Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[C@:5]([NH2:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:6].[CH3:18][NH:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=S>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:20]1[N:19]([CH3:18])[C:3](=[O:17])[C:4]([CH3:15])([CH3:16])[C@:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])([CH3:6])[N:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1ccccc1F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2ccccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=364.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22]([C:21]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:8][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc(OC)cc2)n1
Temperature: 65 °C
Yield: 48.4 %

Procedure:
To an ice-cold solution of 4-methoxy-thiobenzamide (0.50 g, 2.98 mmol) in ethanol (25 ml) was added triethylamine (0.41 ml, 2.98 mmol) followed by dropwise addition of ethyl bromopyruvate (0.56 ml, 4.40 mmol). The reaction mixture was heated at 65° C. for 12 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (0.38 g, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:70])[NH:10][C@H:11]([C:37](=[O:69])[N:38]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)[CH2:39][C:40](=[O:53])[NH:41][CH2:42][C:43]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:46][CH2:45][CH2:44]1)[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:70])[NH:10][C@H:11]([C:37](=[O:69])[N:38]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:59][CH:60]=1)[CH2:39][C:40](=[O:53])[NH:41][CH2:42][C:43]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:46][CH2:45][CH2:44]1)[CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)NCC1(c2ccccc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of the trityl compound from Step 4 above (0.49 g) in DCM (10 mL) was added TFA (10 mL). The solution was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Flash chromatography (10% MeOH in DCM) gave 0.22 g (50% yield over two steps) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:4][C:5](Cl)=[O:6])[CH:2]=[CH2:3].[NH2:8][CH2:9][C:10]([OH:12])=[O:11]>O.[OH-].[Na+]>[CH2:1]([O:4][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: NCC(=O)O
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0°, 12 ml of chloroformic acid allyl ester are added dropwise to a solution of 7.51 g of glycine in 20 ml of water and 44 ml of 5N NaOH solution. The suspension is then stirred for 16 hours at room temperature. After removing the insoluble material by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH2Cl2. The aqueous phase is adjusted to pH 2 with 4N HCl and extracted twice with CH2Cl2. The combined organic extracts are washed once with brine, dried over MgSO4 and concentrated by evaporation to form the white crystals of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[C:4]([CH3:10])[CH:3]=1.[CH:11](=O)[CH2:12][CH3:13]>CCO.C(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:10])[CH:3]=1)[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: Cc1cc(Br)ccc1NN
Reactant: CCC=O
Solvent: CCO
Product: Cc1c[nH]c2c(C)cc(Br)cc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
200 mg of 1-(4-bromo-2-methylphenyl)hydrazine was suspended in 10.0 mL EtOH propionaldehyde (678 μL) was added. The reaction became clear after the addition of propionaldehyde. The resulting solution was then stirred at room temperature for 45 minutes. The reaction was concentrated and zinc(II)chloride (1070.0 mg) was added and the mixture was heated at 170° C. for 30 minutes. The melting mixture was then cooled to room temperature, and diluted with 10% HCl solution. The solution was then extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (0-10% EtOAc/Haptanes gradient) to obtain 317.0 mg of 5-bromo-3,7-dimethyl-1H-indole. LC-MS @ 222.1 (M−1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].ClCCl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OC(=O)C(C)(C)C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
4-Hydroxypyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 28, (1.42 mg, 4.40 mmol) is dissolved in pyridine (22 mL). 4-Dimethylamino-pyridine (10 mg) is added followed by trimethylacetyl chloride (1.63 mL, 13.2 mmol). The reaction is stirred at ambient temperature for 12 hours. The cloudy reaction mixture is then concentrated in vacuo to afford a white residue. Dichloro-methane (75 mL) is added to the residue and the mixture washed with a 1.0 N aqueous solution of hydrochloric acid (75 mL). The aqueous layer is extracted with dichloro-methane (75 mL), the combined organic layers washed with a saturated aqueous solution of NaHCO3 (75 mL), water (75 mL), brine (75 mL), then dried, filtered and concentrated in vacuo to afford the crude product. The crude product is purified over silica(4:1 to 1:1 hexane/ethyl acetate) to afford 1.76 g (98% yield) of the desired product as a clear, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[C:7]1=[O:14].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[C:8]([I:13])[C:7]1=[O:14]
Reactant: O=c1c(I)c(O)ccn1Cc1cccc(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin-2(1H)-one (0.5 g, 1.44 mmol) in DMF (5 mL) was added K2CO3 (0.199 g, 1.44 mmol) followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. 1H-NMR (CD3OD, 400 MHz) δ 7.75 (d, 1H, J=7.6 Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.19 (s, -2H); ES-HRMS m/z 454.0098 (M+H calculated for C19H15NO2F2I requires 454.0110).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].FS(O)(=O)=O.[CH3:18]O>O>[CH3:18][O:1][C@H:2]1[O:10][CH:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Agent: O=S(=O)(O)F
Solvent: O
Product: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an autoclave of 300 cc volume, 50 g of anhydrous crystalline glucose, 5 g of perfluorosulfonic acid resin ("NAFION" powder 511) and 133 g of methyl alcohol were charged. The reaction was effected at 120° C.±1° C. for 30 minutes while stirring at 600 r.p.m. The gauge pressure was 6.0 Kg/cm2. After cooling to room temperature, NAFION was separated by filtration whereby a colorless, transparent methanolic solution was obtained. By adding water and evaporating methanol at 40° C. under reduced pressure, an aqueous methyl glucoside solution was obtained. The aqueous solution was essentially colorless and transparent and 53.6 g of solid matters were contained therein. By liquid chromatography and enzymatic method, the composition of the solid matters was found to be the following:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](O)=[O:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:25](=[O:26])[CH:24]([CH2:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)C(CCCc1ccccc1)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
1-Benzyl-4-aminopiperidine (0.5 g; 2.63 mmol) is dissolved in DMF (25 mL) at ambient temperature. 5-Phenyl-2-(3-phenyl-propyl)-pentanoic acid (22) (0.78 g; 2.62 mmol), triethylamine (0.46 mL; 3.28 mmol), 1-hydroxybenzotriazole (0.444 g; 3.28 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.554 g; 2.89 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then poured onto ethyl acetate (250 mL) and extracted successively with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (10%→67% ethyl acetate in hexanes) affording the desired product (1.07 g) as a white solid. ESMS: MH+ 469.4 (base).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([C:18]4([C:21]([OH:23])=O)[CH2:20][CH2:19]4)[N:17]=[C:13]3[C:12]([O:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.C[N:33](C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[N:15]=[C:16]([C:18]4([C:21]([NH2:33])=[O:23])[CH2:20][CH2:19]4)[N:17]=[C:13]3[C:12]([O:24][CH3:25])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2ccc(C#N)cc2)n2nc(C3(C(=O)O)CC3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C#N)cc2)n2nc(C3(C(N)=O)CC3)nc12
Reaction time: 0.08 h

