Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9]O)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(F)ccc1OCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OCCCCl
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 12.6 parts of 3-(4-fluoro-2-nitrophenoxy)propanol, 0.9 parts of N,N-dimethylformamide and 150 parts of trichloromethane were added dropwise 8.36 parts of thionyl chloride and stirring was continued for 1 hour at room temperature. The whole was further stirred and refluxed for 3 hours. The reaction mixture was evaporated under methylbenzene. The residue was stirred in petroleum ether. The product was filtered off and dried, yielding 7.41 parts (55%) of 1-(3-chloro- propoxy)-4-fluoro-2-nitrobenzene; mp. 143.3° C. (intermediate 25).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:22][OH:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Yield: 71.1 %

Procedure:
A mixture of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (9.13 g, 0.0316 mol), hydroxylamine hydrochloride (2.64 g, 0.0380 mol), and sodium carbonate (4.04 g, 0.0381 mol) in absolute ethanol was refluxed under nitrogen for 13.5 hours and allowed to cool. The resulting suspension was filtered, and the filter cake was washed with ethanol followed by diethyl ether. The filter cake was dried under house vacuum to give a white solid. The solid was dissolved in methanol (450 mL), and the cloudy solution was filtered to remove fines. The filtrate was stirred while one equivalent of 1 M HCl was added dropwise followed by dropwise addition of deionized water (200 mL). The mixture was gently rotary evaporated (bath temperature=40° C.) to a volume of 150 mL. The solids that precipitated were chilled at 5° C. for 10 minutes and filtered. The filter cake was washed with water and dried in vacuo to give 6.82 g of 4-(4′-chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 155-157° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]([NH2:27])=[O:26].O>O1CCCC1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH2:24][C:25]([NH2:27])=[O:26])[C:11]3=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C1NC(=O)c2cc(OCc3ccc(F)cc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CN1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A mixture of 5-(4-fluoro-benzyloxy)-isoindole-1,3-dione (100 mg, 0.37 mmol), sodium hydride (55% in mineral oil, 18 mg, 0.42 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol) in dry tetrahydrofuran (5 mL) at 0° C. was stirred at room temperature for 3 h and then heated at 50° C. for 1 h. After cooling to 0° C., water (2 mL) was added and the product extracted with ethyl acetate. The organic extracts were then washed with brine and dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, heptane-CH2Cl2 2:3 then CH2Cl2— 2N NH3—MeOH 99:1: to 4:1) to afford the title compound (78 mg, 65%) as a white solid. MS: m/e=329.3 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[CH3:1][N:2]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: O=C1CCCC(=O)O1
Reactant: CNCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
8.70 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole) were dissolved in 100 ml of benzene, and 5.7 g of glutaric acid anhydride were added thereto. The mixture was stirred at 80° C. for 3 hours. After the reaction was completed, the mixture was evaporated to remove solvent. 12.0 g of N-methyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-carboxybutanamido)ethyl]-indole) were thereby obtained. Yield: 90%
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:19]I>C(Cl)Cl.C(OCC)C.N([O-])=O.[Ag+]>[F:1][C:2]1[C:3]([C:9]2[C:13]([I:19])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Reactant: II
Agent: [Ag+]
Agent: O=N[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1nc(-c2ncc(Cl)cc2F)c(I)c1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
3.0 g of 3-(3-fluoro-5-chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example H15) are dissolved in 30 ml of methylene chloride, and 1.83 g of silver(I) nitrite and 3.02 g of iodine are then added. The mixture is stirred overnight at 22° C. It is then diluted with diethyl ether and extracted successively with aqueous sodium metabisulfite solution and brine. After drying of the organic phase over sodium sulfate and filtration, the filtrate is concentrated in vacuo together with twice the amount of silica gel. After application of this silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate (3/1). 3.97 g of the desired title compound are obtained as a beige solid of melting point 77-78° C. in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(Cl)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Cl

Procedure:
Tert-butyl 2-(2-chloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:12]Br>ClCCl>[Br:12][CH:10]([CH3:11])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(=O)CC
Reactant: BrBr
Solvent: ClCCl
Product: CCCCOC(=O)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.9 %

Procedure:
A solution of butyl 2-oxobutanoate (described in Patent; IMPERIAL CHEMICAL INDUSTRIES PLC; Publ.: EP 375457 B1 (1994 Mar. 16), Appl.: EP 1989-313521 (1989 Dec. 22), 14 g, 88.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and bromine (4 mL, 80 mmol) was added over 15 minutes. Following stirring at room temperature for 30 minutes, the reaction solution was washed with aqueous sodium bicarbonate solution, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 21.8 g of the title compound as a colorless liquid (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11]N=C[N:8]=1.S1C(N)=N[CH:20]=[N:19]1.S1C=NN=C1N>>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][CH:20]=[N:19][N:8]=1
Reactant: Nc1ncns1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: Nc1nncs1
Product: COc1ccc(CNc2nncs2)c(OC)c1

