Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH3:29])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:31][O:32][CH3:33]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:28][CH3:29])[CH2:31][O:32][CH3:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(COC)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Solid potassium-t-butoxide (0.27 g, 2.5 mmol) is added at room temperature to a solution of (3-chloro-phenyl)-[4-(2-ethylamino-pyridin-4-yl)-pyrimidin-2-yl]-amine (0.5 g,1.5 mmol) in dry tetrahydrofurane (15 ml). The resulting solution is cooled to 0° C. and chloromethylmethylether (0.16 g, 2.0 mmol) is added at such a rate that the temperature does not exceed 5° C. After stirring the mixture for 2 hours at room temperature, the solvent is evaporated under reduced pressure and the product is purified by chromatography. The product is obtained in form of slightly yellow crystals, m.p. 114–115° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:2]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1cc(C2CCCN2)cs1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccsc1

Procedure:
The title compound, white solid, m.p. 135° C. and MS: m/e=312.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-3-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH2:2][C:3]#[CH:4].[CH3:13][C:14]1([CH3:37])[O:19][C:18]2[CH:20]=[CH:21][C:22]([C@@H:24]([OH:36])[CH2:25][NH:26][C@@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][OH:29])=[CH:23][C:17]=2[CH2:16][O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:26]([C@@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])[CH2:25][C@@H:24]([C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:14]([CH3:13])([CH3:37])[O:15][CH2:16][C:17]=2[CH:23]=1)[OH:36])[CH2:2][C:3]#[CH:4]
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Reactant: C#CCCOCCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C#CCCOCCCCCCN(C[C@H](O)c1ccc2c(c1)COC(C)(C)O2)[C@H](CO)c1ccccc1
Reaction time: 48 h
Yield: 79 %

Procedure:
A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol (710 mg) (WO/0196278) in chloroform (10 ml) was treated at 20° C. with sodium triacetoxyborohydride (866 mg) and stirred under nitrogen for 2 days. The mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated and washed with sodium bicarbonate solution, brine, dried and purified on a silica Bond Elut cartridge (log) eluting with dichloromethane, diethyl ether and finally ethyl acetate to give the title compound (810 mg): LCMS RT=2.69 min, ES+ve m/z 496 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[CH3:11][S:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A cooled solution of 4′-aminoacetophenon (10 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (15 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes to afford 4′-(Methylsulfonylamino)acetophenone (13-5, LJO-298).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[O:18][CH3:19].[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:19][O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[C:27]#[C:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc([N+](=O)[O-])ccc1I
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a mixture of triethylamine (60 mL) and tetrahydrofuran (20 mL) were added 1-iodo-2-methoxy-4-nitrobenzene (10 g, 35.8 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.503 g, 0.717 mmol). Phenylacetylene (4.48 g, 43.0 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture and the mixture was stirred for 5 minutes. Copper iodide (0.068 g, 0.358 mmol) was added, and the reaction mixture was stirred and purged with nitrogen for 10 minutes. The reaction flask was sealed and stirred for 2 hours at room temperature. The reaction mixture was treated with 200 mL of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo leaving a solid. The crude solid was recrystallized from absolute ethanol. The solid was collected by filtration and washed with cold ethanol and dried in vacuo to give the title compound as a tan solid (8.87 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]=1.C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:22][N:21]=[N:20][N:8]=2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1ccc(-c2cc(Cl)sc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2cc(Cl)sc2-c2nnn[nH]2)cc1
Reaction time: 72 h
Yield: 265.8 %

Procedure:
A mixture of 5-chloro-3-(4-methylphenyl)thiophene-2-carbonitrile (4.67 g), trimethyltin azide (12.3 g) and xylene (100 ml) was heated under reflux for 15 hours. After standing for 3 days at ambient temperature, the precipitate was collected by vacuum filtration to give 5-chloro-3-(4-methylphenyl)-2-(1H-tetrazol-5-yl)thiophene (14.7 g) as a yellowish powder. This powder was treated with trityl chloride (6.7 g) and 10N aqueous sodium hydroxide (2.4 ml) in dichloromethane (59 ml), and tetrahydrofuran (10 ml) at ambient temperature for 20 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The solvents were evaporated in vacuo to give a residue which was purified by silica gel column chromatography to afford 5-chloro-3-(4-methylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)thiophene (10.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1>CS(C)=O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (300 mg, 1.97 mmol) in DMSO (7.5 mL) was added potassium carbonate (545 mg, 3.94 mmol) the resulting suspension was stirred under nitrogen at room temperature for 10 minutes. 4-(Bromomethyl)-1,2-dichlorobenzene was then added (commercial, 473 mg, 1.32 mmol) and the reaction mixture heated to 90° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and water (40 mL). The organic layer was washed with water (2×40 mL), dried over magnesium sulphate and evaporated in vacuo to yield the title compound as a solid (530 mg, 86%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][C:31]([O:33]CC)=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][C:31]([OH:33])=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)C[C@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@@H]2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 74 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R)-2-(ethoxycarbonylmethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 74%; Rf value: 0.32 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C23H22Cl2N4O4 (489.357); mass spectrum: (M+H)+=489/491/493 (chlorine isotope).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=3)[C:23]([OH:25])=O)[CH:16]=1)[CH2:11]2.[CH3:29][CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:29][CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]1[C:23]([C:22]1[CH:26]=[CH:27][N:28]=[C:20]([NH:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C:3]2([C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:10][C:2]2=[O:1])[CH2:18]3)[CH:21]=1)=[O:25]
Reactant: O=C(O)c1ccnc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1
Reactant: CC1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1C(=O)c1ccnc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1

