Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:10]=3[CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCC1c1ccc(F)cc1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CC2
Temperature: 130 °C
Yield: 52.6 %

Procedure:
A mixture of 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol) and carbonisocyanatidic chloride (19.77 g, 187 mmol) was heated at 58° C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, the tarrified reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (13.527 g, 54.7 mmol, 52.5% yield) as brown solid. LC-MS (M+H)+=248.1. 1H NMR (500 MHz, CDCl3) δ ppm 11.80 (1H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95 (1H, m).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@:21]3([OH:39])[CH2:22][CH2:23][C@@H:24]2[C:34]2[CH:38]=[CH:37][O:36][CH:35]=2)[CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>C(O)C>[N:43]1([CH2:42][CH2:41][NH:40][CH2:12][CH2:13][O:14][C@H:15]2[CH2:32][CH2:31][C@@:30]3([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@:21]4([OH:39])[CH2:22][CH2:23][C@@H:24]3[C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)[CH2:16]2)[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: NCCN1CCCC1
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@H](OCCNCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O

Procedure:
To a solution of 0.20 g of 3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of absolute ethanol 0.15 g of 1-(2-aminoethyl)pyrrolidine were added. The solution was kept at reflux under nitrogen for 3 hrs, then 10 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.15 g of the title compound (I-ag).
Reaction SMILES: [C:1](O)(=O)C.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1.C(=O)CC>CO>[CH2:1]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:9]=2[CH2:8][CH2:7][NH:6]1
Reactant: CC(=O)O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CCC=O
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 75 °C

Procedure:
Acetic acid was added dropwise to a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (200 mg) in 7 mL methanol until the pH=4. Propionaldehyde (0.2 mL) was added and the mixture was heated at 75° C. in a sealed tube for 1 h. The tube was cooled to rt and unsealed. The solvent was evaporated to yield 190 mg of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH2:7])(=[O:3])[CH3:2].[C:8]1([SiH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][Si:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOC(C)=O
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(=O)OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
0.5 ml of a 0.1 N solution of chloroplatinic acid as the catalyst in 2-propanol was added to an excess amount [58.1 g (581 mmol)]of allyl acetate (B). 40 g (15.4 mmol) of triphenylsilane (A) was added thereto and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction according to the disappearance of an absorption due to SiH at 2100 cm-1 in the I.R. absorption spectrum, excess (B) was distilled off under reduced pressure. The residue was purified according to column chromatography to obtain 51.1 g (14.2 mmol) of 3-acetoxypropyltriphenylsilane (C) (yield: 92.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[ClH:1].[Cl:29][C:27]1[CH:26]=[C:25]([OH:30])[CH:24]=[C:23]([NH:22][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cc(O)cc(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (3.24 g, 9.95 mmol) was dissolved in 2-propanol (40 mL). 3-Amino-5-chlorophenol (1.50 g, 10.4 mmol) from Example 64A and a 4 M solution of gaseous hydrogen chloride in dioxane (124 μL, 0.50 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further hydrogen chloride in dioxane (5.0 mL, 20 mmol) was added, and the mixture was heated for additional 3 h. The resulting precipitate was collected by suction filtration to yield 3.63 g (99%) of the title compound.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:14]1([O:22][CH3:23])[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:16][CH3:17]>O1CCCC1.C1(C)C=CC=CC=1>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:15]([O:16][CH3:17])[C:14]=1[O:22][CH3:23]
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 2 L flask, 72 g of veratrole was dissolved in 300 g of tetrahydrofuran and 155.3 g of butyllithium in toluene was added at temperatures from −10° C. to over 30° C. The mixture was stirred from 1-4 hours at ambient temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 180 mL of toluene was added around ambient temperature. The reaction mixture was stirred from 30 minutes to 5 hours. The solution was then cooled to around 5° C. and quenched with 200 mL of water. The phases were separated and the organic phase was distilled to remove the tetrahydrofuran. The residue was taken up in toluene at −5° C. The 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) was collected by filtration and washed with 60 g of toluene.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH3:12]>>[O:4]=[C:2]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:14]([O:13][CH2:11][CH3:12])=[O:23])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)C(C(=O)OCC)c1cccc(Cl)c1

Procedure:
The title compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4,216,218) from diethyl oxalate and ethyl(3-chlorophenyl)acetate.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1CCC(=O)O
Yield: 56.9 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (220 mg), 147 mg 5-chloro-2-oxindole, and 2 drops of piperidine in 2 mL of ethanol were heated to 90° C. for 3 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 172 mg of the title compound (50%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:10]2[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]1=[O:17].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[CH:22]1([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[CH:7][C:6]2=[O:17])[CH2:24][CH2:23]1
Reactant: CSc1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CSc1ncc2ccc(=O)n(Cc3ccccc3C3CC3)c2n1
Temperature: 140 °C
Yield: 65.9 %

