Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[O:18]1[C@H:20]2[CH2:21][C:22]3[C:27]([C@@H:19]12)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>C(O)C.O>[OH:18][C@H:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]1[O:16][C:7]1[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=[C:5]([C:3]([N:2]([CH3:1])[CH3:17])=[O:4])[CH:6]=1
Reactant: c1ccc2c(c1)C[C@@H]1O[C@H]21
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cn2c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c(O[C@H]3c4ccccc4C[C@@H]3O)cc(C(=O)N(C)C)cn2c1C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of 1.5 g (6.4 mmol) 6-(N,N-dimethylamino-carbonyl)-8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine in 30 ml ethanol and 7.5 ml water are added 1.7 g (12.9 mmol) (1R,2S)-epoxyindane and 1.8 ml triethylamine. After 3 h at 70° C., the mixture is cooled down and partitioned between dichloro-methane and water. The organic layer is separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from diisopropyl ether yields 1.7 g (74%) of the title compound as a colourless solid (m.p. 122° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C1CC(C)(C)CC(C)(C)C1
Yield: 47.2 %

Procedure:
The mixture of 3,3,5,5-tetramethylcyclohexanone (2-13) (2.64g, 17 mmol), ethyl cyanoacetate (1.93, 17 mmol), acetic acid (0.2 ml) and ammonium acetate (0.2 g) in benzene (6.4 ml) was refluxed with a Dean-Stark aparatus for 10 h. To this benzene (30 ml) and saline (30 ml) was added, organic layer separated, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography, eluting with hexane to give 2.0 g (50%) of (16) as an oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@@H:9]([C:14]([NH:33][C@H:32]([C:31]([O:30][CH3:29])=[O:35])[CH3:34])=[O:16])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COC(=O)[C@H](C)N
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
Boc-(D)-methionine (50.0 g) is dissolved in dichloromethane (200 ml) and 1-hydroxybenzo-triazole hydrate (29.7 g) and (L)-alanine methyl ester hydrochloride (31.0 g) is added. The mixture is cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.0 g) is added in portions, maintaining the temperature of the mixture at 0-5° C. N-Methylmorpholine (42.2 g) is then added over 30 minutes, maintaining the temperature of the mixture at 0-5° C. The mixture is then stirred at 0° C. for 5 hours. The reaction mixture is washed successively with water (2×100 ml), 10% aqueous citric acid solution (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and evaporated to dryness at 40° C. under reduced pressure to give Boc-(D)-Met-(L)-Ala-OMe (67.0 g estimated to contain 0.17 mol) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][O:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
3-hydroxy-4-methoxybenzaldehyde (15 g, 98.6 mmol) was dissolved in acetonitrile (200 mL). 1-Methoxy-3-bromopropane (16.6 g, 108 mmol) and potassium carbonate (34 g, 247 mmol) were added and the mixture was brought to reflux and stirred for 3 hrs. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 22 g (quantitative yield) of the desired product as a yellow oil, used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[ClH:14].[CH2:15]([OH:17])C>CO>[ClH:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12](=[NH:13])[O:17][CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1cccc(C2(C#N)CC2)c1
Agent: Cl
Solvent: CO
Product: COC(=N)C1(c2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
1-(3-Methoxyphenyl)cyclopropanecarbonitrile (56 mg, 0.32 mmol) was dissolved into a saturated solution of hydrogen chloride in ethanol (1 mL). The reaction mixture was stored in the refrigerator (4° C.) for three days. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in ethanol (0.5 mL) and silica sulfuric acid (125 mg), prepared by following the literature (Tetrahedron, 2001, 57, 9509-9511), was added. The reaction mixture was stirred at room temperature for 2 h. The silica was filtered off and the filtrate was cooled to 0° C. and gaseous hydrogen chloride was bubbled through the solution for 30 seconds. The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure to give an oil. The oil was dissolved into a solution of hydrogen chloride in methanol (1.25 M, 1 mL). Gaseous hydrochloric acid was bubbled into the solution and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as an oil (40 mg, 51%). The material was used without further purification.
Reaction SMILES: CC[C@@H]([C@H](NC([C@@H](NC(CNC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@H]1NC(=O)[C@H]([C@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@@H](NC([C@@H](N)CCCCN)=O)CSSC1)=O)C)=O)[C@H](O)C)=O)CCC(N)=O)=O)CCCNC(N)=N)=O)CC(C)C)=O)C)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)CC(C)C)=O)C(C)C)=O)CC1NC=NC=1)=O)CO)=O)CO)=O)CC(N)=O)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)=O)C)=O)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H:76]([C:85]([OH:87])=[O:86])[CH2:77]C1C=CC(O)=CC=1)=O)[C@H](O)C)=O)CC(N)=O)=O)CO)=O)=O)C(C)C)=O)CC(N)=O)=O)[C@H](O)C)=O)CO)=O)CO)=O)CC(C)C)=O)C.[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277]>>[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277].[C:85]([O-:87])(=[O:86])[CH:76]([CH3:77])[OH:274]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)[C@@H](C)O)C(C)C)[C@@H](C)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)[O-]

Procedure:
At t=-30, vehicle, or amylin ± AC-0253 was begun. Amylin dose rates were 50, 100 and 300 pmol/kg/min. Dose rates of AC-0253 were 500 and 1500 pmol/kg/min. 25% glucose (1 gm/kg) was administered by mouth at t=0 minutes. Amylin ± AC-0253 was discontinued at t=120 minutes. Samples for insulin, glucose and lactate were obtained at 15 minute intervals from t=-45 to t=180 minutes. Samples for rat amylin and AC-0253 were taken at t=60 and 120 minutes.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15].C(=O)([O-])O.[K+]>CC(C)=O.O>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(I)cc1)OC

Procedure:
A solution of 4-iodobenzoyl chloride (100 g, 375.6 mmol) in 300 mL of acetone was added to a solution of aminoacetaldehyde dimethylacetal (41.4 g, 1.05 equiv.) and potassium hydrogen carbonate (39.5 g, 1.05 equiv.) in 270 mL of acetone and 450 mL of water. After completion of the reaction, acetone was removed under reduced pressure at no more than 35° C. to induce crystallization. The crystal slurry was filtered, washed and dried in vacuo at <50° C., to give 120 g (95 M %, HPLC area % 96) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.S(Cl)(Cl)=O.C[N:16](C=O)C.[OH-].[NH4+]>C(Cl)Cl>[CH3:1][C:2]1([C:8]([NH2:16])=[O:10])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CC1(C(=O)O)CC=CCC1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C(N)=O)CC=CCC1
Reaction time: 8 h

Procedure:
To a solution of 1-methylcyclohex-3-ene-1-carboxylic acid, 52a, (54.0 g, 385.2 mmol) dissolved in CH2Cl2 (200 mL) was added thionyl chloride (56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to reflux for 3 hrs, then cooled and concentrated in vacuo. The residue was redissolved in 200 mL of CH2Cl2. To the reaction was added ammonium hydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction was stirred overnight. The reaction was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc), yielding 25 g of 1-methylcyclohex-3-ene-1-carboxamide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:69][NH:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([N:70]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)[CH3:69])=[O:14]
Reactant: CNC1CCCCC1
Reactant: O=C(O)c1cc(Br)cc(OCCNc2ccncc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1cc(Br)cc(OCCNc2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-bromo-5[-2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.034 g), TBTU (0.048 g) and HOBt (0.014 g) in DMF (0.3 ml) was added DIPEA (0.026 ml) followed by N-methylcyclohexylamine (0.020 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.005 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2[C:12]([OH:16])=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1.CS(O[CH:22]1[CH2:25][N:24]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.O>[CH:26]([N:24]1[CH2:25][CH:22]([O:16][C:12]2[C:11]3[O:7][CH:8]=[CH:9][C:10]=3[CH:15]=[CH:14][CH:13]=2)[CH2:23]1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1cccc2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(Oc3cccc4ccoc34)C2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (348 mg, 2.52 mmol) and benzofuran-7-ol (169 mg, 1.26 mmol) were successively added to a solution of 1-benzhydrylazetidin-3-yl methanesulfonate (400 mg, 1.26 mmol) in DMF (8 mL). The reaction mixture was stirred overnight at 90° C. and then diluted by addition of ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (5×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/dichloromethane (1:0 to 2:8 to 0:1) as eluent. The title product was obtained as a yellow oil (350 mg, 69%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:49])([F:48])[C:13]1[CH:14]=[C:15]([C:23]([CH3:47])([CH3:46])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:49][C:12]([F:11])([F:48])[C:13]1[CH:14]=[C:15]([C:23]([CH3:46])([CH3:47])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([NH:41][CH2:42][C:43](=[O:45])[CH3:44])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1
Reactant: CC(O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 457 mg (3.60 mmol) oxalyl chloride in 17 ml dichloromethane was added dropwise during 5 minutes at −75° C. a solution of 562 mg (7.20 mmol) dimethyl sulfoxide in 5 ml dichloromethane. After stirring for 5 minutes a solution of 1.72 g (3.00 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide in 5 ml dichloromethane was added dropwise at −65° C. Stirring was continued at −70° C. for 1 h, followed by addition of 2.6 ml (15 mmol) ethyldiisopropylamine. After stirring at room temperature for 3 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml water, 20 ml 1 N hydrochloric acid solution and 20 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 1.45 g (85%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:10]=1[O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:10]=1[O:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OC(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To the solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanone (0.14 g) in methanol (0.5 ml) and tetrahydrofuran (1.9 ml) was added at the 0° C. temperature sodium borohydride (6.5 mg). The reaction was stirred 15 minutes at 0° C. and 2 hrs at 22° C. temperature. After adding water (5 ml) methanol and tetrahydrofuran were evaporated off. After the residue was stirred at 22° C. 0.5 hr the product was filtered, washed with cold water and dried under reduced pressure. Yield is 0.09 g. 1H NMR (DMSO-d4) δ=4.05 (m, 2H), 4.91 (m, 1H), 4.95 (s, 2H), 5.01 (s, 2H), 5.59 (d, J=4.7 Hz, 1H), 6.47 (dd, J=2.8, 8.8 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 7.24-7.45 (m, 15H).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH:8][CH:9]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CS(C)=O>[C:1]([S:4][CH2:5][C:6]([NH:8][CH:9]([CH2:24][C:25]([OH:27])=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(=O)SCC(=O)NC(CC(=O)O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C

