Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([CH2:5]O)[OH:4].[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8]>C(O)C.[Pd]>[C:7]([NH:11][CH2:5][C@H:3]([OH:4])[CH2:2][OH:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C[C@H](O)CO
Reactant: CC(C)(C)N
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC[C@H](O)CO

Procedure:
30 g of (R)-glyceraldehyde, 36 cc of tert. butylamine in 800 cc of ethanol are hydrogenated over 8 g of 10 % palladium/carbon with H2 for 4 hours, the catalyst is filtered off and the solution is concentrated. (S)-1-tert.butylamino-2,3-dihydroxy-propane is obtained from ethyl acetate/ether (2:1) in the form of crystals having a M.P. of 76°-81°. [α] 20546 = -11.8° (c = 2.0; methanol).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][F:29]>C(#N)C>[F:29][CH2:28][CH2:27][CH2:26][N:15]1[CH2:16][CH2:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=2[F:1])([OH:18])[CH2:13][CH2:14]1
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(C(F)(F)F)c2F)CCN(CCCF)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-3-fluoropropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 323 (M+, 2), 276 (34), 191 (15), 116 (17), 42 (bp).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])O.[Na+].CN(C)C=O.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:1]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)OCC)Cc1ccccc1
Yield: 101 %

Procedure:
Into a 5-L three-necked flask, 523.2 g (2.765 moles) of diethyl iminodiacetate, 465.4 g (5.540 moles) of sodium hydrogencarbonate and 1.4L of DMF (dimethylformamide) were put, and, keeping the mixture at about 40° C., 473.5 g (2.768 moles) of benzyl bromide was slowly dropwise added thereto with stirring. Thereafter, the mixture was stirred at about 40° C. for 16 hours. After the reaction was completed, 1.5L of water was added to the reaction product, which was then extracted with toluene (500 ml×four times). The organic layer formed was washed with water and dried with Glauber's salt. Thereafter, the solvent was evaporated to dryness to obtain 780 g of diethyl N-benzyliminodiacetate (yield: 98.8%).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]/[C:3]/1=[CH:11]\[C:12]([OH:14])=[O:13]>CO.O1CCOCC1.[Pd]>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)/C=C1\Cc2ccccc2C1=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CC1Cc2ccccc2C1

Procedure:
A solution of acid 146 (10.0 g, 53.1 mmol) in MeOH (45 mL) and dioxane (150 mL) with Pd/C (10%, 1.0 g) was stirred under H2 (40 psi) for 16 h. The mixture was filtered through Celite and the solvent evaporated to give acid 147 as an off-white solid: mp 85-88° C. [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 89-91° C.]; 1H NMR δ 8.47 (br s, 1H, OH), 7.08-7.18 (m, 4H, H-4, H-5, H-6, H-7), 2.99-3.06 (m, 2H, H-1, H-3), 2.69-2.74 (m, 1H, H-2), 2.53-2.60 (m, 2H, H-1, H-3), 2.48 (d, J=7.4 Hz, 2H, CH2CO2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5](/[C:10](=[CH:12]/[C:13](=[O:15])[CH3:14])/[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([CH:10]([CH2:12][C:13](=[O:15])[CH3:14])[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(=O)/C=C(\C)c1cc(Cl)c(N)cc1C#N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)CC(C)c1cc(Cl)c(N)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.5 %

Procedure:
(E)-5-amino-4-chloro-2-(4-oxopent-2-en-2-yl)benzonitrile (120 mg, 0.51 mmol) and Pd(OH)2 on carbon (10% w/w, 10 mg) was suspended in MeOH (3 mL). Acetic acid (0.06 mL) was then added and the reaction was stirred at room temperature under a balloon of H2 for 48 h. The reaction was then filtered through a pad of Celite, washing with EtOAc. The eluent was then concentrated in vacuo and the material was purified on ISCO (0-80% EtOAc/Hexane) to give 5-amino-4-chloro-2-(4-oxopentan-2-yl)benzonitrile (73 mg) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 87.9 %

Procedure:
By conducting a procedure similar to that in Synthesis Example 3 except using 2.0 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone, 15 ml of N,N-dimethylformamide, 1.3 g of anhydrous sodium carbonate and 1.6 g of 4-tert.-butylbenzyl chloride, there were obtained white needle-like crystals having the following physical properties (yield: 87.9%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH2:23][CH2:24][N:25]=3)[C:9]([NH:13][C:14]([C:16]3[S:20][C:19]([CH3:21])=[N:18][C:17]=3[CH3:22])=[O:15])=[N:10][C:11]=2[CH:12]=1.ClC[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:21][C:19]1[S:20][C:16]([C:14]([NH:13][C:9]2[N:8]3[CH2:23][CH2:24][N:25]=[C:7]3[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH2:1][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=4)=[CH:12][C:11]=3[N:10]=2)=[O:15])=[C:17]([CH3:22])[N:18]=1
Reactant: COc1ccc2c(c1)N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Product: Cc1nc(C)c(C(=O)NC2=Nc3cc(OCc4ccc(S(C)(=O)=O)cc4)ccc3C3=NCCN23)s1