Procedure:
8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.41 mmol, Example 30), cyclopropylboronic acid (107 mg, 1.25 mmol), K3PO4 (264 mg, 1.24 mmol) and PdCl2(Pcy3)2 (15 mg, 0.02 mmol) were mixed as solids and placed under argon. Argon was bubbled through a mixture of toluene:water (20:1, 1.5 mL) for 20 min. The solvent was added to the solid and the suspension was heated under microwave irradiation at 140° C. for 1.5 h. The reaction mixture was then diluted with toluene (10 mL) and water (1×5 mL), the two phases were separated, and the aqueous layer was extracted with toluene (1×10 mL). The combined organic layers were washed with water (1×10 mL) and evaporated to dryness. The crude compound was purified by silica gel column chromatography using dichloromethane:methanol (100:0.5) to yield 8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as an off-white solid (88 mg, 0.27 mmol, 66%). ESMS m/z 324 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCl.[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15]Br>ClCCCl>[Br:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH:7]=[O:14]
Reactant: BrBr
Reactant: O=Cc1ccccc1
Agent: ClCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=Cc1cccc(Br)c1
Reaction time: 2 h
Yield: 149.7 %

Procedure:
To 1,2-dichloroethane (1,2-dichloroethane: 143.8 g, 1-bromo-2-chloroethane: 60.5 g, 1,2-dibromoethane: 4.8 g) recovered from Example 2 was added fresh 1,2-dichloroethane (41.5 g), and 98% aluminum chloride (0.65 mol, 88.6 g) was mixed. Into this was blown chlorine (0.25 mol, 17.8 g) at °C., and 97% benzaldehyde (0.50 mol, 54.6 g) was added over 1 hour at 40° C. After bromine (0.30 mol, 48.0 g) was added dropwise to this mixture over 2 hours at 40° C., the resulting mixtures were stirred for 2 hours at that temperature. The post-treatment was carried out by the similar procedure to that in Example 1. As a result, 83.1 g of 3-bromobenzaldehyde were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>ClCCl>[Cl:13][CH2:14][C:15]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1CCNC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To an ice-cooled solution of pyrrolidine (0.4 g, 5.62 mmol) in dichloromethane (4 mL), triethylamine (1.176 mL, 8.44 mmol) and chloroacetyl chloride (0.451 mL, 5.62 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was concentrated in vacuo and residue was purified by column chromatography to give title compound (0.5 g, 60.2%); MS: 147.10 (M+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[C:16]1([CH:22]2[O:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:25][NH:24][C:23]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:30]2[CH2:29][CH2:28][C:26]3([CH2:25][NH:24][C:23](=[O:33])[CH:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:27]3)[CH2:32][CH2:31]2)=[O:11])=[CH:7][C:6]=1[CH3:14])([CH3:2])[CH3:3]
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: O=C1NCC2(CCNCC2)OC1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CNC(=O)C(c2ccccc2)O3)ccc1OC(C)C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
To 4-isopropoxy-3-methyl-benzoic acid (114 mg, 0.59 mmol), 4-phenyl-5-oxa-2,9-diazaspiro[5.5]undecan-3-one hydrochloride salt (166 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) in DMF (0.5 mL) was added diisopropylethylamine (228 mg, 307 μL, 1.76 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo, diluted with methanol and purified by prep LCMS (1-99% ACN/H2O, 5 mM HCl modifier) to give 3-(4-isopropoxy-3-methyl-benzoyl)-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-9-one (100 mg, 40%) as a yellow foam. ESI-MS m/z calc. 422.2. found 423.5 (M+1)+; Retention time: 1.61 minutes (3 min run).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@@H:11]([CH3:26])[CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([O:17][Si](CC)(CC)CC)[CH3:16])(C)(C)C.F.O>C(Cl)Cl>[CH3:26][C@@H:11]([CH2:12][CH2:13][CH2:14][C:15]([CH3:25])([OH:17])[CH3:16])/[CH:10]=[CH:9]\[CH2:8][CH2:7][OH:6]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@H](C)/C=C\CCO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: O
Solvent: ClCCl
Product: C[C@H](/C=C\CCO)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.3 %

Procedure:
To a stirred solution of compound 12 (201 mg, 0.4 mmol) in anhydrous CH2Cl2 (10 mL) was added hydrofluoric acid (48%, 6 mL). After 40 minutes of stirring at room temperature, water was added, and the organic layer was separated, washed with water and NaHCO3, dried over MgSO4, and evaporated. The residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (6:4) as an eluent to give an oily diol 13 (76.4 mg, 92%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][NH2:5].[F:8][C@@:9]([CH3:33])([C:13]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14])[C:10](O)=[O:11]>>[F:8][C@:9]([CH3:33])([C:10]([NH:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[O:11])[C:13]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14]
Reactant: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)F
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
The title compound [MS m/e (%): 452.3 (M+H+, 100)]was prepared in analogy to example 14 from 3,3,3-trifluoropropylamine and (2S)-2-fluoro-2-methyl-N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([N:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 98.6 %

