Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22](C(O)=O)=[N:21]2)[CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([C:10]#[N:11])[CH3:9].SCC(O)=O.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:9])[C:10]#[N:11]
Reactant: Cc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc(Cl)c1C(C)(C#N)c1ccc(Cl)cc1
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1C(C)(C#N)c1ccc(Cl)cc1
Temperature: 180 °C
Yield: 50 %

Procedure:
A mixture of 11.1 parts of 2-[3-chloro-4-[1-(4-chlorophenyl)-1-cyanoethyl]-5-methylphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid and 15 parts of 2-mercaptoacetic acid was stirred and heated for 2 hours at 180° C. The reaction mixture was cooled, water was added and the whole was treated with sodium hydrogen carbonate. The product was extracted with trichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 5 parts (50%) of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,6-dimethylbenzeneacetonitrile; mp. 226.7° C. (compound 1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:17]=[CH:16][C:3]=1[O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1>Cl.CO>[NH:7]1[CH2:6][CH:5]([O:4][C:3]2[CH:16]=[CH:17][C:18]([CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:19][C:2]=2[CH3:1])[CH2:8]1
Reactant: Cc1cc(CN2CCCC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: Cc1cc(CN2CCCC2)ccc1OC1CNC1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Intermediate 19A (0.75 g, 2.15 mmol) was dissolved in a 4.0 M solution of HCl in MeOH (20 mL) and the reaction mixture was stirred at RT over night. The mixture was concentrated and the residue was dissolved in water. The solution was basified to pH=10 with aqueous NaOH (1.0 M) and extracted with DCM (4×30 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 0.43 g (72%) of 19B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.71-1.83 (m, 4H), 2.33 (s, 3H), 2.43-2.55 (m, 4H), 3.52 (s, 2H), 3.73-3.85 (m, 2H), 3.85-3.96 (m, 2H), 4.91-5.03 (m, 1H), 6.52 (d, 1H), 6.57 (s, 1H), 7.17 (d, 1H).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]1[CH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[CH2:23](N)[CH2:24][NH2:25]>C(O)C>[NH:20]1[CH2:23][CH2:24][N:25]=[C:19]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][N:4]2[C:3](=[O:2])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:22][CH:21]=1
Reactant: NCCN
Reactant: N#Cc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cold solution of 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzonitrile (7.83 g, 28.3 mmol) in ethanol (400 mL) for 3 h, then the so obtained mixture was kept at 8° C. overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in dry ethanol (400 mL), ethylenediamine (2.0 mL, 29.7 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, the residue was partitioned between dichloromethane (400 mL) and concentrated ammonium hydroxide (400 mL), the phases were separated and the water phase was extracted with dichloromethane (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from 2-propanol to yield 5.58 g (62%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[NH2:21][C@H:22]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[C:23]([NH:25][C@@H:26]([C@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)=[O:28])=[O:24].C(N(CC)C(C)C)(C)C>O1CCCC1.O>[Br:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[C@@H:26]([N:25]2[C:23](=[O:24])[C@@H:22]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)[NH:21][C:2]2=[O:1])[C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[CH:31][CH:32]=1
Reactant: COc1ccc([C@@H](N)C(=O)N[C@H](C(=O)Nc2ccc(Br)cc2)[C@@H](C)c2ccccc2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc([C@H]2NC(=O)N([C@H](C(=O)Nc3ccc(Br)cc3)[C@@H](C)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of diphosgene (20 μL, 0.17 mmol) in 1:1 v/v toluene/tetrahydrofuran (16 mL total) at −35° C. under an atmosphere of dry argon was added a solution of (2S,3S)-2-[(R)-2-amino-2-(4-methoxy-phenyl)-acetylamino]-N-(4-bromo-phenyl)-3-phenyl-butyramide (120 mg, 0.24 mmol) and N,N-diisopropylethylamine (210 μL, 1.2 mmol) in tetrahydrofuran (8 mL) dropwise with stirring over 10 minutes. After an additional 45 minutes ice was added and the reaction mixture stirred vigorously and warmed to ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate (twice) and the combined organic layers were washed sequentially with water (twice), 0.1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel eluted with 2:1 v/v hexanes/ethyl acetate. The isolated product was dissolved in a small volume of dichloromethane and then precipitated by dropwise addition to a vigorously stirred large volume of petroleum ether. The precipitated solid was isolated by filtration and dried in vacuo to give (2S,3S)—N-(4-bromo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyramide as a colorless solid (87 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][C@@H:14]([CH2:16][O:17][CH3:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]3)[C:12]2=[O:30])=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:41]=[C:40]([CH3:42])[C:36]([C:37](O)=[O:38])=[C:35]([CH3:43])[N:34]=1>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH2:15][C@@H:14]([CH2:16][O:17][CH3:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:37]([C:36]4[C:35]([CH3:43])=[N:34][C:33]([Cl:32])=[CH:41][C:40]=4[CH3:42])=[O:38])[CH2:21][CH2:20]3)[C:12]2=[O:30])=[CH:8][CH:9]=1
Reactant: COC[C@@H]1CN(Cc2ccc(C(=O)OC)cc2)C(=O)N1C1CCN(C(C)CCN)CC1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Product: COC[C@@H]1CN(Cc2ccc(C(=O)OC)cc2)C(=O)N1C1CCN(C(C)CCNC(=O)c2c(C)cc(Cl)nc2C)CC1
Yield: 60 %