Procedure:
The procedure used for the preparation of Example 24, Step 2 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide (Step 1) and 1-(chloromethyl)-4-(methylsulfonyl)benzene (15 mg, 51%). TLC: Rf 0.93 in 10% MeOH/CH2Cl2, HPLC MS RT=2.27 min, MH+=510.1; 1H NMR (DMSO-d6) δ: 2.80 (3H, s), 2.86 (3H, s), 3.39 (3H, s), 4.30-4.35 (2H, m), 4.50-4.54 (2H, m), 5.56 (2H, s), 7.39 (1H, d), 7.87 (2H, d), 7.95 (1H, s), 8.11 (2H, d), 8.50 (1H, d).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[N:26][NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccccc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (150 mg, 0.65 mmol) was suspended in methanol (3 ml) and water (1 ml). Benzoic acid hydrazide (102 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 18 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The homogeneous reaction mixture was cooled to room temperature and concentrated in vacuo. C-18 Reverse-Phase SPE (10 g Alltech Hi-load C18, gradient from water to 20% methanol/water) to yield the product, a mixture of approximately 1:1 E:Z isomers, as a colorless solid: 193 mg (85%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.CN(CCN(C)C)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccccc1
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a mixture of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (90 mg, 0.32 mmol) containing [Cu(OH).TMEDA]2Cl2 (14.95 mg, 0.032 mmol) in dry methanol (5 mL) was added phenylboronic acid (81.0 mg, 0.64 mmol) under an air atmosphere and the resulting mixture stirred at room temperature overnight. After this time, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=9:1 to 3:2) afforded the title compound (48 mg, 42%) which was obtained as a white solid. MS: m/e 356.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([O:18][C:29](=[S:30])[N:28]([CH3:32])[CH3:27])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=S)N(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (10 g, 37.3 mmol) in dioxane (157 ml) is added 4-dimethylaminopyridine (476 mg, 3.9 mmol), triethylamine (10 mL, 78.6 mmol), and dimethylthiocarbamoyl chloride (6.1 g, 49.1 mmol). The reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using 20% ethyl acetate in hexanes to give dimethyl-thiocarbamic acid O-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yl)ester (12.2 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15](NC)=[O:16])(=[O:13])=[O:12]>ClC1C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1CCC(F)(F)F
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1CCC(F)(F)F

Procedure:
40.3 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]- N'-methylurea are suspended in 700 ml of chlorobenzene, and dried by the azeotropic distilling off of about 150 ml of solvent. There are then introduced at 120°-130° C. 71 g of phosgene in the course of 90 minutes. The yield after complete concentration of the formed solution by evaporation is 37.3 g of 2-(3,3,3-trifluoropropyl)-phenylsulfonylisocyanate in the form of yellowish oil, which can be directly further reacted.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:24]1([CH:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH:11]=3)[CH2:18][CH2:19]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCNCC1
Reactant: O=C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(N2CCC(N3CCCCCC3)CC2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a suspension of 1-[3-(1H-benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-4-one (0.10 g, 0.31 mmol) in dichloromethane (2 mL) was added azepane (0.05 mL, 0.46 mmol). After 30 min stirring at room temperature a drop of acetic acid was added, and after 1 h a further aliquot of azepane (0.05 mL, 0.46 mmol) was added, followed by sodium triacetoxyborohydride (NaB(OAc)3H) (0.10 g, 0.46 mmol). The reaction mixture was stirred at room temperature overnight, then the solvent was removed under reduced pressure, and the crude product dissolved in dichloromethane (10 mL). To the solution PS-isocyanate resin (PS-NCO) (Argonaut, loading 0.93 mmol/g) was added, then the mixture was shaken at room temperature overnight and filtered. The solvent was removed under reduced pressure to obtain a solid residue that was washed with EtOAc and Et2O then dried to give the desired product (0.07 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][C:11]=1[C:19]([O:21][CH3:22])=[O:20].C1COCC1.B.C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ccc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Temperature: 23 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2′-fluoro-5′-(methyloxy)-2-((methyloxy)carbonyl)-1,1′-biphenyl-4-carboxylic acid T4.3 (35.60 g, 117 mmol) in THF (1170 mL, 117 mmol) at 0° C. was added borane-THF (234 mL, 234 mmol). The reaction was warmed to 23° C., and the mixture was stirred for 6 hours. The mixture was then concentrated in vacuo. 1 N HCl was added, and the mixture was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified on silica gel (0-40% EtOAc in hexane) to give methyl 2′-fluoro-4-(hydroxymethyl)-5′-(methyloxy)-1,1′-biphenyl-2-carboxylate T4.4 as a clear oil (30.00 g, 88% yield). MS ESI (pos.) m/e: 308.0 (M+H2O)+, 291.1 (M+H)+.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11](F)[N:10]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:10]=1
Reactant: COc1ccc(CN)cc1
Reactant: Nc1nc(F)c(F)cc1F
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To 10 ml of N-methylpyrrolidone were added 3.90 g of 2-amino-3,5,6-trifluoropyridine and 7.60 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for one day and allowed to cool. To the solution was added 50 ml of chloroform, and the solution was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to chromatography (silica gel, 32 g; eluent: chloroform) to obtain 4.50 g of the title compound as a pale yellow crude oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18]>CC(C)=O>[NH2:1][C:2]1[N:3]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[C:4]([C:9]#[N:10])=[C:5]([C:7]#[N:8])[N:6]=1
Reactant: CCCCOC(=O)Cl
Reactant: N#Cc1nc(N)[nH]c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCOC(=O)n1c(N)nc(C#N)c1C#N

