Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([C:17]#N)[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].CC(O)=[O:21].O>[Ni].N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]([Cl:16])=[CH:14][C:13]2[C:8](=[C:9]([CH:17]=[O:21])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cc2c(C#N)cccc2cc1Cl
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Temperature: 125 °C

Procedure:
NaH2PO2 x H2O (2.12 g, 20.02 mmol, 8.0 equiv) and Raney nickel (1.50 g) were added at room temperature to a solution of 3-chloro-8-cyano-naphthalene-2-carboxylic acid ethyl ester (0.65 g, 2.50 mmol) in pyridine (16 ml)/AcOH (8 ml)/H2O (8 ml). The heterogeneous mixture was heated to 125° C. for 2 hours. After cooling and filtering off the Raney nickel catalyst, the reaction mixture was diluted with water (100 ml). After extraction with EtOAc (2×400 ml), the combined organic layers were washed with brine (2×50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) to afford the title compound (350 mg, 53%, inseparable 1:1.5 mixture of regioisomers A:B) as a white solid. 1H NMR (400 MHz, CDCl3): δ=10.35 (s, 1H isomer B), 10.33 (s, 1H isomer A), 9.70 (s, 1H isomer B), 9.41 (s, 1H isomer A), 8.39 (s, 1H isomer A), 8.14 (d, J=8.4 Hz, 1H isomer A). 8.08 (dd, J=7.1/1.2 Hz, 1H isomer B), 8.04-8.01 (m, 1H isomer A+1H isomer B), 7.99 (1H isomer B), 7.77-7.70 (m, 1H isomer A+1H isomer B), 4.48 (q, J=7.1 Hz, 2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A), 1.46 (t, J=7.1 Hz, 3H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A). MS (ES+): 263 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](O)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:35])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:35])=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)O)s5)nn34)ccnc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylic acid (prepared by General Method A)(0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:21][C:22]1[N:23]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:24]=[CH:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])=[CH:34][CH:33]=2)[CH:5]=[C:6]([C:8]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: CCOC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
A stirred mixture of ethyl 4-(5-fluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (2.01 g, 7.5 mmol), 4-(2-methylimidazol-1-yl)benzyl chloride hydrocloride (1.82 g, 7.5 mmol) and potassium carbonate (5.18 g, 37.5 mmol) in DMF (30 ml) was heated at 100° C. for 1.33 hr. After cooling to room temperature, the mixture was diluted with a mixture of ethyl acetate and toluene (2:1, 200 ml), and washed with water (4×100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to give 3.38 g of crude product as amber solids. Recrystallization from a mixture of isopropyl ether (25 ml) and ethyl acetate (2 ml) gave the titled compound (2.22 g, 68%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[CH:22]=[N:21][CH:20]=[N:19][C:18]=3[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[CH:10][N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[CH:22]=[N:21][CH:20]=[N:19][C:18]=4[NH:17][CH:16]=3)=[CH:10][N:9]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2)c2cncnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(4-Chloro-benzyl)-5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (43, 0.1 g, 0.16 mmol) was dissolved in 5 mL of acetonitrile and triethylsilane (0.25 mL, 1.6 mmol) was added followed by trifluoroacetic acid (0.12 mL,1.6 mmol). The reaction was stirred overnight at 80° C., then cooled and concentrated under vacuum. Ethyl acetate was added and the mixture was washed with 1 M potassium carbonate and brine. The organic portion was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 0-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound, which was further washed with a mixture of ethyl acetate in hexane (P-0001, 0.025 g, 44%). MS (ESI) [M+H+]+=349.9.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]([C-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:5])[CH3:3].[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16].C[I:18].C(OCC)C>CC(C)=O>[I-:18].[CH3:1][N+:2]([C@@H:4]([C-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:5])([CH3:11])[CH3:3].[CH-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Fe+2:16]
Reactant: C[C@H]([c-]1cccc1)N(C)C
Reactant: CI
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(C)=O
Solvent: CCOCC
Product: C[C@H]([c-]1cccc1)[N+](C)(C)C
Product: [I-]
Temperature: 0 °C
Yield: 200 %

Procedure:
20.0g (77.8 mmol) of (R)-N,N-dimethyl-1-ferrocenyl-ethylamine was added under argon atmosphere to a glass vessel (atmospheric pressure use only) with an agitator and dissolved in acetone 37 ml. After cooling with ice water, methyl iodide 21 ml (337 mmol) was added to the vessel and reacted for 15 minutes under cooling with ice water. After reaction, ethylether 160 ml was added to the vessel and crystals were deposited. The crystals were collected by filtration to obtain (R)-N,N,N-trimethyl-1-ferrocenylethylammonium iodide 31.0 g (77.8 mmol)(yield: 100%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[C:21]([Cl:22])[N:7]2[N:6]=1)[CH2:3][CH3:4].[C:23]([NH:30][CH:31]([CH3:34])C=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:35]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[C:26]([O:25][C:23](=[O:24])[NH:30][CH2:31][CH2:34][CH2:35][NH:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[C:21]([Cl:22])[N:7]2[N:6]=1)[CH2:3][CH3:4])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCC(N)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(=O)O