Procedure:
To a solution of (S)-ethyl 2-aminopropanoate hydrochloride (4.59 g, 30.0 mmol) and K2CO3 (12.4 g, 90.0 mmol) in MeCN was added (bromomethyl)benzene (12.9 g, 75.0 mmol) at RT. The mixture was stirred at 70° C. for 14 h. The reaction mixture was quenched with aq. NH4Cl. After concentration, the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (100:1) to afford 8.8 g (98%) of (S)-ethyl 2-(dibenzylamino)propanoate (26): LCMS (ESI) m/z: 298.2 [M+11]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17]>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 65 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
4-Morpholin-4-ylmethyl-benzene-1,2-diamine (1 mol. eq.) and 4-nitro-1H-pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). O-(Benzot πazol-1-yl)-N,N,N′,N1-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stiffed at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65° C. for ˜12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75° C. The black solution was cooled to 0-5° C. over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pII of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5° C. for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M−H+]− 327).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([Cl:10])[CH:3]=1.CC(C[AlH]CC(C)C)C.C[OH:21].Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:21])=[C:4]([Cl:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(Br)cc1Cl
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To 4-bromo-2-chlorobenzonitrile (2.0 g, 9.2 mmol) in toluene (50 mL) at −78° C. under argon was added DIBAL (1M solution in toluene, 13.9 mL, 13.9 mmol). The mixture was allowed to warm to −50° C. over 4 h. MeOH (4.5 mL) and water (4.5 mL) were added and the mixture stirred for 10 min at −50° C. The mixture was allowed to warm to rt, acidified with 2N HCl (pH<7) and extracted with EtOAc (200 mL) and water (100 mL). The aqueous was further extracted with EtOAc (2×50 mL), the combined organics were then washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (25% DCM: Iso-hexane) to give 4-bromo-2-chlorobenzaldehyde. To a solution of 4-bromo-2-chlorobenzaldehyde (750 mg, 3.4 mmol) in DME (22 mL) and EtOH (15 mL) was added 3-carboxamidobenzene boronic acid (676 mg, 4.1 mmol) and 2M Na2CO3 solution (15 mL). Argon was bubbled through the mixture for 15 min. Bis(triphenylphosphino) palladium dichloride (120 mg, 0.17 mmol) was added and the reaction heated to 75° C. for 6.5 h before cooling to rt. The mixture was partitioned between water (200 mL) and EtOAc (200 mL), the aqueous was extracted with EtOAc (2×50 mL) and the combined organics dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (50% EtOAc: Iso-hexane to 100% EtOAc) to give the title compound: RT=3.19 min; m/z (ES+)=301.0 [M+H+MeCN]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14]CC(O)=O)[C:9]1=[O:19].C(Cl)Cl>CN(C)C=O>[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14][CH2:1][C:2]([Cl:4])=[O:3])[C:9]1=[O:19]
Reactant: CN1C(=O)CN(CCC(=O)O)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)CN(CCC(=O)Cl)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
340.9 g (2.6857 mol) of oxalyl chloride are added dropwise over the course of 18 minutes at an internal temperature of 19°-23° C. to a solution of 100.0 g (0.537 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid, synthesized as described in Example 6, 350 ml of methylene chloride and 1 ml of dimethyl formamide, and the mixture is subsequently stirred at room temperature for 5 hours and 10 minutes. When the reaction is complete, the reaction mixture is evaporated in a rotary evaporator, the residue is stripped 3 times at 50° C. under reduced pressure with 100 ml of toluene in each case, and the residue is dried at 60° C./0.1 mbar to constant weight, giving 106.1 g (97.3% of theory) of solid, brownish 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionyl chloride having the following analytical data:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[CH:16]=[C:15]([N+:6]([O-:9])=[O:7])[C:14]([F:17])=[CH:13][C:12]=1[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1Cl
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To concentrated sulfuric acid (23.81 g), cooled to 0° C., under a nitrogen atmosphere, was added concentrated nitric acid (27.5 g) dropwise. 2-Chloro-5-fluorotoluene (9 g) was added dropwise and the reaction was stirred for 2 hours. The reaction was poured into ice and extracted with ethyl acetate. The organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography [eluting with ethyl acetate/heptane (1:2)] to yield the title compound (9.4 g).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:37]1([C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of Boc-Gly-OH (80) (4.0 g, 22.83 mmol) in dry CH2Cl2 (50 mL) at 0° C. under N2 was added HATU (8.70 g, 22.9 mmol). After stirring for 15 min at r.t., 1,2,3,4-tetrahydroquinoline (2.9 mL, 23.0 mmol), and DIPEA (12 mL, 68.8 mmol) were added. The reaction was stirred for 36 h at room temperature. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3, 5% HCl, water, and saturated NaCl. Dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-50% EtOAc in hexanes) to afford 81 as a solid (5.76 g, 87%).