Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C[O:24][C:25](=[O:34])[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:27].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N=C=N.C([NH+](CC)CC)C.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:27][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]([OH:34])=[O:24])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: N=C=N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79 %

Procedure:
To a mixture of 5.8 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 6.1 mg of (S)-(+)-2-phenylglycine methyl ester hydrochloride, 2.7 mg of 1-hydroxybenzotriazole, 700 μl of DMF, and 19 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 20 hours. Subsequently, 50 mg of macroporous triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage) were added thereto, followed by stirring at room temperature for 2 hours. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 100 μl of THF, 200 μl of methanol, and 50 μl of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 20 hours. To the reaction mixture that had been left to be cooled to room temperature were added 0.5 ml of water and 50 μl of 1 M hydrochloric acid, followed by concentration under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 6.7 mg of (2S)-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)(phenyl)acetic acid.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.C(O)(=O)C>C1COCC1.O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
CH3MgBr (3.2M in 2-methyltetrahydrofuran, 3.76 mL, 12.02 mmol) was added dropwise over 10 minutes to a solution of indole (1.42 g, 12.02 mmol) in THF (4.9 mL) at 0° C. The solution was then stirred at 0-2° C. for 0.5 h. A solution of 2,4-dichloro-5-methylpyrimidine (1 g, 6.01 mmol) in THF (3 mL) was then added dropwise to the solution. The ice bath was then removed, then the solution was stirred at r.t. for 1 h then 60° C. for 21 h. While still at 60° C., acetic acid (708 μL, 12.32 mmoles) was added dropwise, followed by water (10 mL). The resulting biphasic suspension was stirred at 60° C. for 0.5 h. The resulting solid was collected by filtration, washed with water (5 mL), and dried in a vacuum oven to give the title compound (805 mg, 50%) as a white solid; 1H NMR: 2.49 (3H, s), 7.20-7.28 (2H, m), 7.52-7.55 (1H, m), 8.20 (1H, d), 8.48 (1H, d), 8.51-8.54 (1H, m), 12.10 (1H, s); m/z: ES+ MH+ 244.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)(=[O:25])[CH3:24]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione (50 g) dissolved in 100 ml of pyridine and 250 ml of acetic anhydride was swirled while being warmed on a steam bath. When solution was complete, the reaction was allowed to stand at room temperature. After two hours ice and water were added and the resultant oil was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 58 g of the title compound as an amorphous solid. The product, homogeneous by thin-layer chromatography using 1:1 ethyl acetate/Skellysolve B on silica gel, was employed for subsequent reactions without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[P:7]([OH:10])([OH:9])[OH:8]>CC(C)=O>[NH2:2][C:1]([P:7]([OH:10])([OH:9])=[O:8])([P:7]([OH:10])([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: OP(O)O
Reactant: N#CCC(=O)O
Solvent: CC(C)=O
Product: NC(CC(=O)O)(P(=O)(O)O)P(=O)(O)O
Temperature: 165 °C

Procedure:
A mixture of cyanoacetic acid (4.3 g, 0.5 mole), phosphorous acid (8.2 g, 0.1 mole), ISOPAR-M (20 g), and the wetting agents (0.25 g each) was heated at 165° C for 2 hours. The product was worked up with acetone to get yellow crystals of 1-amino-1,1-diphosphono-2-carboxy ethane, m.p. 255° C (decomposition), 55%, associated with traces of impurities.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1.C(N(CC)CC)C>C(Cl)Cl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([S:34][CH:35]2[CH2:40][CH2:39][N:38]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)[CH2:37][CH2:36]2)=[CH:32][CH:33]=1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: Fc1ccc(SC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCC(Sc2ccc(F)cc2)CC1
Yield: 35.4 %