Reactant: CC(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of (±)-2-(1-aminopropyl)-3-benzyl-7-chloro-3-H-pyrrolo[2,1-f][1,2,4]triazine-4-one (0.45 g, 1.42 mmol), N-BOC-aminopropanal (J. Med. Chem., 1985, 28, 317–323, 2.36 g, 13.6 mmol) and HOAc (0.2 mL) in MeOH (12 mL) was treated with NaBH(OAc)3 (1.5 g, 6.7 mmol) and stirred at rt overnight. The reaction mixture was quenched with saturated NaHCO3 solution, extracted with EtOAc (3×80 mL). The EtOAc solution was dried over MgSO4 and concentrated to an oil. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 3.5:6.5 to 3:2) gave the title compound as a pale oil (0.52 g, 77.6%): MS (ESI+) 474.24, 474.26 (M++H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]([OH:25])=[O:24])=[N:17][C:16]=3[S:15][CH:14]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:26](Cl)(=O)[C:27](Cl)=O.N1C=CC=[CH:34][CH:33]=1>CN(C=O)C.C1COCC1>[CH2:33]([O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:17][C:16]=3[S:15][CH:14]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:34]
Reactant: O=C(O)c1ccc(COCc2csc3nc(C(=O)O)[nH]c(=O)c23)cc1
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)OCC)[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 5-({[(4-carboxyphenyl)methyl]oxy}methyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylic acid (2.88 g, 7.99 mmol) and THF (30 mL) were added oxalyl chloride (4.60 mL, 52.7 mmol) and DMF (one drop), and the mixture was stirred at room temperature for 1 hr, and concentrated. THE (15 mL) and ethanol (15 mL) were added to the residue. Pyridine (5.69 mL, 70.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 hr, and concentrated under reduced pressure. Ethyl acetate and 1N hydrochloric acid were added to the residue, and the precipitated solid was collected by filtration, and washed with 1N hydrochloric acid (×2), water (×4) and diethyl ether (×1). The obtained crude crystals were recrystallized from THF-ethyl acetate to give the title compound as a white powder (1.87 g, 56%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Product: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-formylbenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.98 (s, 1H), 8.21 (d, 1H), 8.05 (s, 1H), 7.95 (s, 3H), 7.82 (d, 1H), 7.60 (m, 3H), 7.00 (d, 1H), 6.58 (s, 1H), 6.40 (s, 1H), LC-MS: 370 (MH+); HPLC RT: 4.83 minutes.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)=[O:13].O>CS(C)=O>[C:1]1([S:7]([C:17]2[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH3:11])=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 87.3 %

Procedure:
Preparation 1 of WO 96/262,196 described the reaction of sodium benzenesulfinate (43 g, 0.26 mol) and 4-fluoroaceto phenone (30 g, 0.22 mol) at 130° C. in dimethyl sulfoxide (200 mL) for 48 hours. The mixture is then poured into 1000 mL of water. The solid formed is colled and dried to give 50 g of 1-(4-phenylsulfonyl-phenyl)-ethanone. This solid is suspended in ethanol (350 mL), heated to 60° C. and treated as described in J. Med. Chem., 34, 3295 (1991) to give 4-phenylsulfonyl benzoic acid melting at 269–271° C. A suspension of 4-phenyl sulfonylbenzoic acid (15 g, 0.57 mol) in toluene (50 mL) is treated with thionyl chloride (25 mL). A few drops of N,N-dimethylformamide are added and the suspension is heated to 70° C. for three hours. The solution is concentrated to give the title intermediate compound which is used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].Cl>C(O)C.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(CCCCCl)Cc1ccccc1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
13.1 g of 6-chloro-1-phenyl-hexan-2-one in 75 ml of ethanol is loaded into a 250 ml three-necked flask. The reaction medium is cooled down to -5° C. and a solution of sodium borohydride (2.18 g) in 15 ml of water is added over 5 minutes. Agitation is carried out for 2.5 hours at -5° C., the temperature is allowed to rise to 20° C. over 1 hour, followed by cooling down to -5° C. 110 ml of 0.14 M hydrochloric acid is then added. Agitation is carried out for 10 minutes, followed by extraction 3 times with 80 ml of methylene chloride, drying over magnesium sulphate, filtering and concentration. In this way, 12.3 g of expected product is obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:28]=[O:29].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]([OH:29])[C:13]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH2:16]2)[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)C1CCC1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
21.65 ml (54.12 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 7.6 ml (54.12 mmol) of diisopropylamine in 30 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 6.2 g (39.7 mmol) of tert-butyl cyclobutanecarboxylate in 10 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 7.9 g (36.1 mmol) of 3-bromo-4-chlorobenzaldehyde in 10 ml of abs. THF was then added. The reaction mixture was slowly warmed to RT overnight, saturated aqueous ammonium chloride solution was then added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→10:1). This gave 7.77 g of the target compound (56% of theory).