Procedure:
1-[5-(4-Cyano-phenyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-cyclopropanecarboxylic acid (27 mg, 0.08 mmol) was dissolved in DCM (0.3 mL). Oxalyl chloride (0.008 mL, 0.09 mmol) and drop of DMF was added. Stirring for 5 min. Oxalyl chloride (0.003 mL) was added. After 20 min the suspension was concentrated and re-suspended in dioxan (0.3 mL). Aq. NH3 (25%, 0.1 mL) was added. The suspension was stirred at rt for 2 h after which it was concentrated in vacuo. The crude product was mixed with aq. Na2CO3 and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as a slightly coloured solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1[C:37]([CH3:38])=[CH:36][C:26]2[NH:27][C:28]([C:30]3[C:34]([NH2:35])=[CH:33][NH:32][N:31]=3)=[N:29][C:25]=2[CH:24]=1.[N:39]1([CH2:44][C:45](O)=[O:46])[CH:43]=[N:42][N:41]=[N:40]1>CN(C)C=O>[CH3:38][C:37]1[C:23]([CH3:22])=[CH:24][C:25]2[NH:29][C:28]([C:30]3[C:34]([NH:35][C:45](=[O:46])[CH2:44][N:39]4[CH:43]=[N:42][N:41]=[N:40]4)=[CH:33][NH:32][N:31]=3)=[N:27][C:26]=2[CH:36]=1
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Reactant: O=C(O)Cn1cnnn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)Cn3cnnn3)[nH]c2cc1C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
A stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 μl) in dimethylformamide (10 ml) were treated with 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg, Example 233(c)] and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). The reaction mixture was stirred for 72 hours then treated further with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 μl) and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). Stirring was continued for a further 48 hours then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to give N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide (13.7 mg) as an off-white solid. MS: 338.14 (M+H)+. HPLC (METHOD B1): RT=7.26 minutes.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]2[O:24][CH:25]=[CH:26][N:27]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].CO>O>[O:24]1[CH:25]=[CH:26][N:27]=[C:23]1[C:11]1[NH:10][C:14]2=[N:15][CH:16]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:18]=[C:13]2[CH:12]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ncco3)cc2c1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.35 g), potassium hydroxide (0.34 g) and methanol (30 ml) was stirred at 15 to 30° C. for 30 minutes. To the reaction mixture was added water, the resulting mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.19 g of the desired product.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[OH-].[NH4+].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)=[O:16]>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[NH:17][C:15](=[O:16])[CH2:14][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Yield: 326.5 %