Procedure:
According to general procedure E, 4-{(S)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl}-benzoic acid methyl ester (40 mg) and 6-chloro-2,4-dimethyl-nicotinic acid gave 4-[(S)-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl]-benzoic acid methyl ester (32 mg, 60%).
Reaction SMILES: ClS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>C(OCC)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[C:12]2/[CH:11]([N:10]3[CH2:9][CH2:8][CH2:7]3)[CH2:16][CH2:15][CH2:14][CH2:13]/2)=[CH:19][CH:20]=1
Reactant: COc1ccc(C=C2CCCCC2NCCCO)cc1
Agent: O=S(=O)(O)Cl
Solvent: CCOCC
Product: COc1ccc(/C=C2\CCCCC2N2CCC2)cc1
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid was added dropwise during 7 min to a solution of N-(3-hydroxypropyl)-N-[2-(4-methoxyphenylmethylene)cyclohexyl]amine, 5 g (0.017 mole) in 325 ml of diethyl ether keeping the temperature at about 3° C. with cooling. The mixture was then stirred at this 3° C. temperature for 30 min and then at room temperature for 2 hr to ensure complete reaction. The resulting suspension was filtered and the solid washed with diethyl ether. The solid was added to a cold solution of 6.5 g of sodium hydroxide in 50 ml of water and the mixture was heated at 95° C. for 2 hr, then cooled in ice, saturated with solid sodium hydroxide and extracted with chloroform. The chloroform extract was dried with magnesium sulfate and evaporated. The residue was chromatographed on a Merck silica gel size C column using an 8% v/v methanol in chloroform solution containing 1% v/v ammonium hydroxide solution mixture as eluent. Elution of the residue loaded column with 560 ml of this mixture gave no material. The next 500 ml gave 0.41 g of (±)-(E)-1-[2-[(4-methoxyphenyl)methylene]cyclohexyl]azetidine as an oil. The NMR was consistent for this named product. A crystalline p-toluenesulfonate salt was prepared, mp 114°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11]([NH2:19])=[N:10][C:9]2([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:3]=1)[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cncnc3)c2)c2cccc(F)c21
Yield: 29 %