Procedure:
150 mg (0.40 mmol) 2-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)isonicotinic acid, 55 μL (0.42 mmol) 2-methylindoline, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:12]>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:12])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Add sodium hydride (5.91 g, 147.8 mmol) to a rapidly stirred solution of 2-bromo-3-pyridinol in DMF (anhydrous, 200 mL). After 30 minutes, add iodomethane (9.2 mL, 147.8 mmol) and stir under N2 for 2.5 hours. Quench with water and concentrate. Partition residue between Et2O) and water, separate layers. Extract from aqueous layer with Et2O (×2), dry combined layers over MgSO4 and concentrate. Purify residue by flash chromatography on silica gel eluting with 0-25% EtOAc/hexanes to afford 2-bromo-3-methoxy-pyridine (21.0 g, 83%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)=[CH:26][C:25]=1[F:40])[CH2:22][OH:23]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH2:20][OH:19])[CH2:22][OH:23])=[C:25]([F:40])[CH:26]=2)=[O:32])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(C(CO)CO)c(F)c1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C(CO)CO)c(F)c2)n(-c2cccc(Cl)c2)n1
Yield: 88.1 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A153) (102 mg, 0.387 mmol, 1.0 eq) in MeCN (9 mL) was added TEA (0.2145 mL, 1.55 mmol, 4.0 eq) followed by phenyl 4-(1,3-dihydroxypropan-2-yl)-3-fluorophenylcarbamate (120 mg, 0.395 mmol, 1.02 eq) at RT and the mixture was stirred at reflux for 16 h. The solvent was evaporated and the crude product was purified by CC using EtOAc as eluent to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxypropan-2-yl)-3-fluorophenyl)urea (162 mg; 88%).
Reaction SMILES: [N:1]([C:4]1[C:5]([N+:17]([O-:19])=[O:18])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([OH:15])[C:8]([OH:16])=[N:7]2)=[N+]=[N-]>C1(C)C(C)=CC=CC=1>[Cl:14][C:13]1[C:4]2[C:5](=[N+:17]([O-:19])[O:18][N:1]=2)[C:6]2[N:7]=[C:8]([OH:16])[C:9]([OH:15])=[N:10][C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Solvent: Cc1ccccc1C
Product: [O-][n+]1onc2c(Cl)cc3nc(O)c(O)nc3c21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 1 g (3,5 mmol) 6-azido-7-chloro-2,3-dihydroxy-5-nitroquinoxaline and 15 ml xylene was refluxed for 3 h. After cooling to 25° C. the precipitate was filtered off and washed with toluene and ether to give 0,86 g (96%) 4-chloro-7,8-dihydroxy-1,2,5-oxadiazolo(3,4-f)quinoxaline-1-oxide, m.p.>300° C. NMR (DMSO-d6) 12.6 (1H, broad s), 12.0 (1H, broad s), 7.10 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][OH:12])[C:9]#[N:10])=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([O:17][CH3:18])=[O:16].[CH3:19]I>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11][O:12][CH3:19])[C:9]#[N:10])=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)NCc1cc(C(C#N)=NO)ccc1Cl
Reactant: CI
Solvent: CO
Product: CON=C(C#N)c1ccc(Cl)c(CNC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
0.36 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-hydroxyiminoacetonitrile and 0.54 g of a 28% sodium methylate methanol solution were added to 5 ml of methanol, and 0.49 g of methyl iodide was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was vacuum concentrated, the solvent was distilled off, water was added to the residue, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=4/1-5/1) to obtain 0.18 g of 2-[4-chloro-3-(methoxycarbonylaminomethyl)phenyl]-2-methoxyiminoacetonitrile as colorless crystals (m.p. 104-107° C.)
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21](CC)[CH2:22][CH3:23])[CH3:20].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:20]
Reactant: O=C(O)CCCCc1nnnn1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CCCCc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
5-(1-Phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (2.5 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at room temperature, and the mixture is stirred for 2 hours. After distilling off dimethylformamide under reduced pressure, acetone is added to the resulting residue, and the insoluble materials are filtered off. The mother liquor is concentrated and then purified by column chromatography (Kieselgel 60, made by Merck & Co.). By eluting with chloroform, there is obtained N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (1.2 g), colorless liquid, nD25 =1.5303.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[CH:7]=[C:6]([CH3:12])[N:5]=2.C(N(CC)C(C)C)(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:7]=[C:6]([CH3:12])[N:5]=2
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(-n2c(C)nc3c(N)cc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(C)c(-n2c(C)nc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine (0.8 g, 2.85 mmol), and N,N-diisopropylethylamine, (0.54 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.25 mL, 3.13 mmol). Heat the solution to reflux for 5 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1

Procedure:
Same procedure as above with Z-Trp-OH (2 g, 5.9 mmol), benzylamine (645 μL, 5.9 mmol), DCC (1.58 g, 7.65 mmol) and THF (88 mL). A white solid was obtained after precipitation in methanol/pentane (777 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 3.18 (dd, J=14.3 Hz, J=8.1 Hz, 1H, CH2), 3.39 (dd, J=14.3 Hz, J=4.9 Hz, 1H, CH2), 4.3 (m (AB), 2H, CH2 (Bn)), 4.53 (m, 1H, CHα), 5.11 (s, 2H, CH2 (Z)), 5.52 (m, 1H, NH), 5.90 (m, 1H, NH), 6.91-7.70 (m, 15 aromatic H), 8.01 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.7 (CH2 Trp), 43.4 (CH2), 56.1 (CHα), 67 (CH2 (Z)), 111.2, 118.7, 119.7, 122.2, 123.2, 123.4, 127.2, 127.3, 127.6, 128, 128.2, 128.5, 136.1, 136.2, 137.5, 137.6 (20 aromatic C), 156 (CO carbamate), 171.2 (CO amide). Anal. Calcd. for C26H25N3O3, 0.75H2O: C, 70.81; H, 6.06; N, 9.53. Found: C, 70.84; H, 6.80; N, 9.21.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH3:7][C:8]([CH3:10])=[O:9].Cl>C1COCC1>[OH:9][C:8]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=1)([CH3:10])[CH3:7]
Reactant: Cn1ccnc1
Reactant: CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1C(C)(C)O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The 1-methylimidazole was dissolved in dry THF and the solution cooled to 5° C. A 10% excess n-butylithium was added over one hour period with the reaction vessel being maintained at a temperature range of 5°-20° C. under nitrogen. The solution at the end of the addition was homogenous and purplish in color. After stirring two hours at room temperature, the reaction flask was then cooled to ~10° C. and the acetone in dry THF was added slowly with stirring. After the addition the solution was allowed to stir at ambient temperature one hour then poured onto ice-water. The aqueous layer was acidified with dilute HCl and extracted with ether. The aqueous layer was then basified with K2CO3 then extracted with CH2Cl2 several times. The combined and dried CH2Cl2 extracts were concentrated to yield a white solid which was recrystallized from ethyl acetate; mp 128°-129° C. Structure was confirmed by IR and NMR.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:33]=[C:16]3[CH:17]=[CH:18][C:19]([NH:21][C:22]([C:24]4[N:28]([CH3:29])[N:27]=[CH:26][C:25]=4[C:30]([OH:32])=O)=[O:23])=[CH:20][N:15]3[N:14]=2)[CH2:9]1>>[CH3:6][O:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:33]=[C:16]3[CH:17]=[CH:18][C:19]([NH:21][C:22]([C:24]4[N:28]([CH3:29])[N:27]=[CH:26][C:25]=4[C:30]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:32])=[O:23])=[CH:20][N:15]3[N:14]=2)[CH2:9]1
Reactant: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)O)cnn4C)cn3n2)C1
Reactant: C1CCNC1
Product: COC1CCN(c2nc3ccc(NC(=O)c4c(C(=O)N5CCCC5)cnn4C)cn3n2)C1

Procedure:
Using pyrrolidine and 5-[2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Off white solid (72 mg, 53%). MS: m/z=439 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20]>CN1CCCC1=O>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:11][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Fc1cnccc1Cl
Reactant: Cc1cc2ccccc2n1N
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1Nc1ccncc1F

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in 1-methyl-2-pyrrolidone for 1 hour in substantially the same manner as in Example 1, m.p. 157°-158° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][C@H:3]1[C:9](O)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>CCOCC>[CH3:1][C:2]1([CH3:12])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: CC(C)=C1C[C@@H](C(=O)O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)=C1C[C@@H](CO)C1(C)C

Procedure:
With methylethylidene compound 5 in hand the remaining steps were as follows: The resulting acid 5a was treated with LiAlH4 in ether to furnish the (R)-(−)-maconelliol 6a {[α]24D−31.0 (c 0.1, MeOH)} in good yield, and its enantiomeric purity was determined to be 78% ee. Similarly, (1S)-(−)-verbenone (80% ee, commercially available) was also converted into (S)-(+)-maconelliol 6b {70% ee, [α]24D+22.0 (c 0.1, MeOH)}. The various spectral and GC data of synthetic (R)-(−)-6a were in good agreement with those of the natural product (Zhang, A., et al., Proc. Natl. Acad. Sci. U.S.A., 101: 9601-9606 (2004)). Thus, we were able to determine the absolute configuration of the naturally occurring maconelliol 6 to be R.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(N)CC2)nc1N
Reactant: CC(=O)Cl
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(NC(C)=O)CC2)nc1N

Procedure:
The similar procedure as described in Example 60 was used, starting from [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl-phenyl)-methanone (Example 337) and acetyl chloride (Aldrich) to give N-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-acetamide. MS (M+H)+, 398.