Procedure:
A mixture of ethanol (1100 mls), hexamethylenetetramine (35 g., 0.25 mol), 26% ammonium hydroxide (58 ml), and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) were permitted to react as described in Example 11 except that the reflux period was increased from 5 to 7 hours. The reaction product, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (221 g.) isolated in a manner identical with Example 11, was obtained in 81.6% yield, melting point 208.5° to 209° C.
Reaction SMILES: [OH:1][C:2]1C=CC(C=O)=C(OC)C=1.Cl[C:13]1[CH:14]=[C:15]([CH:20]=[C:21](OC)[C:22]=1[OH:23])[C:16]([NH:18][OH:19])=[NH:17]>>[OH:23][C:22]1[CH:13]=[CH:14][C:15]([C:16]([NH:18][OH:19])=[NH:17])=[C:20]([O:1][CH3:2])[CH:21]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: COc1cc(C(=N)NO)cc(Cl)c1O
Product: COc1cc(O)ccc1C(=N)NO

Procedure:
The title compound is prepared form commercially available 4-hydroxy-2-methoxy-benzaldehyde in analogy to 3-chloro-4,N-dihydroxy-5-methoxy-benzamidine; LC-MS: tR=0.42 min; [M+1]+=183.04.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=2)[NH:7][CH:6]=1.O.[OH-].[Li+]>CO>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: COC(=O)CCc1ccc2[nH]cc(CCN(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(CCC(=O)O)cc12

Procedure:
A mixture of Methyl 3-[2-(Dimethylamino)ethyl]-1H-indole-5-propanoate (4.6 g) and lithium hydroxide hydrate (0.7 g) in aqueous methanol (1:1) (80 ml) was stirred under reflux for 4.5 h. The solvent was removed by evaporation to leave a foam which was purified by flash chromatography (E). Evaporation of the appropriate fractions gave a solid which was triturated with ether to present the title compound as a powder (2.92 g) m.p. 195°-200°.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.CCCCC>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccccc1Oc1ccccn1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: BrC(Br)=Cc1ccccc1Oc1ccccn1
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a solution of carbon tetrabromide (54.09 g, 162.9 mmol), and zinc (10.97 g, 162.9 mmol) in CH2Cl2 (800 mls) was added triphenylphosphine (42.68 g, 162.9 mmol) and the mixture was allowed to stir for 18 hrs. 2-(2-Pyridyloxy)benzaldehyde (16.21 g, 81.5 mmol) was then added as a solution in CH2Cl2 (50 mls) and the reaction was stirred for 2 hrs. It was then poured into pentane (1.6 liters) with good stirring, then allowed to stand for 1 hr. The solution was decanted and concentrated. The residue left after decantation was taken up in 1N NaOH (500 mls) and filtered through Celite. It was then washed with CH2Cl2 (500 mls). This organic was dried with MgSO4, concentrated and combined with the material obtained from the decanted solution to afford 29.01 g of 1,1-dibromo-2-(2-(2-pyridyloxy)phenyl)ethene as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DIEA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C[O-].[Na+].Cl.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CCO.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[N:3]=1)[C:8]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[NH:9]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: NC1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: N=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
2,6-dichloropyridine-4-carbonitrile (5 g, 28.9 mmol), methanol (50 ml) and sodium methoxide (0.66 ml, 2.89 mmol) were mixed and stirred at r.t. for 3 h. HCl in EtOH (24% w/w, 10 ml) and cyclopropylamine (3 mL, 43.4 mmol) were added at 0° C., followed by stirring at r.t. o.n. The reaction mixture was concentrated in-vacuo. The isolated residue was treated with cold aq. NaOH (1N, 75 ml) and extracted with EA. The combined organic phase was washed sequentially with aq. NaOH and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The isolated residue was triturated with Et2O to isolate the title compound (3.82 g). 1H-NMR: 7.59 (br. s, 2H), 4.96 (br. s, 2H), 2.60 (m, 1H), 0.90 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][N:34]([C@H:35]1[CH2:36][CH2:37][C@H:38]([CH3:41])[CH2:39][CH2:40]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccc(F)c(F)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 3,4-difluorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.74 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-difluorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties: