Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])=[CH:7][CH:6]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 8 h
Yield: 91.9 %

Procedure:
tert-Butyl 4-(3-hydroxypropyl)phenylcarbamate (327 mg, 1.301 mmol) in DCM (15 ml) was cooled in an ice-bath. Triethylamine (0.23 ml, 1.626 mmol) was added, and then methanesulfonyl chloride (164 mg, 1.431 mmol) was added. The mixture was stirred overnight and the temperature was allowed going up to room temperature. It was then washed with water, sodium hydrogencarbonate aqueous solution (1%), water and brine and dried with magnesium sulfate. Evaporation in vacuum to remove the solvent gave the desired product (394 mg), yield 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: C1CCNCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCCCC2)c1

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(piperidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and piperidine (0.049 mL; 0.5 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished the title compound as a white solid, quantitatively.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[C:32]([F:34])[CH:33]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(N)Cc1cc(F)cc(F)c1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: CC(C)(Cc1cc(F)cc(F)c1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2

Procedure:
Prepared from 1.73 g (4.84 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.80 g (4.32 mmol) of 2-(3,5-difluorophenyl)-1,1-dimethylethylamine in the usual way. Yield: 1.50 g (58%, hydrochloride); melting point: 240° C.–244° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[N:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4cnc5ccccc5n4)cc3CC[C@@H]12
Yield: 55.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloroquinoxaline (76 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 82 mg (55%) of the title compound as an amorphous foam. FDMS: m/e=389. α[D]589 =+68.96 (c=0.81, chloroform).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3OC(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethoxybenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (83% yield). 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.53-7.32, 7.01, 4.12-3.36, 1.75-1.66, 1.54-1.48, 0.98. MS (ES+) m/z 466.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:3].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:3][C:2]([CH3:12])([C:4](=[O:11])[CH:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)C(CCCCOc1ccccc1)n1cncn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.3 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (cf. German Laid-Open Application DOS No. 2,638,470) in 20 ml of dimethylformamide was added dropwise, under a dry nitrogen atmosphere, to a stirred suspension of 2.3 g of sodium hydride in 20 ml of dimethylformamide, the reaction temperature being kept at 20°-30° C. by cooling; the mixture was subsequently stirred for 20 hours at room temperature. A solution of 19.5 g of 1-bromo-4-phenoxybutane in 20 ml of dimethylformamide was then added dropwise at 5°-10° C., with continued stirring, and while cooling with ice. After completion of the addition, stirring was continued for 10 hours at 5°-10° C., after which 200 ml of water were added and the mixture was extracted with twice 100 ml of methylene chloride. The combined organic phases were extracted by shaking with water and dried over magnesium sulfate; removal of the solvent under reduced pressure gave an oil from which, on trituration with 20 ml of diisopropyl ether, 17 g of colorless crystals were precipitated; melting point 59°-62° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[N:8][C:9]=1S(C)(=O)=O.Cl.[CH3:31][CH:32]([OH:34])[CH3:33]>>[NH2:3][C:4]1[N:5]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([C:14]2[CH:15]=[CH:16][C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[N:19]=2)=[N:8][C:9]=1[O:34][CH:32]([CH3:33])[CH3:31]
Reactant: CC(C)O
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
In a sealed tube, NaH (60% in oil suspension) (31.1 mg) was added 2-propanol (0.6 ml) and the mixture was stirred at 25-30° C. for 30 minutes. 6-[5-Amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (150 mg) was added and the mixture was heated at 100-105° C. for 15 hours. After addition of 0.1N HCl (3 ml) was added to the mixture and an aqueous layer was removed by decantation to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give a solid. The solid was crystallized from a mixture of acetone and n-hexane to give 6-(5-amino-6-isopropoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (102 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:13][O-].[Na+]>>[CH2:11]([O:10][C:1](=[O:9])[C:2]1[CH:8]=[C:7]([Cl:13])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH3:12]
Reactant: [O-]Cl
Reactant: CCOC(=O)c1ccccc1N
Agent: [Na+]
Product: CCOC(=O)c1cc(Cl)ccc1N

Procedure:
Prepared from ethyl anthranilate and sodium hypochlorite (according to M. Okabe and R-C Sun, Tetrahedron, 1995, 51, 1861) to give an off-white solid, mp 80° C., m/z 199.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1)#[CH:2].C([Li])CCC.CCCCCC.[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29]>CCOCC>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH:12]=[CH:11][C:10]1=2
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a cold solution (-78° C.) of 2-ethynyl,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (900 mgs, 4.3 mmols) in ether (20 ml) was added n-butyllithium in hexane (5.6 mmols). The mixture was stirred for 45 mins, and ethylchloroformate (1.3 g, 12 mmols) was added via syringe. Stirring was continued for 45 mins then the mixture was warmed gradually to -10° C. and quenched by adding sodium bicarbonate (NaHCO3) solution (10 ml). Diethyl ether (100 ml) was added, the organic phase washed with water (10 ml), brine (10 ml), and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue over silicagel (5% ethylacetate in hexane) gave the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32]Br)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]>C1COCC1.CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32][O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc([N+](=O)[O-])c3)csc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 3-nitrophenol (457 mg, 3.29 mmol) (Aldrich) and potassium carbonate powder (498 mg, 3.60 mmol) in dry THF (10 mL) and DMF (5 mL) was stirred at 50° C. for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.00 g, 2.99 mmol) (from Example 1 supra) in THF (8+2 mL) was added. The reaction was stirred at 50° C. for 3 hours and the resulting mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (200 mL), washed with water (2×25 mL) and brine (25 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 90/10) to give 4-chloro-3-(3-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 911 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25].O>C(O)C>[CH3:21][C:22]1[CH:23]=[C:24]([CH3:25])[N:18]([C:16]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH3:20])=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:17]=2)[N:19]=1
Reactant: Cn1cnc2c(Nc3ccc(F)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(F)cc3)c3ncn(C)c3n2)n1
Yield: 99.1 %

