Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]1=[O:14].C1C(=O)N([Br:25])C(=O)C1>ClCCl>[Br:25][C:8]1[C:7](=[O:14])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)[C:11]([CH3:12])=[CH:10][C:9]=1[OH:13]
Reactant: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(O)c(Br)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A mixture of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.8 g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL) was stirred at room temperature, under argon atmosphere. After 1.5 h, the reaction mixture was diluted with dichloromethane (15.0 mL), cooled and filtered the solids. The residue was washed with dichloromethane and dried in vacuo to give 0.93 g of the title compound as a white powder: 1H-NMR (CD3OD/400 MHz) δ 7.33 (m, 1H), 7.2-6.8 (m, 3H), 6.07 (s, 1H), 5.34 (s, 2H), 2.26 (s, 3H); ESHRMS m/z 312.0016 (M+H C13H12NO2BrF requires 312.0035).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:26]([N:39]1[CH2:42][C:41](=O)[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH:26]([N:39]1[CH2:42][C:41](=[CH:4][O:5][CH3:6])[CH2:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 52 %

Procedure:
To a suspension of sodium hydride (60% mineral oil dispersion, 0.10 g, 2.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added (methyoxymethyl)triphenylphosphonium chloride (0.80 g, 2.3 mmol) at 0° C. The mixture was stirred at 0° C. for 40 minutes, then a solution of 1-benzhydryl-azetidin-3-one (0.50 g, 2.1 mmol) in tetrahydrofuran was introduced at 0° C. The resulting mixture was refluxed for 2 hours. The reaction was quenched with water and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude oil was column chromatographed on silica gel (20% ethyl acetate-hexane). The product-containing fractions were concentrated under vacuum to give 0.29 g (52%) of the title compound as a light yellow solid, m.p. 56-58° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:31])[N:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[N:24]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:26]=[CH:27][N:23]([CH:22]([F:31])[F:21])[N:24]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccn(C(F)F)n1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccn(C(F)F)n3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=432.2.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][C:17]=3[Cl:26])=[CH:12][CH:11]=2)[C:7]([CH3:27])=[N:6][C:5]=1[CH3:28])(=[O:3])[NH2:2].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.[NH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64]>CN(C=O)C>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])=[O:24])=[CH:18][C:17]=3[Cl:26])=[CH:12][CH:11]=2)[C:7]([CH3:27])=[N:6][C:5]=1[CH3:28])(=[O:3])[NH2:2]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
A solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 250 mg, 0.63 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0.79 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (85 mg, 0.63 mmol) and N-ethyl-N-isopropylpropan-2-amine (242 μL, 1.39 mmol) in DMF (2499 μL) was treated with a solution of methyl 2-aminoacetate hydrochloride (87 mg, 0.69 mmol) in DMF (417 μL) at 23° C. The resulting solution was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (25 mL), and washed sequentially with saturated brine (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)acetate (266 mg, 90%) which was used without further purification.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:9]1[CH2:10][N+:11](=[O:15])[CH:12]=[CH:13][CH:14]=1)[C:7]#[N:8]>CO.O>[CH3:3][O:4][N:5]=[C:6]([C:9]1[CH2:10][N:11]([OH:15])[CH2:12][CH2:13][CH:14]=1)[C:7]#[N:8]
Reactant: CON=C(C#N)C1=CC=C[N+](=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=C(C#N)C1=CCCN(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Sodium borohydride (0.13 g, 0.0034 mol) was added to a mixture of methanol (5 ml) and water (5 ml) at 0° C. To this was added dropwise a solution of α-(methoxyimino)-α-(1-oxopyridinium-3-yl)acetonitrile (D5) (0.2 g, 0.0011 mol) in methanol (30 ml) and water (5 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. The mixture was evaporated to dryness and the residue partitioned between saturated aqueous potassium carbonate (25 ml) and chloroform(3×30 ml). The organic extracts were combined and dried (Na2SO4) then filtered and evaporated to dryness. The residue was subjected to column chromatography on silica gel eluting with 0-2% methanol/chloroform to give a solid which was recrystallised from ethyl acetate/pentane to afford the title compound (E2) as a white crystalline solid (0.135 g, 67%) m.p. 145°-147° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([OH:19])=O)[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:19])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2c(C#N)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN1CCOc2c(C#N)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 7 %

