Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)ccc1C#N
Product: Cc1nc(Cl)ccc1C#N
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A mixture of 131 (1.5 g, 11 mmol) and phosphorus oxychloride (9 mL, 0.1 mol) was heated at reflux for 6 h. The reaction mixture was cooled to room temperature, and the excess phosphorus oxychloride was removed under reduced pressure. Ice cold water (50 mL) was added to the residue. The brown precipitate was collected and washed with ice cold water (3×25 mL), ether (2×20 mL), and dried to provide 132 as a light-brown solid (0.9 g, 54%): mp 104-105° C. (lit. (Synthesis 1991, 894-896) mp 106-108° C.). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 2.77 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:35])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH2:26][O:27]CC3C=CC=CC=3)=[O:23])[CH:17]=2)=[C:8]([NH2:36])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.C1COCC1>[Pd].CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:35])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH2:26][OH:27])=[O:23])[CH:17]=2)=[C:8]([NH2:36])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)OCCOCc4ccccc4)c3)c2n1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)OCCO)c3)c2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 33.3 %

Procedure:
2-Butoxy-8-hydroxy-9-{3-(2-benzyloxyethoxycarbonyl)benzyl}adenine (0.03 g, 0.06 mmol) obtained by Example 5, 5% Pd/C (60 mg) and concentrated hydrochloric acid (0.1 ml) were added to a mixed solvent of THF (30 ml) and methanol (30 ml), and the mixture was stirred under hydrogen atmosphere at room temperature for 60 hours. The reaction mixture was filtered, neutralized with saturated sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) and washed with methanol to give the captioned compound (0.01 g, 0.02 mmol, yield: 42%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([C:19]([F:22])([F:21])[F:20])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C)C=O.O>[C:30]1([CH2:29][O:1][C:2]2[CH:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]([C:19]([F:22])([F:20])[F:21])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-hydroxy-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 51; 230 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (5 mL) and cesium carbonate (264 mg, 0.81 mmol) and benzyl bromide (0.12 ml, 1.01 mmol) were added. The mixture was heated at 40° C. for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer was separated and washed with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (1:1 cyclohexane/ethyl acetate-10% 7M NH3 in methanol/dichloromethane) gave the title compound as oil. 232 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=O)[C:5](=[CH:8][NH:9][CH3:10])[C:4]([CH3:12])([CH3:11])[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>COCCOC>[CH3:1][C:2]1([CH3:13])[C:6](=[S:23])[C:5](=[CH:8][NH:9][CH3:10])[C:4]([CH3:12])([CH3:11])[O:3]1
Reactant: CNC=C1C(=O)C(C)(C)OC1(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CNC=C1C(=S)C(C)(C)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 133.4 %

Procedure:
A mixture of dihydro-2,2,5,5-tetramethyl-4-methylaminomethylene-3(2H)furanone (3.2 g, 18 mmol) and Lawesson's Reagent (3.8 g, 9.4 mmol) in 40 mL of DME was stirred for 30 min. at room temperature. The solvents were evaporated from the homogeneous orange solution. The residue was taken up in a small volume of methylene chloride and eluted through a short column of 1/1 silica gel/basic alumina with methylene chloride. The solvent was evaporated to leave a yellow solid. Recrystallization from CH2Cl2 /hexanes gave 2.5 g of dihydro-2,2,5,5-tetramethyl-4-methylaminomethylene-3(2H)furanthione as an orange solid. An analytically pure sample was made by chromatographing a small amount on the Chromatotron (Silica 1/1 EtOAc/hexanes): mp 115°-117° C.; Anal. Calc'd for C10H17NOS: C, 60.30; H, 8.54; N, 7.04; S, 16.08. Found: C, 60.27; H, 8.62; N, 7.04; S, 16.15.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phthalic anhydride (17.8 g, 0.1 mole) is suspended in 100 ml. dry methylene chloride (previously distilled over anhydrous potassium carbonate). To the suspension is added anhydrous aluminum chloride (30.5 g, 0.23 mole) in one portion. The suspension quickly became bright yellow and is stirred at room temperature for 2 hours. A solution of p-dimethoxybenzene (27.6 g, 0.2 mole) in methylene chloride (100 ml) is added slowly to the vigorously stirred solution. The reaction mixture is stirred overnight at 25° and poured onto ice (300 g) and concentrated hydrochloric acid (50 ml). The slurry was stirred for 30 minutes and extracted with chloroform (4 × 150 ml). A white precipitate suspended in the aqueous layer is collected by filtration. The organic extract was washed once with water (200 ml) and washed with saturated sodium bicarbonate (4 × 150 ml). The aqueous bicarbonate extract is washed once with chloroform (150 ml) and acidified with concentrated hydrochloric acid, the mixture cooled on an ice bath and filtered. The residue is washed well with water and dried under reduced pressure and combined with the white precipitate to yield 2-(2' ,5'-dimethoxybenzoyl) benzoic acid (I) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N2CCSCC2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(N2CCSCC2)nc1
Temperature: 88 °C