Procedure:
N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (INTERMEDIATE Y) was prepared in a manner analogous to INTERMEDIATE A wherein 1,2,4-thiadiazol-5-amine was replaced with 1,3,4-thiadiazol-2-amine.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[S:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>CC(C)=O>[Br-:1].[C:6]([O:5][C:3](=[O:4])[CH2:2][S+:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCSC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C[S+]1CCCC1
Product: [Br-]
Temperature: 20 °C
Yield: 92.5 %

Procedure:
Add t-butyl bromoacetate (2.44 L, 16.52 mole, 1 eq) to a solution of tetrahydrothiophene (2.19 L, 24.8 mole, 1.5 eq) in acetone (11.38 L), in a 22 L flask over 30-60 minutes while maintaining the temperature between 15-25° C. using a water bath. Stir the reaction for 22 hours and assay a sample by 1H NMR to confirm the completion of the reaction. Filter the precipitate, wash with acetone (2 L), and vacuum dry for 3 days at 28-33° C. to give 4.328 Kg (92.5% yield) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]3=[O:51])=[CH:41][C:40]=2[F:52])=CC=1)([O-])=O>>[F:52][C:40]1[CH:41]=[C:42]([N:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]2=[O:51])[CH:43]=[CH:44][C:39]=1[NH:38][C:37]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)=[O:36]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1cc2cc(Cl)ccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc2cc(Cl)ccc2s1

Procedure:
66.3 Using general method H, 5-chloro-benzo[b]thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-chloro-benzo[b]thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 523.0 ([M−H]−)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23]CC(N)=O)([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:30][C:31]#[N:32].[C:33](O)(C)(C)C>>[NH2:32][C:31]([CH3:33])([CH3:30])[CH2:23][C@@:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: CC#N
Reactant: CC(C)(C)O
Agent: Cl
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide following a procedure analogous to that described in Example 612 using t-butanol as solvent followed by treatment with 2 N aq HCl/CH3CN at rt. LC-MS Method 1 tR=1.41 min, m/z=449, 451 (M+1); 1H NMR (CD3OD) 7.28-7.20 (m, 4H), 7.04 (t, J=8.6 Hz, 2H), 6.96 (d, J=8.2 Hz, 2H), 5.46 (q, J=7.0 Hz, 1H), 2.99-2.94 (m, 1H), 2.34-2.28 (m, 3H), 2.16-2.07 (m, 2H), 1.43 (d, J=7.0 Hz, 3H), 1.13 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CN(C)C=O.Cl[CH2:28][C:29]#[N:30]>C(N(CC)CC)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:28][C:29]#[N:30])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: N#CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC#N)C[C@H]1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a stirred solution of 12.55 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide in 180 parts of N,N-dimethylformamide were added 5.05 parts of N,N-diethylethanamine and 3.4 parts of 2-chloroacetonitrile. The whole was stirred for 18 hours at 50° C. The solvent was 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. The residue was triturated in 1,1'-oxybisethane. The product was filtered off and dried, yielding 12.21 parts (86.5%) of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 130.4° C. (interm. 2).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]Cl)=[CH:15][CH:14]=1.C(Cl)(Cl)(Cl)[Cl:22]>C(O)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:4])=[O:5])[CH2:2][Cl:22])=[CH:15][CH:14]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: ClSc1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)C(CCl)Sc1ccc(Br)cc1
Reaction time: 72 h

Procedure:
A solution of 24.8 g (0.147 mole) of phenyl vinyl sulfone in 50 ml of carbon tetrachloride and 25 ml of glacial acetic acid at 28° was treated with 32.8 g (0.146 mole) of p-bromobenzenesulfenyl chloride. A 4° exotherm occurred. The reaction mixture was allowed to stand for 72 hours. The solvent was removed by evaporation at reduced pressure. The residue was recrystallized from 50 ml of benzene to give colorless needles, m.p. 97.5°-98.5°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a pre-cooled suspension of 2-bromo-5-fluorophenol (5 g, 26.18 mmol) and potassium carbonate (10.84 g, 78.54 mmol) in DMF (15 mL) at 0-5° C., was added methyl iodide (4.75 mL, 39.27 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined, washed with saturated brine solution (20 mL) and dried over Na2SO4, filtered and concentrated in vacuo to afford 1-bromo-4-fluoro-2-methoxybenzene as a colourless liquid in 93% yield, 5.00 g.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(OCC)(=O)C>[Br-:12].[CH2:19]([O:18][C:16]([CH2:15][CH2:14][CH2:13][C:3]1[CH:2]=[NH+:1][C:11]2[C:6]([C:4]=1[CH3:5])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: Cc1ccnc2ccccc12
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1c[nH+]c2ccccc2c1C
Product: [Br-]
Temperature: 145 °C
Yield: 77 %

Procedure:
A mixture of 1.43 g of lepidine and 2.5 g of ethyl 4-bromobutyrate is heated at 140-150° C. for 1.5 hours. The mixture is cooled to room temperature and stirred in 100 mL of ethyl acetate for 3 hours and filtered to yield 2.6 g of Compound 5.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2-:16][C:17]([CH3:19])=[O:18].Cl[CH2:21][C@H:22]([OH:25])[CH2:23]O.O>CN(C=O)C>[CH3:16][C:17]1([CH3:19])[O:25][C@@H:22]([CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:21][O:18]1
Reactant: OC[C@@H](O)CCl
Reactant: O=Cc1ccc(O)cc1
Reactant: [CH2-]C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc(C=O)cc2)O1
Temperature: 160 °C
Reaction time: 16 h