Procedure:
A solution of 4-Butyl-8-cyano-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (129 mg), HBTU (284 mg), and diisopropylethylamine (0.26 mL) was stirred in methylene chloride (6 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (204 mg) in methylene chloride (4 mL) was added and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydrochloric acid (15 mL), saturated sodium bicarbonate (15 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 20 mg of the title compound: ESI MS m/z 577 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH3:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][C:5]([CH3:6])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:16])[CH3:2]
Reactant: CCI
Reactant: CCNCC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CC(C)(C)c1ccc([N+](=O)[O-])cc1
Yield: 85.8 %

Procedure:
In a 100 mL round bottom flask was charged N-ethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (1.50 g, 6.75 mmol), anhydrous acetonitrile (22 mL), ethyl iodide (1.16 mL, 7.43 mmol), and potassium carbonate (1.87 g, 13.5 mmol). The reaction was brought to reflux for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water and ethyl acetate and layers were separated. The organic layer was washed with once each with water, and then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give N,N-diethyl-2-methyl-2-(4-nitrophenyl)propan-1-amine (1.45 g, 86.1%). LC/MS (ESI+) 251 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]#[N:17])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cc(F)cc(F)c2)CCC1

Procedure:
3,5-Difluoro-aniline (Aldrich Chemicals) (2.6 g, 20.0 mmol), 2-oxocyclopentane carbonitrile (Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) and T.H.F. were heated under reflux for 24 hours. After cooling the mixture was filtered and the solvent evaporated. Kugelrohr distillation (140° C., 0.3 mmHg) gave the product as pale yellow crystals.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH2:10][CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH3:9])=[O:7]>C(Cl)(Cl)Cl>[Br:1][CH:10]([CH2:11][CH3:12])[C:4](=[O:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCC(=O)CC(=O)OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of bromine (8.61 mL, 167 mmol) in chloroform (20 mL) was added drop-wise over a period of 2 h to a solution of methyl 3-oxohexanoate (Fluka, 24.1 g, 167 mmol) in chloroform (147 mL), at 0° C. (ice bath). The reaction mixture was stirred for 30 min at 0° C. and then allowed to warm to room temperature overnight. While stirring, a stream of air was bubbled through the solution for 1 hour. The reaction mixture was dried over sodium sulfate and the solvent evaporated under reduced pressure to provide the desired compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:33]>O1CCOCC1.O>[CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[C:8]([OH:9])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: 105 °C
Yield: 59 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (715 mg, 1.63 mmol) in dioxane (5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.3 mL). The resulting solution was then heated at 105° C. for 16 h. The reaction was then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (12 g column, 10% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-propionic acid (278 mg, 59%) as a white solid: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C17H22O2S (M−H)− 289.1268, observed 289.1268; 1H NMR (300 MHz, CDCl3) δ 1.61-2.05 (m, 4H, 2×CH2), 2.45 (s, 3 H, ArCH3), 3.76 (m, 2H, OCH2), 4.00 (m, 2H, SO3CH2), 4.08 (m, 1H, OCH), 7.35 (brd, 2H, Ar), 7.81 (brd, 2H, Ar).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2c([nH]c1=O)CCCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(O)c(=O)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione (207 mg, 1.00 mol) in dry CH2Cl2 (2 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (2.0 mL, 1M, Aldrich) in one portion over 5 seconds at rt. A brown precipitate immediately formed. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (15 mL) and the resulting orange solution was allowed to stir for 15 min. The solution was extracted with CH2Cl2 (1×4 mL). The aqueous solution was acidified with coned HCl (pH 2), the resulting precipitate collected by filtration and washed to neutrality with water (6×2 mL). Crystallization from 95% EtOH yielded beige flakes (115 mg, 60%, pure by TLC, 1H NMR and C,H,N analysis); mp 237°-238° C. (dec.); 1H NMR (DMSO-d6) δ1.55 (m, 4H), 2.27 (m, 2H), 2.45 (m, 2H), 6.30 (s, 1H), 10.14 (bs, 1H), 10.84 (s, 1H). Anal. Calcd for C10H11NO3 : C, 62.17; H, 5.74; N, 7.25. Found: C, 62.23; H, 5.62; N, 7.26.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:4]=2[O:3]1.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:15][CH3:14])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2c1OC(C)(C)C2
Reaction time: 3 h
Yield: 99.6 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbaldehyde (281 mg, 1.59 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.63 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (61.5 mg, 1.63 mmol) was added and the mixture was stirred overnight at room temperature. Water (5 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (2,2-Dimethyl-2,3-dihydro-benzofuran-7-ylmethyl)-methyl-amine (303 mg, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.02 (m, 2H), 6.76-6.71 (m, 1H), 3.52 (s, 2H), 2.97 (s, 2H), 2.24 (s, 3H), 1.39 (s, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:10]([CH2:12][C:13]3[S:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].O.Cl>CO>[Cl:18][C:15]1[S:14][C:13]([CH2:12][C:10]2[N:9]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:8]3[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[CH:17][CH:16]=1
Reactant: CCC(CC)n1c(Cc2ccc(Cl)s2)nc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(CC)n1c(Cc2ccc(Cl)s2)nc2cc(C(=O)O)ccc21
Yield: 54.7 %