Procedure:
(4-Fluoro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (900 mg, 3.29 mmol) and 2,4-pentanedione (0.47 mL, 4.16 mmol) in ethanol (25 mL) were heated to reflux for 20 min. Water was added and the white crystalline compound was collected by filtration, washed with water and dried to give [2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-(4-fluoro-phenyl)-amine (1.1 g, 100%).
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH2:21]1)=[C:13]=[CH2:14]
Reactant: C#CCOC1(c2ccccc2)C=CC=CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=COC1(c2ccccc2)C=CC=CC1
Yield: 63.2 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 1.342 parts of t-BuOK and 7.607 parts of THF and to this, a mixture of 10.000 parts of 1propargyloxybiphenyl and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 1-allenyloxy biphenyl as colorless oily product. This compound was identified by FT-NMR(H) and IR spectrum. The reaction yield was 63.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=12)([O-])=O>[Zn].C(O)C.O>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=12
Reactant: O=[N+]([O-])c1ccc2c([N+](=O)[O-])cnn2c1
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(N)cnn2c1

Procedure:
The reduction of 3,6-dinitropyrazolo[1,5-a]pyridine was carried out using zinc in an ethanol/water mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=2[NH:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=4[NH:15][C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CCc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([N:24]([CH3:26])C)=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:38]=[O:39]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:24][CH3:26])=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=3)[C:13]([CH:38]=[O:39])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2ccc3cc(N(C)C)c(C(F)(F)F)cc32)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2cc(C=O)c3cc(NC)c(C(F)(F)F)cc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(5-dimethylamino-6-trifluoromethylindol-1-yl)benzoic acid ethyl ester (0.054 g) in N,N-dimethylformamide (2 mL) was added phosphoryl chloride (0.026 g) under ice cooling, and this mixture was stirred at room temperature for 16 hours. To this mixture was added 2 mol/L aqueous sodium hydroxide solution (5 mL), and this resulting mixture was stirred at 50° C. for 30 minutes. After cooling to ambient temperature, 1 mol/L hydrochloric acid (10 mL) was added to this mixture, and the precipitated solid was collected by filtration. This solid was washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (0.026 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25]([OH:27])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]2[CH:43]=[CH:44][C:45]([NH:48][C:25]([C:23]3[CH:22]=[CH:21][C:19]4[NH:20][C:16]([C:3]5[CH:4]=[C:5]([C:8]6[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=6)[CH:6]=[CH:7][C:2]=5[OH:1])=[N:17][C:18]=4[CH:24]=3)=[O:27])=[CH:46][CH:47]=2)[CH2:36][CH2:35]1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Reactant: Nc1ccc(CCN2CCN(c3ccccn3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)Nc4ccc(CCN5CCN(c6ccccn6)CC5)cc4)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 4-[2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-phenylamine (28.2 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.6 mg, 39%). 1H NMR (MeOH-d4) δ 3.10-4.01 (12H), 3.98 (s, 3H), 6.87 (m, 1H), 7.04-7.12 (2H), 7.21 (d, J=9 Hz, 1H), 7.36 (d, J=6 Hz, 2H), 7.72-7.83 (5H), 7.89 (d, J=6 Hz, 1H), 8.09 (d, J=6 Hz, 1H), 8.17 (t, J=3 Hz, 2H), 8.26 (s, 1H), 8.37 (s, 1H). ESI-MS m/z 626.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32](Br)[CH:33]=[CH2:34].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:34]([C@@H:12]1[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]1=[O:14])[CH:33]=[CH2:32]
Reactant: CC[C@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1.45 g (3.14 mmol) of tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mL of THF was added dropwise at −78° C. 3.3 mL of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (3.3 mmol). After being stirred at −78° C. for 3 h, the reaction was quenched with sat. aqueous NH4Cl solution, extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (50 g SiO2, eluent: 5 to 20% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate as the faster eluting major isomer.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][C:14]=1[Cl:25])OC1C=CC=CC=1)#[N:2].[NH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].ClCCl>C(O)(C)C>[Cl:25][C:14]1[CH:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:27]=1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1Cl)Oc1ccccc1
Reactant: NNc1ccccn1
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2Cl)nn1-c1ccccn1
Temperature: 115 °C
Yield: 76.8 %

Procedure:
A mixture of N-cyano-N′-(2-chloro-4-morpholino-phenyl)-O-phenylisourea (0.10 g, 0.28 mmol) and 2-hydrazinopyridine (0.046 g, 0.42 mmol) in iso-propanol (3 mL) was heated at 115° C. for 20 h. The precipitate was filtered, washed with iso-propanol and purified by flash chromatography (SiO2) eluted with 2:98 methanol: dichloromethane to provide the title compound (0.080 g, 79% yield) as a white solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[N:38]O)[NH2:37]>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[N:38]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:37]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3Cl)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 56 mg (52% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]1([CH3:22])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[NH2:21]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:22])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.25 g (12.5 mmol) of 3-nitrophenylisothiocyanate and 1.4 mL (10 mmol) of mesityl amine in 10 mL of methanol was stirred at room temperature for 2 h. The resulting precipitate was collected by filtration and dried to give a quantitative yield of 1-(3-nitrophenyl)-3-(mesityl)thiourea. To 1.8 g (5.7 mmol) of the thiourea thus prepared slurried in 20 mL of CCl4 was added 0.35 mL (6.9 mmol) of bromine. The mixture was heated at reflux for 4 h, allowed to cool to room temperature and diluted with dichloromethane. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude title compound was obtained in quantitative yield and was used without further purification.