Reaction SMILES: C(OC([C:6]1[CH:38]=[CH:37]C=C[C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][N:40]1C=CC=C(O)[C:41]1=[O:47]>>[CH3:39][N:40]1[CH:37]=[CH:38][CH:6]=[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)[C:41]1=[O:47]
Reactant: Cn1cccc(O)c1=O
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: Cn1cccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Oc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 1-methyl-2-oxo-1,2-dihydro-pyridin-3-ol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[N+](C1C=CC=CC=1[C:12](Cl)=[O:13])([O-])=O.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]>[Al+3].[Cl-].[Cl-].[Cl-]>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C:12]([N:1]2[CH:5]=[CH:4][NH:3][C:2]2=[O:6])=[O:13])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc([N+](=O)[O-])cc1)n1cc[nH]c1=O
Temperature: 65 °C
Yield: 45 %

Procedure:
To a solution of dihydroimidazolone 1a (1.0 g, 11.9 mmol) in 24 mL 1M AlCl3 in nitrobenzene was added 2-nitrobenzoyl chloride (2.2 g, 11.9 mmol), and the reaction was heated in a 65° C. oil bath for 6 h. The reaction was poured over ice during which a solid formed. The reaction was filtered through a sintered glass funnel and the solid washed with water and diethyl ether and dried in vacuum dessicator to give 1.26 g (45% yield) of 4-nitrobenzoyl-1,3-dihydroimidazol-2-one 1b.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:7][CH2:8]Cl)[CH2:4][CH2:5]Cl.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:2][N:3]1[CH2:7][CH2:8][N:16]([C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of N-methylbis (2-chloroethyl)amine hydrochloride (9.8 g) and 3-nitroaniline (7.0 g) in 1-butanol (100 ml) was heated at reflux for 60 h then cooled to room temperature. Sodium carbonate (2.8 g) was then added and the mixture heated at reflux for a further 18 h, then cooled to 0° C. and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200 ml) and sodium hydroxide solution (1M, 150 ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200 ml). The combined organic layers were dried (K2CO3) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an orange oil. The oil crystallised on standing and the resultant solid was triturated with petrol (60/80) to give the desired piperazine (5.64 g). 1H NMR (360 MHz, CDCl3) δ2.37 (3H, s), 2.58 (4H, t, J=5 Hz), 3.30 (4H, t, J=5 Hz), 7.18 (1H, dd, J=9 and 3 Hz), 7.35 (1H, t, J=8 Hz), 7.64 (1H, dd, J=9 and 2 Hz), 7.71 (1H, d, J=2 Hz). MS (CI, NH3) 222 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:42]=[CH:41][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([C:24]3[CH:25]=NC(C(F)(F)F)=[CH:28][CH:29]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.CN1C([C:54](C2CCOCC2)=[O:55])=CN=C1.C1C[O:65][CH2:64]C1>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([O:65][CH3:64])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:34]3[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=3)([CH:24]3[CH2:25][CH2:54][O:55][CH2:28][CH2:29]3)[OH:23])=[CH:16][CH:15]=4)=[CH:41][CH:42]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: C1CCOC1
Reactant: Cn1cncc1C(=O)C1CCOCC1
Agent: [Li]CCCC