Procedure:
To 0.57 g of 2-(5-Chloro-thiophen-2-ylmethyl)-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid methyl ester in 3 ml of methanol were added 0.08 g of lithium hydroxide and 1 ml of water. The reaction was heated to reflux for 1 h. The reaction mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The product precipitated after treatment with diethylether and 0.30 g (55%) of 2-(5-Chloro-thiophen-2-ylmethyl)-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:14]1[CH:13]=[CH:12][NH:11][C:10]=1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:25][N:24]=1
Reactant: NN
Reactant: O=C(c1cccnc1Cl)c1[nH]ccc1-c1c(Cl)cccc1Cl
Solvent: CCO
Solvent: O
Product: Clc1cccc(Cl)c1-c1cc[nH]c1-c1n[nH]c2ncccc12

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-[3-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone (160 mg) and hydrazine hydrate (0.5 mL) in ethanol (8 mL) was heated at 90–100° C. for 24 hours. The reaction was concentrated, the residue was purified on a silica gel column to give 30 mg of the titled compound.
Reaction SMILES: C(O[C:4](=[O:24])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)[CH3:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:11]1[CH:10]=[C:9]2[C:14]([C:4]([OH:24])=[CH:5][C:6]([CH3:7])=[N:8]2)=[CH:13][C:12]=1[Br:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C=C(C)Nc1ccc(Br)c(OCc2ccccc2)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1cc(O)c2cc(Br)c(OCc3ccccc3)cc2n1
Temperature: 250 °C
Yield: 213.2 %