Procedure:
2-(6-Thiomorpholinopyridin-3-yl)malonate 219-3 (564 mg, 1.67 mmol) was stirred with NaOH (334 mg, 8.35 mmol) in dioxane (5 ml) and water (5 ml) for 4 hours. HCl solution was added to adjust the pH around 1 and the reaction mixture heated at 88° C. for 1 hour. Then Na2CO3 was used to adjust the pH to around 4 before the solvents were evaporated. The residue was extracted with ethyl acetate and the organic extraction dried over Na2SO4 and concentrated by rotary evaporation. Purification with reverse phase HPLC afforded 2-(6-thiomorpholinopyridin-3-yl)acetic acid 219-4.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9](N)[N:10]=2)[CH:7]=1.BrC1C(C)=C(C2C=CC=C(C(F)(F)F)C=2)C([Cl:30])=NC=1>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([Cl:30])[N:10]=2)[CH:7]=1
Reactant: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(Br)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 356 mg, 0.959 mmol) using a similar method to that employed in Intermediate 14 (130 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[N:7][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:20]([C:26]([F:28])([F:27])[F:29])([C:22]([F:24])([F:23])[F:25])[OH:21])=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 13.4 %

Procedure:
5-(6-Bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (400.0 mg, 0.80 mmol) prepared in Step 4 of Preparation 20, 1-BOC-piperazine (222.4 mg, 1.19 mmol), Pd2(dba)3 (36.7 mg, 0.04 mmol), BINAP (49.8 mg, 0.08 mmol) and sodium t-butoxide (137.8 mg, 1.43 mmol) were added to toluene (20.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 65.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1)c1ccncc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Compound 186 (209 mg, 0.770 mmol) was dissolved in DMF (4 mL), and isonicotinic acid (190 mg, 1.54 mmol), EDC hydrochloride (296 mg, 1.54 mmol) and 1-hydroxybenzotriazole monohydrate (236 mg, 1.54 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, followed by reslurrying with ethanol to afford the entitled Compound 187 (211 mg, 72%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([C:21](N(OC)C)=[O:22])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>C1COCC1>[CH3:1][N:2]1[C:6]([C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:12](=[O:14])[CH3:13])[CH2:20][CH2:19]2)=[O:22])=[CH:5][N:4]=[N:3]1
Reactant: Cn1ccnn1
Reactant: CON(C)C(=O)C1CCN(C(C)=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)c2cnnn2C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1H-1,2,3-triazole (0.28 g, 3.37 mmol) in dry THF (3 mL) was cooled in a −78° C. bath and n-butyllithium (2.5 M in hexanes, 1.26 mL, 3.15 mmol) was added dropwise over a 20 minute period. The suspension was stirred in the cold bath for 30 minutes and then 1-acetyl-N-methoxy-N-methylpiperidine-4-carboxamide (0.74 g, 3.45 mmol, Intermediate 52: step a) dissolved in THF (3 mL) was added dropwise. The resulting suspension was stirred at −78° C. for 5 minutes then warmed to 0° C. and stirred for an additional 30 minutes. The mixture was warmed to room temperature and stirred for 2.5 hours then quenched with saturated aqueous NH4Cl. The aqueous mixture was extracted with EtOAc (2×). The combined EtOAc extracts were dried over Na2SO4, filtered, concentrated to dryness and chromatographed (EtOAc/DCM) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.O=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][N:8]([C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=4)[NH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:7]1
Reactant: Fc1cccc(OC2CNC2)c1
Reactant: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2[nH]cc([C@H]3CC[C@@H](N4CC(Oc5cccc(F)c5)C4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 0.170 g of 3-(3-fluoro-phenoxy)-azetidine in 10 mL of CH2Cl2 was added 0.180 g of 3-(4-oxo-cyclohexyl)-1H-indole-5-carbonitrile followed by 0.420 g of sodium triacetoxyborohydride. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH and the product was extracted with ether. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated. The product was filtered through 150 mL of silica gel using 50% ethyl acetate/hexane, 75% ethyl acetate/hexane and finally 100% ethyl acetate to give 0.095 g of the desired product: mp 187-190° C. 1H NMR (300 MHz, CDCl3) δ 1.51-1.65 (m, 2H), 1.69-1.75 (m, 4H), 1.77-1.90 (m, 2H), 2.45 (m, 1H), 2.90 (m, 1H), 3.03 (dd, 2H), 3.81 (dd, 2H), 4.77 (m, 1H), 6.53-6.59 (m, 2H), 6.66 (m, 1H), 7.13-7.22 (m, 2H), 7.39 (dd, 2H), 8.00 (s, 1H), 8.28 (s, 1H); MS (ES) m/z (relative intensity): 390 (M++H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[C:28][C:29](O)=[O:30]>ClCCl.CO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:29](=[O:30])[C:28]#[C:27][C:18]3[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:24])[F:26])=[CH:22][C:17]=3[Cl:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(OCCn2cccn2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCn2cccn2)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-(2-pyrazol-1-ylethoxy)phenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 56 mg (43% of theory); melting point: 120° C.-125° C.; C21H15ClF3N3O2 (M=433.82); calc.: molecular ion peak (M+H)+: 434/436; found: molecular ion peak (M+H)+: 434/436; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=2[CH:14]=1)([O-])=O.CCN(CC)CC.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O.[Pd]>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:4]2[CH:5]=[CH:6][C:7]3[CH2:12][CH2:11][O:10][B:9]([OH:13])[C:8]=3[CH:14]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)B(O)OCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OCC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (694.6 mg, 3.6 mmol) in THF (70 mL) was passed through H-cube equipped with a 10% Pd/C cartridge. The collected light yellow solution was treated with Et3N (0.6 mL, 4.3 mmol, 1.2 eq.) and divided evenly into 12 portions. To a portion of the solution was added 4-chloro-benzenesulfonyl chloride (63.3 mg, 0.29 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with EtOAc (20 mL), washed with 1N HCl (10 mL), H2O (10 mL), brine (10 mL) and concentrated under reduced pressure. The residue was dissolved in minimal amount of THF and then titrated with heptanes to vive a white suspension. The precipitate was collected by filtration, washed with heptanes to give the title compound as a white solid. LCMS (M/Z): 338 (M+H); 1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 8.39 (s, 1H), 7.65-7.70 (m, 2H), 7.56-7.61 (m, 2H), 7.32 (d, J=1.8 Hz, 1H), 7.02-7.08 (m, 2H), 3.96 (t, J=5.9 Hz, 2H), 2.72 (t, J=5.9 Hz, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:27]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:25][CH2:26]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.5 parts of 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 1-{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 218° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[C:32]([Cl:39])[CH:31]=1)=[O:28].O>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:25]=4[CH3:24])=[CH:31][C:32]=3[Cl:39])=[O:35])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.30 g of N,N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.45 g of [4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous after 5 minutes and is stirred at room temperature for 18 hours. Water is added and the separated organic layer washed with saturated sodium bicarbonate, dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. The methylene chloride is removed in vacuo to give 4.60 g of the desired product as a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 191°-195° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][C@H:19]1[CH2:28][OH:29])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][C@H:19]1[CH:28]=[O:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.5 %