Product: COc1nc2ccc(C(O)(c3cncn3C)C3CCOCC3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (579 mg, 1.22 mmol, Intermediate 4: step e) in THF (5 mL) at −78° C. under argon was added n-butyllithium (1.6 M in hexane, 0.725 mL, 1.16 mmol) over 1 minute. The resulting dark brown solution was stirred for 1 minute before addition of a solution of (1-methyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (237 mg, 1.22 mmol, Intermediate 1: step b) in THF (4 mL). The resulting orange solution was stirred at −78° C. for 5 minutes, then was transferred to an ice bath and stirred 30 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash column chromatography (0-6% MeOH-DCM) to afford the title compound. MS m/e 544.2 [M+H]+. Example 1a was purified by chiral HPLC (Chiralcel OD-H, 20% EtOH-heptane) to give 2 enantiomers. The second enantiomer to elute was then further purified on a silica gel column (0-5% MeOH-DCM). Example 1b: (first enantiomer to elute off chiral column) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 8.09 (d, J=2.53 Hz, 1H), 7.75 (d, J=8.59 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.56 (d, J=8.59 Hz, 2H), 7.43-7.52 (m, 2H), 7.34 (d, J=8.59 Hz, 2H), 7.24 (s, 1H), 6.38-6.54 (m, 1H), 4.28 (s, 2H), 4.05 (s, 3H), 4.00 (dd, J=3.28, 11.37 Hz, 1H), 3.79 (dd, J=3.54, 11.12 Hz, 1H), 3.54 (t, J=11.12 Hz, 1H), 3.32-3.37 (m, 1H), 3.30 (s, 3H), 2.46-2.61 (m, 1H), 2.07 (d, J=13.64 Hz, 1H), 1.57-1.75 (m, 1H), 1.39 (qd, J=4.55, 12.63 Hz, 1H), 0.95 (d, J=13.14 Hz, 1H); MS m/e 544.1 [M+H]+ and Example 1c: (second enantiomer to elute off chiral column) 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.86 (d, J=2.02 Hz, 1H), 7.76 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.59 Hz, 2H), 7.36-7.46 (m, 3H), 7.32 (s, 1H), 7.21 (s, 1H), 6.43 (s, 1H), 4.32 (s, 2H), 4.03-4.14 (m, 4H), 3.90 (dd, J=3.28, 11.37 Hz, 1H), 3.52 (t, J=11.12 Hz, 1H), 3.33 (t, J=11.37 Hz, 1H), 3.25 (s, 3H), 2.42-2.54 (m, 1H), 2.36 (s, 1H), 2.12 (d, J=13.64 Hz, 1H), 1.42 (qd, J=4.29, 12.72 Hz, 1H), 1.21-1.35 (m, 1H), 1.03 (d, J=13.14 Hz, 1H); MS m/e 544.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28]>C(Cl)Cl>[N:19]([C:15]1[CH:14]=[N:13][C:12]2[C:17](=[CH:18][C:9]([CH3:8])=[CH:10][CH:11]=2)[N:16]=1)=[C:27]=[S:28]
Reactant: Cc1ccc2ncc(N)nc2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc(N=C=S)nc2c1
Yield: 46 %

Procedure:
A mixture of 7-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg, 2 mmol) 78263-058-01, triethylamine (243 mg, 2.40 mmol), and 1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in 5 mL DCM for 2 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-7-methylquinoxaline (185 mg, 0.919 mmol, 46% yield).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)C(C[NH-])=O.Cl.[CH3:22][N:23](C)[CH:24]=[O:25]>>[CH3:22][NH:23][C:24]([C:3]1[CH:2]=[C:1]([NH:7][C:8]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=1)=[O:25]
Reactant: [NH-]CC(=O)c1cccc(N)c1
Reactant: CN(C)C=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: CNC(=O)c1cccc(NC(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
Phenylisocyanate (209 mg) and 3-aminobenzoylmethylamide (239 mg) were dissolved in dimethylformamide (2 ml). After starring for 6 hours at room temperature, dilute hydrochloric acid (15 ml) was added. The obtained crystals were filtered and washed with water to obtain crude crystals. The crude crystals were dried under reduced pressure and added to ethyl acetate (8 ml), and the mixture was heated under reflux for 10 minutes. The mixture was cooled to room temperature, and the crystals were collected by filtration and washed with ethyl acetate to obtain the desired compound (386 mg, yield 90%).