Procedure:
The product 26 was dissolved in 10 ml of dry DCM, cooled to 0° C., and treated with 9 ml trifluoroacetic acid (TFA). The reaction was then removed from the ice bath and allowed to warm to ambient temperature over a period of one hour. Solvent was removed under reduced pressure, and the residue redissoved twice in DCM and evaporated to remove residual TFA. The crude product 13 was purified by reverse-phase high-pressure liquid chromatography to yield 101.9 mg (0.234 mmol, 32% from 25) of white hygroscopic powder. Expected MW=436.37, found 437 (M+1). This was dissolved in dimethylsulfoxide (DMSO) to yield a 50 mM stock solution.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:37]1[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:44]=2[CH:35]([N:34]([CH2:17][C:9]2[NH:8][C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:20]3[N:19]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:45])=[CH:28][CH:29]=2)[CH2:36]1
Reactant: O=C(Nc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Nc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 47.6 %

Procedure:
N-BOC-chloromethylbenzimidazole (115 mg, 0.43 mmol), N-Pyridin-2-yl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9362) (155 mg, 0.43 mmol), and K2CO3 (179 mg, 1.29 mmol) were heated to reflux in CH3CN (3 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (2 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2), afforded AMD9370 (100 mg, 47%) as white foam. 1H NMR (CDCl3) δ 1.68-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.26-2.32 (m, 1H), 2.71-2.84 (m, 1H), 2.86-2.91 (m, 1H), 3.84 (s, 2H), 3.95 (d, 1H, J=16.5 Hz), 4.08-4.14 (m, 1H), 4.22 (d, 1H, J=16.0 Hz), 7.03-7.07 (m, 1H), 7.16-7.22 (m, 3H), 7.45 (d, 1H, J=6.9 Hz), 7.52-7.61 (m, 3H), 7.65 (d, 1H, J=7.5 Hz), 7.73 (ddd, 1H, J=1.8, 7.2, 8.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 8.27-8.29 (m, 1H), 8.33 (d 1H, J=8.4 Hz), 8.44 (br, s, 1H), 8.72-8.80 (m, 1H); 13C NMR (CDCl3) δ 21.72, 23.30, 29.56, 49.29, 54.16, 60.83, 111.39, 114.52, 120.17, 122.29, 122.81, 127.72, 129.28, 133.58, 135.17, 137.76, 138.77, 144.61, 147.38, 148.21, 152.00, 156.13, 157.54, 165.99; ES-MS m/z 489.2 (M+H); Anal. Calcd. for (C30 H28N6O)•0.6(H2O)•0.7(CHCl3): C, 63.25; H, 5.17; N, 14.42. Found: C, 63.56; H, 5.25; N, 14.31.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:5]#[N:6])[N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccccc1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
Trimethylsilyl cyanide (14.56 g, 19.6 ml, 0.147 moles) was added dropwise to a solution of 2-benzylpyridine-N-oxide (10.86 g, 0.059 moles) and triethylamine (8.91 g, 12.3 ml, 0.088 moles) in acetonitrile (40 ml) at 20° C. After complete addition the mixture was heated under reflux for 20 hours, cooled to room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulphate. Removal of the solvent gave an orange oil which was purified by column chromatography (silica gel eluted with hexane:ethyl acetate 9:1) to give 2-benzyl-6-cyanopyridine (1.84 g, 16%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)C(C)O
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Solvent: CN1CCCC1=O
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758 mg, 7.35 mmol) in 1-methyl-2-pyrrolidinone was heated in 130° C. oil bath for 24 hr. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a white crystal, mp 133-135° C.