Procedure:
4-[[7-(Trifluoromethyl)-4-quinolyl]amino]benzoyl chloride hydrochloride (0.94 g) was added slowly to a stirred mixture of 4-[(4-fluorophenyl)thio]piperidine hydrochloride (0.60 g) and triethylamine (1.69 ml) in dry methylene chloride (12.5 ml) at room temperature. The resultant mixture was stirred at the same temperature for 3.5 hours. The precipitated powder was collected by filtration and washed with methylene chloride and diethyl ether to give 4-[(4-fluorophenyl)thio]-1-[4-[[7-(trifluoromethyl)-4-quinolyl]amino]benzoyl]piperidine (0.45 g) as colourless powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:46]([NH2:49])([CH3:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH:46]([NH:49][C:21](=[O:22])[CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[CH:13]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:15]=1)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)([CH3:48])[CH3:47]
Reactant: CC(C)N
Reactant: CC(C)c1cc(-c2cccc(C(Cc3ccc(S(C)(=O)=O)cc3)C(=O)O)c2)c2ncccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)NC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)c1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of Example 93 (100 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added DMAP (26 mg, 0.21 mmol), EDCI (45 mg, 0.23 mmol), then isopropyl amine (1 mL, 12 mmol). The resulting reaction mixture was stirred 18 h at 21° C., then diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 80:20 to 20:80) provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([I:10])=[CH:4][N:3]=1.[Br:11]CC1C(Cl)=NC(Cl)=C(F)C=1>>[Br:11][CH2:8][C:6]1[C:5]([I:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OCc1cc(Cl)ncc1I
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Product: Clc1cc(CBr)c(I)cn1
Yield: 60 %

Procedure:
Compound 25D (0.28 g, 60%) was prepared from 25C (0.38 g, 1.4 mmol) using a procedure similar to the synthesis of 1B. HPLC Rt=2.72 min.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[C:12]([O:14]CC)=[O:13].C(O)(=O)C>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)[C@H](CCCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCCCCC[C@H](N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
In 10 ml of 1N aqueous sodium hydroxide solution is dissolved 0.35 g of 3(R)-[8-amino-1(S)-ethoxycarbonyloctyl]amino-4-0xo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride, and the solution is left standing at room temperature for 30 minutes. Acetic acid (2.5 ml) is added to the solution and the resulting mixture is purified by Amberlite XAD-2 column chromatography (methanol:water=1:2). The eluate is concentrated under reduced pressure and lyophilized to give 0.24 g of 3(R)-[8-amino-1(S)-carboxyoctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>[Cu](I)I.C(NCC)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH:32]=[CH:33][C:15]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccc(N)c(I)c2)cc1OC
Reactant: C#CCCCNC(=O)OC(C)(C)C
Agent: I[Cu]I
Solvent: CCNCC
Product: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCNC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom flask was charged with pent-4-ynyl-carbamic acid tert-butyl ester (1.35 g, 7.37 mmol), 4-amino-N-(3,4-dimethoxyphenyl)-3-iodobenzamide (1.35 g, 6.98 mmol), copper iodide (0.16 g, 0.814 mmol), palladium tetrakistriphenylphosphine (0.81 g, 0.701 mmol), and diethylamine (230 mL) and the resulting mixture stirred at room temperature for 24 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF40-400 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-carbamic acid tert-butyl ester. MS (ES+) 454 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:16][CH:15]3[S:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:17][CH:15]([CH2:14][CH2:13]3)[CH2:16]2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)C1CC2CCC(C1)S2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)C1CC2CCC(C1)S2
Reaction time: 24 h
Yield: 91.8 %

Procedure:
To a solution of (4-bromo-phenyl)-(8-thia-bicyclo[3.2.1]oct-3-yl)-methanol (1.99 g, 6.35 mmol) in DCM (100 ml) was added a total of manganese dioxide (8.28 g, 95.2 mmol) at RT and the reaction mixture was stirred for 24 hrs. The suspension was filtered and the residue was washed with DCM, dried in vacuo to yield the title intermediate (1.87 g, 5.83 mmol, 92%) as a colourless solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:23]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCN1CCCCCC1=O
Yield: 80.4 %

Procedure:
Following example 10, 15.3 g of 50% sodium hydride-mineral oil dispersion (7.65 g NaH, 0.319 M), 30 g (0.266 M) of azacycloheptan-2-one and 66.1 g (0.265 M) of 1-bromododecane on 20 hr. reflux gave 60 g (80%) of colorless product; b.p. 175°-180°/0.3 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[OH-].[Na+].[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].CCOC(C)=O>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.07 g, 3.04 mmol), 6 N NaOH solution (6 mL), (Bu4N)2SO4 (50% wt. solution in H2O, 0.20 mL), and TsCl (646 mg, 3.39 mmol) were combined in toluene (20 mL) and the resulting suspension was stirred at 25° C. for 1.5 h. H2O and EtOAc were added to the suspension and the phases were separated. The organic phase was washed with H2O, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.39 g, 91%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.66 (d, J=6.6 Hz, 2H), 7.35 (d, J=8.2 Hz, 1H), 7.28-7.21 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 4.47 (s, 2H), 3.77-3.65 (br m, 2H), 3.11-3.03 (br m, 2H), 2.36 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC(=O)[NH:14][CH2:15][C:16](=[O:34])[NH:17][CH:18]1[CH2:21][N:20]([CH:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:19]1)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:14][CH2:15][C:16]([NH:17][CH:18]1[CH2:21][N:20]([CH:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:19]1)=[O:34]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as colorless oil from the TFA de-protection of {[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (as prepared in the previous step) using the procedure described in step E of Example 1.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: COc1cc(C(=O)C2CC2)ncn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1cc(OC)ncn1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.13 g) in THF (100 ml) was added ethyl diethylphosphonoacetate (13.2 mL) at 0° C. To the obtained solution was added cyclopropyl(6-methoxypyrimidin-4-yl)methanone (entire amount) obtained in Example 2, step C, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give an isomer mixture of the title compound (E:Z=93:7 or 7:93, 5.57 g) as a yellow oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]=1>CO>[CH3:15][O:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1
Reactant: COCC1=NCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COCC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (8.11 g, 38.3 mmol) was added to a stirred, ice-cooled solution of the product from (b) above (6.1 g, 34.8 inmol) in methanol (80 ml), then the resulting mixture stirred for 18 hours at room temperature before being quenched with water. The bulk of the solvent was removed under reduced pressure, then the residue basified with 1M aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to furnish the required product (6.19 g) as an orange oil, Rf 0.25 (SS 3), m/e 178 (M+H)+, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(C)cc3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Bromo-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carboxylic acid butyl ester (130 mg, 0.30 mmol) and CuCN (54 mg, 0.61 mmol) were suspended in DMF (1.2 mL). The resulting mixture was heated to reflux for 40 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 65 mg. MS: (−) m/z 375.29 (M−1).
Reaction SMILES: Br.[CH:2]1([CH2:7][CH:8]([C:17]2[N:22]=[C:21]([O:23]C)[C:20]([CH3:25])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:2]1([CH2:7][CH:8]([C:17]2[NH:22][C:21](=[O:23])[C:20]([CH3:25])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1nc(C(CC2CCCC2)c2ccc(SC)cc2)ccc1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CSc1ccc(C(CC2CCCC2)c2ccc(C)c(=O)[nH]2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-2-methoxy-3-methylpyridine (220 mg) in acetonitrile (2 mL), and the mixture was stirred at 110° C. for two hours. The reaction solution was poured into saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=0:1) to give the title compound as a colorless amorphous (200 mg, 94%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[CH2:11]([N:18]([CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]=[C:41]=[O:42])[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=1)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:29][CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([N:40]3[C:41](=[O:42])[NH:3][N:2]=[N:1]3)[CH:38]=2)[NH:33][C:32]=1[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.7 %

Procedure:
To a solution of freshly prepared aluminum azide (0.6 mmol in 6 niL dry tetrahydrofuran) was added 120 mg benzyl-{2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl } -(4-pyridin-3-yl-butyl)amine and the mixture heated to reflux on an oil bath. After 20 hours, the mixture was cooled to room temperature concentrated poured into a mixture of 1M sodium potassium tartarate and ice, stirred vigorously for 40 minutes then partitioned between ethyl acetate and water. The organic portion was washed successively with 1M sodium potassium tartarate, water and brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 88:12) gave the title compound (58 mg).
Reaction SMILES: O1CC[CH2:3][CH2:2]1.[H-].[Na+].[CH3:8][O:9][CH2:10][O:11][CH2:12][C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][C:17]=1[CH:18]=O.Cl>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CS(C)=O.O>[CH3:8][O:9][CH2:10][O:11][CH2:12][C:13]1[N:14]=[C:15]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:16][C:17]=1[CH2:18][CH2:2][CH3:3]
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Reactant: C1CCOC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1oc(-c2ccccc2)nc1COCOC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
To a mixture of dimethyl sulfoxide (80 mL) and tetrahydrofuran (200 mL) was added sodium hydride (6.0%, oil, 1.81 g) at room temperature and the mixture was stirred at 50° C. for 1.5 hrs. After allowing the reaction mixture to cool to room temperature, ethyl triphenylphosphonium bromide (13.66 g) was added and the mixture was stirred at room temperature for 30 min. A solution (20 mL) of 4-methoxymethoxymethyl-2-phenyl-5-oxazolecarbaldehyde (7.0 g) in dimethyl sulfoxide was added to the reaction mixture and the mixture was heated under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:6, v/v). A mixture of the obtained oil, 5% palladium carbon (2.0 g) and tetrahydrofuran (200 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give 4-methoxymethoxymethyl-2-phenyl-5-propyloxazole as a colorless oil (2.65 g, 36%).