Procedure:
A solution of dimethyl sulfoxide (4.2 ml, 59.3 mM) in anhydrous methylene chloride(20 ml) was added dropwise into a solution of oxalyl chloride (3.5 ml, 40.3 mM) in anhydrous methylene chloride (100 ml) at −70 ° C. in a nitrogen gas stream and the mixture was stirred for 20 minutes. A solution of (2S,4R)-N-tert-butoxycarbonyl-4-methanesulfonyloxy-2-hydorxymethylpyrrolidine (7 g, 23.7 mM) in anhydrous methylene chloride (20 ml) was added dropwise and the mixture was further stirred for 20 minutes. After adding dropwise triethylamine (11.6 ml, 83.0 mM) thereto, the mixture was warmed up to room temperature. The reaction mixture was poured into water and the organic layer was washed with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium carbonate and brine in this order and dried over anhydrous magnesium sulfate. After removing the solvent, the resulting solid matter was washed with hexane to give the title compound (6.5 g, 93%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C:14]=3[C@@H:13]1[CH2:12][CH2:11][CH:10]2[OH:28].N.[Li].[NH4+].[Cl-]>NC1C=CC=CC=1.C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C@@H:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C@H:14]3[C@@H:13]1[CH2:12][CH2:11][CH:10]2[OH:28]
Reactant: COCCOCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: COCCOCCC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2O
Temperature: -20 °C

Procedure:
A solution of 51 (46.9 g, 0.12 mol) in aniline (250 mL) and dry THF (2 L) was added to ammonia (800 mL). Lithium metal (4.9 g, 0.72 mol) was added in pieces, and the blue mixture was stirred at −20° C. At −78° C., a solution of saturated aqueous NH4Cl was added upon depletion of lithium and the ammonia was allowed to evaporate. The solution was extracted with ethyl acetate (3×500 mL), water (500 mL), and brine. The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo, and the product 52 was purified by column chromatography on SiO2 (hexanes to hexanes-acetone/8-3) to provide 48.3 g (82%, over three steps from 49). 1H NMR (400 MHz, acetone-d6) δ 1.11-2.36 (m, 14H), 2.85 (m, 2H), 3.25-4.00 (m, 15H), 4.63 (m, 2H), 6.63 (m, 1H), 6.69 (m, 1H), 7.20 (d, J=8.6 Hz, 1H) ppm.