Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][OH:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>>[C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:18])[CH3:17]
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A 250 mL Erlenmeyer flask was charged with 9-fluorenemethanol (30.0 g, 153 mmol, Aldrich), sodium acetate (15.0 g, 183 mmol, Aldrich), and acetic anhydride (0.150 L, 1580 mmol, Aldrich). The reaction mixture was heated over a steam bath, under continuous stirring for 4 hours. The warm mixture was poured into ice (150 g). After reaching room temperature, the solid product was isolated by filtration and washed with cold water. The dried product was used without further purification (35.7 g, 150 mmol, 98% yield, >99% purity by GC).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:42])([F:41])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23]>CC(C)=O>[F:9][C:10]([F:41])([F:42])[C:11]1[CH:12]=[C:13]([CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=1)[CH2:14][O:15][CH2:16][C:17]([OH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH3:1])[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(NCCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(CCC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1)C(=O)C(F)(F)F
Temperature: 60 °C

Procedure:
Excess amount of potassium carbonate (150 mg, 1.1 mmol) and excess amount of methyl iodide (0.040 ml, 0.064 mmol) were mixed with N-(4-(3,5-bis(trifluoromethyl)benzyloxy)-3-hydroxy-3-phenylbutyl)-2,2,2-trifluoroacetamide (15 mg, 0.030 mmol) in acetone (2 ml). The reaction mixture was heated in microwave at 60° C. for 10 minutes. The salt precipitate was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired N-methylacetamide. 1H NMR (300 MHz, MeOH) δ ppm 7.84 (s, 3 H) 7.46–7.54 (m, 2 H) 7.35 (ddd, J=8.14, 6.50, 4.76 Hz, 2 H) 7.22–7.30 (m, 1 H) 4.61–4.73 (m, 2 H) 3.62–3.75 (m, 2 H) 3.40–3.55 (m, 1 H) 3.11–3.37 (m, 1 H) 3.01 (s, 2 H) 2.93 (s, 1 H) 2.15–2.31 (m, 2 H); LRMS [ESI, (MH+−H2O)] m/z calcd for C22H19NO2F9 500.13, found 499.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])[CH:7]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:16]2=[S:17])[CH:7]=1
Reactant: CCNCCCNc1cc(Cl)ccc1C
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Yield: 24.9 %

Procedure:
A solution of the diamine of Step A (7.1 g) in dioxane (250 mL) and 1,1′-thiocarbonyldiimidazole (5.6 g) was refluxed under nitrogen for 2.5 hrs. Following the addition of para-toluenesulfonic acid monohydrate (11.9 g), the reaction mixture was heated at reflux for 48 hrs. The reaction was cooled and filtered and the filtrate was concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane provided a brown solid which was triturated with diethyl ether to give the title product (2.1 g, 25.0%) as a white solid, m.p. 111-112° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].CCN(C(C)C)C(C)C.[CH:44]1([N:50]=[C:51]=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[C:51]([NH:50][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:52])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a suspension of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate hydrochloride (500 mg, 1.05 mol) in anhydrous DCM (10 ml) was added DIEA (0.2 mL, 1.18 mmol) and cyclohexyl isocyanate (Aldrich, 0.28 mL, 2.20 mmol). The reaction mixture was stirred at rt for 15 hrs. Then PS-trisamine resin (670 mg, Novabiochem, 3.5 mmol/g) was added and the resulting mixture was stirred at rt for 5 additional hrs. The resin was removed by filtration, washed with DCM and the solvent was evaporated off under reduced pressure. Purification by flash chromatography on silicagel (c-Hex/EtOAc (2/1)) gave 500 mg (84%) of the title compound as a pale yellow oil. HPLC, Rt: 5.9 min (purity: 100%). LC/MS, M+(ESI): 567.4. 1H NMR (DMSO-d6) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.18 (d, J=7.6 Hz, 1H), 4.76 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.68 (s, 3H), 3.48 (m, 1H), 2.60 (t, J=7.5 Hz, 2H), 1.75-1.01 (m, 14H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:53]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:53]([N:60]1[CH2:65][CH2:64][N:63]([C:21]([C:20]2[CH:19]=[CH:18][C:17]([O:16][C:13]3[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:26]=[CH:27][C:3]([C:2]([F:28])([F:29])[F:1])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:25][CH:24]=2)=[O:23])[CH2:62][CH2:61]1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(O)c1ccc(Oc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cn2)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(4-trifluoromethyl-benzoylamino)pyridin-2-yloxy]benzoic acid (1.19 g, 2.3 mmol) in DMF (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.8 mmol), 1-hydroxybenzotriazole monohydrate (370 mg, 2.7 mmol) and benzylpiperazine (0.475 mL, 2.7 mmol) under ice cooling. The resulting solution was stirred for 1 day gradually warming up to room temperature. To the residue was added a saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), to thereby yield 800 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[N:62]1([C:68]2[CH:69]=[C:70]([CH2:74][NH2:75])[CH:71]=[CH:72][CH:73]=2)[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.[OH-]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([CH2:15][NH:75][CH2:74][C:70]3[CH:71]=[CH:72][CH:73]=[C:68]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)[CH:69]=3)[CH:13]=2)=[CH:4][N:3]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Reactant: NCc1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(CNCc3cccc(N4CCOCC4)c3)c2)cnc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.9 %

Procedure:
A solution of 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (0.081 g, 0.30 mmol), HOBt (0.048 g, 0.36 mmol) and HBTU (0.17 g, 0.45 mmol) in DMF (1.0 mL) was stirred at r.t. for 10 min. A solution of [(3-morpholin-4-ylphenyl)methyl]amine trifluoroacetate (0.13 g, 0.30 mmol) in DMF (1.0 mL) was added and the resulting solution was stirred for 12 h at r.t. The solution was concentrated in vacuo and the crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in EtOAc (100 mL) and washed with 1M NaOH(aq) (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Trituration and collection of a solid by vacuum filtration provided 11.6 mg (and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 14.1 mg (9% yield) of 3-amino-N-methyl-6-[3-({[(3-morpholin-4-ylphenyl)methyl]amino}methyl) phenyl]pyrazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 9.15 (t, 1H), 8.91 (s, 1H), 8.87 (m, 1H), 8.55 (s, 1H), 8.37 (d, 1H), 7.88 (d, 1H), 7.57 (t, 1H), 7.19 (t, 1H), 6.95 (s, 1H), 6.82 (m, 2H), 4.48 (d, 2H), 3.72 (t, 4H), 3.08 (t, 2H), 2.85 (d, 3H); MS (EI) for C24H26N6O3: 447 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Product: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([NH:28][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)NCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
The title compound was prepared based on a modified procedure of Shih and Rankin [Synthetic Communications, 1996, 26(4), 833-836]: To a mixture of cyclopropane-1,1-dicarboxylic acid (5.0 g, 38.4 mmol, 1.0 eq.) in anhydrous THF (50 mL) under nitrogen was added dropwise triethylamine (3.89 g, 38.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C., followed by the addition of thionyl chloride (4.57 g, 38.4 mmol, 1.0 eq.) with stirring for another 30 minutes at 0° C. To the resulting mixture under nitrogen was added dropwise a solution of benzylamine 5 (4.53 g, 42.3 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for 1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetate and extracted with 2N NaOH (to pH 10). The aqueous phase was titrated with 2N HCl to pH 1-2 and then extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated in vacuo to give 1-Benzylcarbamoyl-cyclopropanecarboxylic acid as a white solid (4.39 g, 52.15%). 1H NMR (400 MHz, CDCl3): 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.32-7.26 (m, 3H), 1.82-1.70 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2[Cl:21])[CH:10]=1)=[O:4].O.[OH-].[Na+]>O1CCOCC1>[Cl:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=1[C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7][C:8]=1[O:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cnc(OC2CCCC2)c(-c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-(2-Chloro-5-trifluoromethyl-phenyl)-6-cyclopentyloxy-3-pyridinecarboxylic acid methyl ester (0.27 g, 0.7 mmol) was dissolved in dioxane (6 mL). Water (6 mL) and sodium hydroxide solution (2 mL, 2N) was added and the mixture was boiled with stirring for 2.5 h, cooled to room temperature and partitioned between diethyl ether and hydrochloric acid (1N). Organic phases were pooled, dried with Na2SO4 and the solvent was evaporated. The residue, 0.27 g of the title compound as a orange-yellow solid was introduced into the next step without purification, MS (ISP) 386.5 (M+H)+.
Reaction SMILES: [Li].N.[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>O.CCOCC>[CH2:3]([OH:6])[C:4]#[C:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCO
Reactant: CCCCCBr
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CCCCCC#CCO
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a small amount of lithium pieces was added to liquid ammonia (250 ml). The reaction mixture became dark blue in color. A catalytic amount of ferric nitrate nonahydrate was added and the mixture was stirred until the dark blue color disappeared. Lithium pieces (2.75 g, 396 mmol) were further added and the reaction mixture was stirred for one hour. Subsequently, propargyl alcohol (8.16 g, 146 mmol) was added and the mixture was stirred for 30 minutes. Then, n-pentyl bromide (20 g, 132 mmol) was added, and the mixture was stirred for 10 minutes and allowed to stand overnight at room temperature. Water-containing ether (50 ml) and water (200 ml) were added and the resulting mixture was extracted with ether (200 ml, 100 ml, 50 ml×3). The organic layers were combined, washed with water (400 ml) and with brine (400 ml), dried over anhydrous sodium sulfate (50 g) to concentrate. The residue was distilled (b.p.=58°-61° C. at 0.3 mmHg), yielding a colorless oil, 2-octyne-1-ol (9.5758 g, 52% yield). The above described structure of this product was confirmed by the following data.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br.[F:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]([CH2:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)[C:26]2=[NH:43])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:39][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:27]4[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[N:25]([CH2:24][CH2:23][CH2:22][O:21][C:20]5[CH:19]=[CH:18][C:17]([F:16])=[CH:45][CH:44]=5)[C:26]4=[NH:43])=[CH:42][CH:41]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(C=O)cc1
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1ccc(CN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a solution of 1-(4-chloro-benzyl)-piperazine (70 mg, 0.33 mmol) in THF (10 ml) was added 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde, hydrobromide salt (0.20 g, 0.41 mmol), sodium cyanoborohydride (31 mg, 0.49 mmol), H2O (1 drop) and glacial acetic acid (0.068 ml). The reaction was warmed to 55° C. where it was maintained for 6 h. After this time, the mixture was cooled to rt and stirred for 16 h. The mixture was concentrated under reduced pressure and then partitioned between 1N HCl and EtOAc. The organic layer was removed and the aqueous phase was made basic using 10% K2CO3. The basic aqueous phase was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with MeOH/dichloromethane provided 1-{4-[4-(4-chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (23 mg, 11%). HPLC-MS 598 [M+1]+, 300.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.O.NN>C1COCC1>[CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (5.22 g, 11 mmol) in dry THF (130 mL) was added hydrazine hydrate (2.63 mL, 54 mmol). The reaction mixture was stirred at room temperature for 6 h, then insolubles were removed by filtration and washed with ethyl acetate. The filtrates were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (2×100 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as an orange solid [3.56 g, yield 89%; HPLC/MS: m/z=353 (M+H); logP(HCOOH)=1.19].
