C:36]([CH:37]=6)=[CH:35][CH:34]=[CH:33][CH:32]=7)[CH:24]=[CH:23][C:22]=5[N:21]=[CH:20][C:19]=4[C:38](=[O:40])[O:39][C:46]3=[O:48])=[CH:13][C:12]=2[C:41]([F:42])([F:43])[F:44])[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1CCN(c2ccc(Nc3c(C(=O)O)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCN(c2ccc(-n3c(=O)oc(=O)c4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
The crude compound 5.5 4′-(4-(4-propionylpiperazin-1-yl)-3(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylic acid (20 mg, 0.033 mmol, 1 equiv.) in CH2Cl2 (3 mL) at 0° C. was added triphosgene (10 mg, 0.033 mmol, 1 equiv.) and DIEA (17 μL, 0.1 mmol, 3 equiv.). The resulting solution was warmed to room temperature in 3 hours and further stirred for 1 hour before being quenched with NaHCO3 (sat. 1 mL) and extracted with CH2Cl2 (5 mL×2). The organic phase was dried over Na2SO4 and the residue was purified via preparative LC-MS (CH3CN: H2O) to afford the desired product 5.6 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)-1H-[1,3]oxazino[5,4-c]quinoline-2,4-dione (1.3 mg). LC-MS (M+H): 626.20
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 620.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[N:31]=[C:32]=[O:33]>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:32]([NH:31][C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1cccs1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccs1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (60 mg, 0.17 mmoles) and 2-thienyl isocyanate (18 mg, 0.14 mmoles), the title compound was isolated as a grey solid after Silica gel column chromatography by eluting with 5% ethyl acetate:methanol. Yield: 12 mg (14%); (M+H)=470.