Procedure:
The title compound was synthesized as described for Example 12 in 29% yield, starting from 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyridin-4-yl)-1H-isoindol-3-amine (44 mg, 0.11 mmol) and 5-pyrimidinylboronic acid (18.66 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].C([O:7][C:8](=[O:14])[CH2:9][C:10]([CH2:12]Cl)=[O:11])C>[Pt].O>[OH:11][CH:10]([CH2:9][C:8](=[O:14])[O-:7])[CH2:12][N+:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN(C)C
Agent: [Pt]
Solvent: O
Product: C[N+](C)(C)CC(O)CC(=O)[O-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
In a 1 liter flask with a cooling jacket equipped with a mechanical stirrer and a thermometer, 295.5 gm. of aqueous trimethylamine solution (TMA) (40.0 percent, 2.00 moles) was prepared and cooled to 10° C. (in a cryometer, or tap water). With a hose-equipped perpex compression pump and a teflon hose, which was submerged (extended) into the TMA solution, 73.50 gm. of γ-chloroacetoacetic ethyl ester (89.6 percent, 40 moles) was added in doses during 3.5 hours at 10° C., while stirring well. The vessel and the teflon hose were flushed with 5 gm. of ethanol. After 1 hour of continued stirring, the excess TMA was sucked off on a rotavapor and condensed. The reaction solution was adjusted from pH 7.5 to pH 6.0 (using 11 ml of concentrated HC1). The brown solution was reacted with 2.2 gm. of platinum on activated charcoal (ex Fluka, 5% purest) and was hydrogenated in a 1 liter SFS laboratory autoclave during 5 hours at 10° C., 10 atm. and 750 rpm. The solution was filtered off from the catalyst. The resultant bright yellow solution was hydrolyzed with approximately 10 ml of concentrated hydrochloric acid (at most the pH was 0.5) in distillation apparatus. Subsequently this was evaporated to dryness and the residue was dried at 40° C. under high vacuum. The residue was suspended in 330 ml of absolute ethanol during 1.5 hours, was filtered and dried to a constant weight. 72.55 gm. of carnitine hdrochloride, with a melting point of 198° to 199° C, were obtained - this corresponded to a 90.5 percent yield, related to the starting γ-chloroacetoacetic ethyl ester.
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].S([O-])([O-])(=O)=O.[Al+3:15].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3]>>[O-:3][Si:1]([O-:4])=[O:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Al+3:15]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Na+]
Product: O=[Si]([O-])[O-]

Procedure:
U.S. Pat. No. 3,424,602 to Nauroth mixes a soluble sodium silicate with an aluminum sulfate solution to form sodium alumino silicate precipitates. The final product is also different from the alumina-silica-sulfates of this invention in that the precipitate is a product substantially lacking in sulfate content, with sulfate only present as sodium sulfate by-product.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)[CH3:2].C(N=C=S)C.[NH2:13][C:14]1[C:15]([Cl:30])=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[CH:21][CH:20]=[CH:19][CH:18]=2>N1C=CC=CC=1>[Cl:30][C:15]1[C:14]2[N:13]=[C:4]([NH:3][CH2:1][CH3:2])[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCN=C=S
Product: CCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Temperature: 80 °C
Yield: 77.2 %

Procedure:
Triethylamine (3.15 mL, 22.6 mmol) and ethyl isothiocyanate (1.19 mL, 13.6 mmol) were sequentially added to a solution of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) in pyridine (50 mL), and the reaction was heated for five minutes at 80° C. 1,(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.60 g, 13.6 mmol) was added slowly, and the reaction was heated overnight at 80° C., allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), and the resulting solution was washed with brine (3×) and water (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 2.78 g of 1-[4-chloro-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1OB(O)O.[F-].[Cs+].CN(C=O)C>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Ag]=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:19]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2
Reactant: CCOC(=O)c1cnc2cccc(Br)c2c1
Reactant: OB(O)Oc1c(F)cc(F)cc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=[Ag]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cccc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.9 %

Procedure:
Under argon gas atmosphere, a mixture of ethyl 5-bromoquinoline-3-carboxylate (113 mg), 2,4,6-trifluorophenylboric acid (106 mg), bis(tri-t-butylphosphine)palladium (41 mg), cesium fluoride (123 mg), silver oxide (112 mg), and DMF (2 mL) was heated under stirring in an oil bath at 100° C. for 15 hours. The reaction liquid was returned to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl 5-(2,4,6-trifluorophenyl)quinoline-3-carboxylate (60 mg).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[O:22][C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>O1CCOCC1>[CH:26]([C:23]1[O:22][C:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:25][N:24]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nnc(C2CCNCC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.3 %