Procedure:
2 g of 2-amino-4,5-dicyanoimidazole was dissolved in 20 ml of suspension of acetone containing 1.3 g of sodium bicarbonate and then 2.1 g of n-butyl chloroformate was added dropwise to said solution at a room temperature. The resulting solution was refluxed during 30 minutes, and white crystal was separated out when the rection mixture was poured into ice-water. After recrystallizing the crude product from methanol, 2.7 g of the purified compound having a melting point of 170° to 172°C was obtained as needles (Yield rate: 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:49])[NH:39][C@H:40]([CH2:45][N:46]=[N+]=[N-])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:49])[NH:39][C@H:40]([CH2:45][NH2:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](CN=[N+]=[N-])CC(C)C)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](CN)CC(C)C)C(=O)OCC

Procedure:
A solution of 108 (717 mg, 1.07 mmol) in THF (25 ml) was shaken together with PS-triphenylphosphine resin (diphenylphosphino polystyrene) (3.24 g, 1.65 mmol PPh3/g) and methanol (2.5 ml) for 78 hrs. The mixture was filtered and the polymer was washed repeatedly with DCM and methanol. The combined filtrates were evaporated to yield the title compound as a light beige solid foam (685 mg, 99%) with more than 95% purity as determined by reversed phase HPLC. M+H+644.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([CH:9]=1)[NH2:1]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C#N)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nnn[nH]2)c(N)c1
Temperature: 100 °C
Yield: 42.2 %

Procedure:
To a mixture of 2-amino-4-methylbenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 244 mg of 5-methyl-2-(1H-tetrazol-5-yl)aniline. MS (EI) for C8H9N5: 176 (M+H). Step 2: N-[5-Methyl-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 5-methyl-2-(1H-tetrazol-5-yl)aniline (240 mg, 1.4 mmol) in 6 mL of DCM was added DIPEA (7.5 mmol, 5.5 eq.) followed by thiophene-2-carbonyl chloride (6.8 mmol, 5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. This crude material was further purified by redissolving the material into minimum volume of aqueous NaOH (0.1 M), and then reacidified with concentrated HCl. The solid was collected by filtration, washed with EtOAc, and dried under vacuum to afford 26.8 mg of the desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.35 (s, 1H), 7.98-7.94 (m, 2H), 7.90 (d, 1H), 7.33 (t, 1H), 7.20 (d, 1H), 2.42 (s, 3H). MS (EI) for C13H11N5OS: 286 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]([CH2:13][OH:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH2:32]([NH:39][C:10](=[O:11])[C@H:9]([N:8]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To the suspension of (R)-2-(dibenzylamino)-3-hydroxypropanoic acid (285.34 g, 1.0 moL) in dichloromethane (2.86 L) was added HOBt (202.68 g, 1.50 moL), triethylamine (111.31 g, 1.1 moL), benzyl amine (117.86 g 1.1 moL) and EDC.HCl (230.04 g, 1.2 moL) at 0-5° C. under constant stirring. The reaction mixture was stirred at below 10° C. for 16 hours. When the reaction was considered complete, the agitation was stopped and the phases were allowed to separate. The organic phase was washed with water (856 mL), saturated sodium bicarbonate (2×713 mL), water (713 mL) and finally with a mixture of 2.85 mL of 30% HCl and 570 mL of water. The organic phase was concentrated under reduced pressure to a final volume of about 485 mL. MTBE (770 mL) was added and distilled again under reduced pressure to a final volume of about 485 mL. The reaction mixture was cooled to 20-25° C., and charged with heptanes (856 mL). The reaction mixture was heated to 28-32° C. and stirred for 1 hour, then cooled to 0-5° C. and stirred for 3 hours. The obtained mixture was filtered and the cake was washed with cold (0-5° C.) heptanes (285 mL). The resulting solid was dried under vacuum at 45-50° C. for 12 hours to provide (R)—N-benzyl-2-(dibenzylamino)-3-hydroxypropanamide as a white solid (353.82 g, yield 95%, HPLC purity >99.95%).