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:25]([O-:30])([N+]([O-])=O)=[O:26].C(O)(=O)C>ClCCl>[N+:25]([C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:24][C:11]=2[C:12]=1[C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1)([O-:30])=[O:26]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc(-c2coc3ccc(-c4ccccc4)cc23)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c([N+](=O)[O-])oc3ccc(-c4ccccc4)cc23)cc1

Procedure:
A mixture of 3.2 g. of the product of step D, 2 g. of dinitrogen tetraoxide, 1 ml. of acetic acid and 200 ml. of dichloromethane is stirred at 20° C. for 16 hours, washed with water and evaporated. The residue is treated with cold 5 percent sodium hydroxide solution, then acidified with 6N hydrochloric acid. The solid residue is separated and recrystallized from N,N-dimethylformamide to provide 4-(2-nitro-5-phenylbenzofuran-3-yl)benzoic acid, m.p. 235°-249° C.
Reaction SMILES: [I:1]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39](O)[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.CCCCCC>[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39]([I:1])[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(O)C1(F)F)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(I)C1(F)F)c1ccccc1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
I2 (0.524 g) and dichloromethane (8 mL) were charged into a round bottom flask in the dark. To this solution was added dropwise a solution of Ph3P (0.634 g) in dichloromethane (8 mL) at ambient temperature. The resulting suspension was stirred at this temperature for 30 minutes and imidazole (0.734 g) was added. After the resulting suspension was stirred for 5 minutes at room temperature, a solution of lactol 8 (0.8 g) in dichloromethane (8 mL) was added dropwise and the resulting solution was stirred overnight at room temperature. Hexane (30 mL) was added and then the suspension was stirred for 10 minutes, filtered, and concentrated to give 1.1 g of (2R,3R)-4,4-difluoro-5-iodo-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 10.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:15][CH2:14][N:13]1[S:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:40]3[C:35](=[C:36]([F:44])[C:37]([F:43])=[C:38]([F:42])[C:39]=3[F:41])[NH:34][CH:33]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])=[O:11])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:15][CH2:14][N:13]1[S:23]([N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[C:40]3[C:35](=[C:36]([F:44])[C:37]([F:43])=[C:38]([F:42])[C:39]=3[F:41])[NH:34][CH:33]=2)[CH2:30][CH2:31]1)(=[O:24])=[O:25])=[O:11]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4c(F)c(F)c(F)c(F)c34)CC2)[C@@H](C(=O)NO)C1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
A solution of N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (8.90 g, 13.97 mmol) [prepared as described in Step 6 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (470 ml) was treated with 10% Pd/C (3.5 g) and stirred under a hydrogen atmosphere (1 atm) for 45 min. The reaction was degassed under argon, filtered through Celite, and the filtrate was concentrated in vacuo. Ethyl acetate (5 ml) was added and the solution was added dropwise to hexane (250 ml) with vigorous stirring. The solid was filtered to afford N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (96%) as a white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.C(Cl)(Cl)Cl.N>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: COC(=O)c1cccc2nc(-c3cccnc3N)oc12
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
1-bromopyrrolidine-2,5-dione (233 mg) was added to a stirred solution of methyl 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carboxylate (335 mg) dissolved in tetrahydrofuran (10 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the mixture was washed with water and dried over phosphorus pentoxide under reduce pressure to afford a brown solid. The mixture was adsorbed on silica gel with chloroform and methanolic ammonia (7N). The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carboxylate (405 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 3.99 (s, 3H), 7.56 (dd, 1H), 7.85 (bs, 2H), 7.97 (d, 1H), 8.12 (d, 1H), 8.29 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+ 348-350.