Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:35])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:38])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH3:38][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:35])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 77.1 %

Procedure:
To a solution of 2.4 g (4.8 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one in 20 ml of tetrahydrofuran was added a solution of 6 mmoles of diazomethane in diethyl ether. The clear solution was treated with acetic acid to remove excess diazomethane and was concentrated to a small volume. After addition of diethyl ether the formed precipitate was filtered off and dried to obtain 1.9 g (3.7 mmoles or 76% yield) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][C:11]#[N:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:12][CH2:11][CH2:10][C:9]#[N:8]
Reactant: N#CCCN
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N#CCCNCc1cccs1

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-propionitrile was prepared following general procedure D using thiophene-2-carboxaldehyde (477 μL, 98%, 5 mmol), 3-amino-propionitrile (373 μL, 99%, 5 mmol), 1 M acetic acid solution in DCE (6 mL), DCE (9 mL) and sodium triacetoxyborohydride (1.31 g, 97%, 6 mmol). The crude product was used without further purification. LCMS m/z: 167 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 60 °C
Yield: 77.4 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60 g, 271 mmol) in anhydrous N,N-dimethylformamide (600 mL) was cooled to 0C. Triethylamine (44.8 mL, 326 mmol) was added drop wise followed by tert-butyl 2-aminoethylcarbamate (52.2 g, 326 mmol). After 30 minutes the ice bath was removed and the reaction mixture was heated to 60° C. The reaction was heated at 60° C. overnight and then it was concentrated under reduced pressure to provide an orange oil. The oil was dissolved in ethyl acetate (1 L), washed with water (3×500 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil. The oil was triturated with methanol (˜100 mL). The resulting solid was isolated by filtration and washed with cold methanol to provide 72.3 g of tert-butyl 2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate as a solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([CH:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:7][CH:8]=[O:9])[CH3:5].Cl>CCOCC>[CH2:4]([CH:6]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:7][CH:8]([OH:9])[C:1]#[N:2])[CH3:5]
Reactant: CCC(CC=O)C(C)[N+](=O)[O-]
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: CCC(CC(O)C#N)C(C)[N+](=O)[O-]
Yield: 92.3 %

Procedure:
To a suspension of sodium cyanide (4.5 g) and 3-ethyl-4-nitro-pentanal (7.5 g) in ether (50 ml) was added conc. hydrochloric acid (7.5 ml) at 0° C. with stirring. The resulting mixture was stirred at 0° C. for an hour, diluted with ether, washed successively with water and brine, dried over magnesium sulfate, and then evaporated to dryness in vacuo to give 4-ethyl-2-hydroxy-5-nitro-hexanenitrile (8.1 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:22]=[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:22]=[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: Cc1cc2c(CO)cccn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc2c(C=O)cccn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (18.9 mL, 216 mmol) in dichloromethane (200 mL) was added dimethyl sulfoxide (35.4 mL, 499 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (2-methylpyrazolo[1,5-a]pyridin-4-yl)methanol (27.0 g, 166 mmol) in dichloromethane (133 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (117 mL, 831 mmol) at −78° C., and the mixture was stirred for 1 hr and warmed to room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (7.00 g, yield 26%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:15]([Si:19]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[O:20][CH2:21][CH2:22][C@@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[O:25][C@@H:24]1[CH2:30]OS(C(F)(F)F)(=O)=O)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][O:11][CH2:30][C@@H:24]1[C@H:23]([CH2:22][CH2:21][O:20][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:27][C:26]([CH3:28])([CH3:29])[O:25]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC1(C)O[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](COS(=O)(=O)C(F)(F)F)O1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(CCOC[C@H]1OC(C)(C)O[C@H]1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
(2-Hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (73.9 mg, 0.42 mmol) was dissolved in THF (1.15 mL). Sodium hydride (50%, 22.1 mg, 0.46 mmol) was added at 0° C. and the mixture was stirred at 0° C. for 10 minutes in a nitrogen atmosphere. Trifluoro-methanesulfonic acid (4R,5S)-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester was added to the reaction solution, and the mixture was stirred at room temperature for two hours in a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (2-{(4R,5S)-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy}-ethyl)-methyl-carbamic acid tert-butyl ester (82.2 mg, 38%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Na+].[Na+].C(O)C.FC1C=C([C:29]2[C:34](=[O:35])[N:33]3[CH:36]=[CH:37][S:38][C:32]3=[N:31][C:30]=2[CH3:39])C=C(F)C=1>C1(C)C=CC=CC=1.O>[CH3:39][C:30]1[N:31]=[C:32]2[S:38][CH:37]=[CH:36][N:33]2[C:34](=[O:35])[C:29]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1