Procedure:
Dowtherm®A (320 mL) was heated to 250° C. then a solution of 3-(3-benzyloxy-4-bromo-phenylamino)-but-2-enoic acid ethyl ester (55.5 g, 99.5 mmol) in Dowtherm®A (120 mL) was slowly added. The reaction mixture was heated 16 min at 250° C. and ethanol was collected by distillation. The mixture was cooled down, diluted with hexanes (1.5 L) and filtered. The solid was washed with ether and dried under vacuum. 73.0 g of the title compound were obtained. Brown solid, ISP-MS: m/e=345.2 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](I)[CH2:21][CH3:22]>>[NH2:1][C:2]1[N:7]([CH2:20][CH2:21][CH3:22])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Product: CCCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and n-propyl iodide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:6][OH:7])#[N:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2]
Reactant: N#Cc1cc(CO)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A solution of the product from Example 82B (0.40 g, 2.6 mmol) in chloroform (50 mL) was treated with manganese dioxide (0.55 g, 7.8 mmol), stirred at room temperature overnight, filtered, solvent evaporated and the residue flash chromatographed over silica gel eluting with ethyl acetate:hexane (1:1) to provide 0.21 g 3-cyano-4-fluorobenzaldehyde.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:9]1[C:8](=[O:19])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2ccc(=O)n(C3CCCCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(Br)c(=O)n(C3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4 g, 14.5 mmol) was dissolved in dimethyl formamide (100 mL) and to this solution was added N-bromosuccinimide (3.9 g, 21.8 mmol) and benzoylperoxide (0.53 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 3 days then diluted with ethyl acetate and washed with water then twice with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6-bromo-8-cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one a cream colored solid (8 g). This crude intermediate was redissolved in CH2Cl2 and treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (3.78 g, 14.5 mmol). The resulting solution was stirred at room temperature overnight then concentrated under reduced pressure and chromotographed on silica gel eluting with ethyl acetate. 6-Bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was obtained as a colorless solid (3.72 g, 67%). 1H NMR: δ (400 MHz, CDCl3) 8.90 (s, 1H), 8.13 (s, 1H), 5.41 (br s, 1H), 2.96 (s, 3H), 2.58–1.70 (m, 2H), 1.87 (br d, J=13 Hz, 2H), 1.31–1.47 (m, 2H), 1.28 (t, J=3 Hz, 2H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1.[ClH:14].N([O-])=O.[Na+]>O>[Cl:14][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N)nc1CC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1sc(Cl)nc1CC
Reaction time: 0.5 h

Procedure:
Ethyl 2-chloro-3-oxo-pentanoate is prepared from ethyl 3-oxo-pentanoate and sulfuryl chloride utilizing the procedure of Bankowski et al, Rocz. Chem., Volume 49, Page 1899 (1971). A mixture of 9.2 g (0.0515 mole) of ethyl 2-chloro-3-oxo-pentanoate, 3.92 g (0.0515 mole) of thiourea and 30 ml. of ethanol was held at reflux for 17 hours. Ethanol was removed under reduced pressure and the residue was treated with 300 ml. of saturated sodium bicarbonate solution. The solid precipitate was collected to give 11.2 g of white solid, m.p. 165°-170° C. which was recrystallized from ethanol to give 7.7 g (75%) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate as colorless prisms, m.p. 177°-179° C. To a solution of 7.0 g (0.0349 mole) of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate and 0.2 g of CaSO4 in 60 ml. of concentrated HCl was added dropwise a solution of NaNO2 in 20 ml. of water in such a way that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 30 minutes and poured into a solution of 3.5 g (0.035 mole) of cuprous chloride in 30 ml. of 6 N HCl. The resulting dark blue solution was stirred for 30 minutes and extracted with ether. The ether solution was dried and concentrated under reduced pressure. The residue was Kugelrohr distilled at 2 mm. to give 4.35 g of yellow liquid which was chromatographed on silica gel to give 4.0 g (52%) of the desired product as colorless liquid, nD25 =1.5189.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([CH2:21]Cl)=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]([SH:27])([CH3:26])[CH3:25]>>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([CH2:21][S:27][C:24]([CH3:26])([CH3:25])[CH3:23])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(CCl)ccc2n1CC1CCOCC1
Reactant: CC(C)(C)S
Product: CC(C)(C)SCc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in step F of Example 15 from 2-tert-butyl-5-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole (step F of Example 25) and 2-methyl-2-propanethiol.