Procedure:
100 mL saturated dioxane-HCl was added to 16 g 4-(5-isopropyl-(1,3,4) oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester in 100 mL dioxane at 0° C. The mixture was stirred at RT for 2 h. The precipitate was filtered and washed with ethyl acetate to give 12.3 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N+:23]([O-])=O)([CH3:22])[CH2:20][OH:21])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Zn]>[NH2:23][C:19]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:18]=[CH:17]2)([CH3:22])[CH2:20][OH:21]
Reactant: CCCCCCCOc1ccc2cc(C(C)(CO)[N+](=O)[O-])ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc2cc(C(C)(N)CO)ccc2n1
Temperature: 20 °C
Reaction time: 15 h
Yield: 27.4 %

Procedure:
2-(2-(heptyloxy)quinolin-6-yl)-2-nitropropan-1-ol (200 mg, 0578 mmol) was dissolved in acetic acid (5 mL). zinc (376 mg, 5.78 mmol, 10.0 eq.) was added to the mixture at 0° C. and the mixture was stirred at 20° C. for 15 h. Saturated sodium carbonate solution was added to the mixture until pH=8. Then the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel column chromatography using dichloromethane/methanol (10/1) as eluent to give product (50 mg, 27%) as a slight yellow solid. ESI-MS: 317.2 (M+H)+. HPLC: 95.99%. 1H NMR (400 MHz, CD3OD) δ 8.09 (d, 1H), 7.81-7.79 (m, 2H), 7.68 (q, 1H), 6.92 (d, 1H), 4.38 (t, 2H), 3.84 (d, 1H), 3.74 (d, 1H), 1.86-1.75 (m, 2H), 1.70 (s, 3H), 1.43-1.25 (m, 8H), 0.85 (t, 3H).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
48 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 50 mg of potassium carbonate were dissolved in 0.6 ml of water and 3 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.019 ml of n-hexyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]([CH3:16])[CH3:15])[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=1)[C:7]2=[O:54])([O-])=O>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]([CH3:15])[CH3:16])[N:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=1)[C:7]2=[O:54]
Reactant: CC(C)c1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CC(C)c1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
6-Nitro-2-isopropyl-3-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)-methyl]-quinazolin-4-(3H)-one was hydrogenated overnight at 1 atm H2 in dioxane solution in presence of Raney nickel catalyst as described above. The product was purified by flash chromatography over silica gel eluting with CH2Cl2 /MeOH-20/1 to give a pale yellow solid. 1H-NMR (CDCl3): 1.20, (d, 6H, J=6.4 Hz), 2.89-3.06, (m, 1H), 5.34, (br.s, 2H), 6.85-7.68, (m, 24H), 7.84-7.92, (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](I)=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)#[CH:14].N#N>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)nc1I
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)nc1C#Cc1ccc(F)cc1
Temperature: 85 °C
Yield: 73.4 %

Procedure:
6-bromo-2-iodopyridin-3-yl acetate (3.50 g, 10.24 mmol), 1-ethynyl-4-fluorobenzene (1.11 g, 9.21 mmol), copper (I) iodide (117 mg, 0.614 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (359 mg, 0.512 mmol) were combined and evacuated/backfilled with N2 (3×) then diluted with triethylamine (100 ml) and heated to 85° C. for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL) and brine, dried over Na2SO4, filtered, and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 6-bromo-2-((4-fluorophenyl)ethynyl)pyridin-3-yl acetate (2.26 g, 6.76 mmol, 66.1% yield) consistent by NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (2H, s), 7.70 (2H, dd, J=8.78, 5.52 Hz), 7.34 (2H, t, J=8.91 Hz), 2.41 (3H, s). LC-MS retention time: 2.18 min; m/z: parent ion not observed, -Ac: 292, 294. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.