Procedure:
This compound was prepared from Step 2 intermediate (10 g, 34.234 mmol), 4-cyanophenylboronic acid (6.5 g, 44.235 mmol), Pd[(C6H5)3P]4 (1.62 g, 1.401 mmol) and Na2CO3 (21.7 g, 2.051 mmol) in a mixture of toluene (250 ml), ethanol (150 ml) and water (100 ml) according to the procedure described in Intermediate 3, Step 3 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 5 g of the product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 7.53 (d, J=7.8 Hz, 3H), 7.88 (d, J=7.8 Hz, 2H) 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 265.31 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:5][CH:4]=1>O=[Mn]=O.C(Cl)Cl>[CH:2]([C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:5][CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)n3cnnc23)CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)n3cnnc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A 250 mL round bottom flask was charged with tert-butyl 4-(5-(hydroxymethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (0.30 g, 0.90 mmol) and dry CH2Cl2 (20 mL). To the above was added activated MnO2 (0.23 g, 2.6 mmol). The resulting suspension was stirred at room temperature for 16 h. Work-up: the reaction mixture was filtered. The filtrate was concentrated in vacuo, to afford 0.26 g (87%) of the product as a yellow solid. MS m/z: 333 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:25]#[C:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[N:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:24]=[C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[N:19]=[CH:20]2)=[CH:15][N:14]1[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:33])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCn4ccnn4)ncc3cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2cc3cc(C#CCn4ccnn4)ncc3cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 4-[3-oxo-7-(3-[1,2,3]triazol-1-ylprop-1-ynyl)-2H-6-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester (0.29 g, 0.66 mmol, Example 14A) is treated with trifluoroacetic acid (10 mL) and stirred at room temperature for 40 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid collect by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 5-(methylsulfonyl)-1H-indole (intermediate-21) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29) (0.188 g, 11%).
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20](=[O:35])[C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:34])[CH2:27][NH:28]OC(C)(C)C)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=1)([OH:46])(=[O:45])=[O:44].[C:1]1([N:7]=[N:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20](=[O:35])[C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:34])[CH2:27][NH2:28])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)ONCC(=O)N1CCC[C@H]1C(=O)Nc1ccc(N=Nc2ccccc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: NCC(=O)N1CCC[C@H]1C(=O)Nc1ccc(N=Nc2ccccc2)c2ccccc12

Procedure:
t-Butyloxy-glycyl-L-proline 4-phenylazo-1-naphtylamide (1.0 g, 0.002 mole) was treated with p-toluenesulfonic acid monohydrate (0.76 g, 0.004 mole), and the reaction mixture was worked up as in Example 18. The glycyl-L-proline 4-phenylazo-1-naphthylamide tosylate thus obtained was dissolved in methanol, and neutralized with 5% sodium hydrogen carbonate solution to precipitate the product. The precipitate was were removed by filtration, washed with water, dried, and recrystallized from methanol-water.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[CH2:33]([N:35](CC)CC)[CH3:34].BrCC#N>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:34][C:33]#[N:35])[CH2:9][CH2:8]1)=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: N#CCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCN1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C:15]([NH:26][CH2:27][C:28]([NH:30][CH:31]2[CH2:34][N:33]([CH:35]3[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=O)[CH2:37][CH2:36]3)[CH2:32]2)=[O:29])=[N:14]1.[NH2:44][CH2:45][CH2:46][OH:47]>>[OH:47][CH2:46][CH2:45][NH:44][C:41]([CH:38]1[CH2:39][CH2:40][CH:35]([N:33]2[CH2:34][CH:31]([NH:30][C:28](=[O:29])[CH2:27][NH:26][C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=4)[N:13]([CH3:12])[N:14]=3)[CH2:32]2)[CH2:36][CH2:37]1)=[O:43]
Reactant: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)NCCO)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared from EDCI coupling of 4-{3-[2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexanecarboxylic acid (as prepared in Example 39, Step A) and 2-aminoethanol using the procedure described in Example 39.
Reaction SMILES: Cl.C(O[C:5]([CH:7]1[C:11](=O)[CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=[O:6])C.Cl.[C:21]([NH2:26])(=[NH:25])[CH:22]([CH3:24])[CH3:23].CC([O-])(C)C.[K+]>C(O)(C)(C)C>[CH2:13]([N:9]1[CH2:8][C:7]2[C:5]([OH:6])=[N:26][C:21]([CH:22]([CH3:24])[CH3:23])=[N:25][C:11]=2[CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Reactant: CC(C)C(=N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)c1nc(O)c2c(n1)CN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 23 %

Procedure:
To a solution of 1-benzyl-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride (U.S. Pat. No. 3,312,716; 0.568 g, 2.30 mmol) in tert-BuOH was added isobutyramidine hydrochloride (0.282 g, 2.30 mmol) and KOtBu (0.516 g, 4.6 mmol). After heating for 6 h at 100° C., the reaction was cooled to rt, concentrated, diluted with water and washed with Et2O. The organic layer discarded. The aqueous layer was adjusted to pH 7 and extracted with Et2O. The organic layers were then dried and concentrated to give 0.145 g (23%) of the title compound of yellow solid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>CC(CC)=O>[Br:1][C:2]1[C:7]([O:8][CH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H](CO)CBr
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@@H](CO)COc1cccnc1Br
Temperature: 100 °C
Yield: 80 %

Procedure:
2-bromo-3-pyridinol (230 mg) and potassium carbonate (216 mg) was dissolved in methylethylketone (10 ml) and reacted for 30 minutes. Then, (S)-3-bromo-2-methyl-1-propanol (0.21 ml) was added to the solution and refluxed for 3 hours at 100° C. Potassium carbonate was filtered out and separated by flash chromatography under a silica gel phase (ethyl acetate:normal hexane=1:1). As a result, (S)-3-(2-bromopyridine-3-yloxy)-2-methyl-1-propanol (260 mg, yield: 80%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:13])=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:35]Br)=[CH:30][C:29]=1[NH:45][CH:46]=[O:47])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(=O)C>O.CS(C)=O>[NH2:13][C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][CH2:35][C@@H:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:29]([NH:45][CH:46]=[O:47])[CH:30]=2)[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reactant: NCCc1ccc(NC[C@H](N)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@H](N)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 100 °C
Reaction time: 1.42 h

Procedure:
Under nitrogen, (R)-N2-[4-(2-aminoethyl)phenyl]-1-phenylethane-1,2-diamine (Example 5) (22.4 g, 1.4 equiv), N-[2-benzyloxy-5-((R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl)phenyl]formamide (29.2 g, 1.0 equiv), potassium carbonate (34.7 g, 4.0 equiv) were combined with dimethyl sulfoxide (35 mL). The resulting slurry was stirred at 100° C. for 85 minutes. The mixture was cooled to room temperature and water (200 mL) and isopropyl acetate (200 mL) were added. The layers were separated and the organic layer was washed with water (200 mL) followed by aqueous saturated sodium chloride (150 mL) and dried over anhydrous magnesium sulfate (20 g). The solids were removed by filtration and the filtrate concentrated to yield crude title intermediate as an amber colored oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[BH4-].[Na+]>C(O)C.CO>[CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC1(C)NC(=O)c2sc(-c3ccncn3)cc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
To a solution of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.034 g, 0.10 mmol) in ethanol (2 mL) and methanol (15 mL) was added sodium borohydride (0.092 g, 2.4 mmol) in four portions over 20 min, and the reaction was stirred at room temperature for 15 h. Then, the reaction mixture was concentrated, the residue was dissolved in water (15 mL), and the solution was extracted with 75:25 ethyl acetate/tetrahydrofuran (2×40 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated, and the residue was purified by flash chromatography (silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.012 g, 46%) as a yellow solid:
Reaction SMILES: C([O:5][C:6](=[O:59])[C:7]([O:10]/[N:11]=[C:12](/[C:46]1[N:47]=[C:48]([NH:51]C(OC(C)(C)C)=O)[S:49][CH:50]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:59])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:17]([CH2:25][N:26]3[CH:30]=[C:29]([CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[N:28]=[N:27]3)[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C:19]2=[O:20])[N:47]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)nn2)cs1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cc(CCN2CCNCC2)nn1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a solution of (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (120 mg, 0.138 mmol) in DCM (1.4 mL) at 0° C. added TFA: DCM (1:1, 4.2 mL) followed by triethylsilane (65 μL, 0.411 mmol). The reaction mixture was stirred at 0° C. for 30 min and slowly warmed to room temperature. After 2 h at rt it was concentrated in vacuo and triturated with MTBE: Heptane (1:2) whereupon a solid was observed. The crude solid was purified by reverse phase prep HPLC (C18 column, acetonitrile: water solvent system with 0.1% formic acid modifier) to afford the title compound (9.3 mg, 11%); LCMS: m/z=612.8 (M−1); 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.99 (s, 1H), 7.30 (s, 2H), 6.66 (s, 1H), 5.27 (dd, J=8.8, 5.5 Hz, 1H), 4.82 (dd, J=14.7, 4.0 Hz, 1H), 4.68 (dd, J=14.7, 6.6 Hz, 1H), 4.24 (td, J=5.9, 4.2 Hz, 1H), 3.10 (t, J=5.2 Hz, 4H), 2.76 (t, J=7.0 Hz, 2H), 2.64-2.54 (m, 6H), 1.37 (s, 3H), 1.30 (s, 3H).