Procedure:
An amount of 12.5 g (102.4 mmol) of 4-hydroxybenzaldehyde were introduced under argon in 166 ml of dry DMF and admixed at RT with 42.4 g (307.1 mmol) of potassium carbonate and also 20.05 g (133.1 mmol) of (R)-(−)-3-chloro-1,2-propanediol acetonide. The batch was stirred at 160° C. for 16 hours. The batch was then admixed with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Following filtration, the solvent was removed on a rotary evaporator and the residue was purified by means of column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][NH:17][C:16](=[S:19])[NH:15][CH2:14]1>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2([OH:9])[N:17]3[CH2:18][N:13]([CH3:12])[CH2:14][N:15]=[C:16]3[S:19][CH2:7]2)=[CH:4][CH:3]=1
Reactant: CN1CNC(=S)NC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CC(C)=O
Product: CN1CN=C2SCC(O)(c3ccc(Br)cc3)N2C1

Procedure:
A solution of 6.95 grams (0.025 moles) of p-bromophenacylbromide in 60 milliliters of acetone was mixed with a solution of 3.27 grams (0.025 moles) of 3,4,5,6-tetrahydro-5-methyl-s-triazin 2(1H) thione in 450 milliliters of acetone. 6-p-Bromophenyl-6-hydroxy-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a-]-s-triazine hydrobromide crystallized out as a colourless solid, m.p. 138°-140° C. (decomposition). The yield was 7.5 grams (75%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:23][CH:24]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27](/[CH:26]=[CH:25]/[C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:15][C:11]3[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)[CH:14]=[CH:13][CH:12]=3)[N:21]=2)=[CH:28][CH:29]=1
Reactant: Oc1cccc(CCCn2ccnn2)c1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccc(/C=C/c2nc(COc3cccc(CCCn4ccnn4)c3)co2)cc1
Yield: 88.4 %

Procedure:
Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol(208 mg), 65% oily sodium hydride (39 mg) and 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg), the same reaction as Example 2 was carried out to yield the titled compound (366 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[O:20]=[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[NH:22]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]3[C:24]4[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=4[NH:22][C:21]3=[O:20])[CH2:31][CH2:30]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a suspension of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (550 mg, 2.92 mmol) in methanol (11 mL) was added triethylamine (0.55 mL, 3.94 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine (638 mg, 2.94 mmol). The mixture was stirred at ambient temperature for 1 h and then 10 wt % Pd on C (wet) was added and the mixture was stirred under hydrogen for 1 h. The mixture was diluted with methanol and was filtered through Celite. The filtrate was concentrated and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the aqueous slurry was filtered and dried to afford 1-{1-[5-amino-6-(methylamino)pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (842 mg, 2.48 mmol, 85% yield) as a peach colored solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.82 (s, 1H), 7.43-7.36 (m, 1H), 7.01-6.94 (m, 3H), 6.29 (q, 1H), 4.31 (tt, 1H), 4.20 (s, 2H), 3.50 (br d, 2H), 2.85 (d, 3H), 2.74 (t, 2H), 2.54 (qd, 2H), 1.68 (dd, 2H). MS (EI) for C17H21N7O: 340 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][CH:42]1[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:44]1[C:43]2[CH:42]([CH2:41][O:40][C:38](=[O:39])[NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C@H:29]([NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[C:30]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:16]3[C:14]3[CH:13]=[N:12][CH:11]=[C:10]([C:8](=[O:9])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:15]=3)=[O:31])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(c1ccc(F)cc1)c1cncc([C@@H]2CCCN2)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reaction time: 16 h

Procedure:
To a solution of (4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (1.0 g, 3.7 mmol), (S)-2-tert-butoxycarbonylamino-6-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (2.0 g, 4.4 mmol) and ethyldiisopropylamine (3 mL) in DMF (20 mL) was added a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (1.67 g, 4.4 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.6 g, 4.4 mmol) in DMF (10 mL) and the mixture was shaken for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed sequentially with brine (2×) (300 mL), saturated aqueous bicarbonate solution (300 mL), brine (300 mL), water (300 mL), and brine (300 mL), then dried over Na2SO4/MgSO4, and concentrated in vacuo to provide crude ((S)-5-tert-butoxycarbonylamino-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[C:18](/[C:24]([O:26]C)=[O:25])\[CH2:19][C:20]([O:22]C)=[O:21].ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[C:24]([C@:18]1([OH:36])[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[O:21][C:20](=[O:22])[CH2:19]1)([OH:26])=[O:25]
Reactant: COC(=O)C/C(=C\CCCCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C[C@](O)(C(=O)O)[C@@H](CCCCCCCCc2ccc(Cl)cc2Cl)O1
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
(E)-Methyl 12-(2,4-dichlorophenyl)-3-methoxycarbonyl-3-dodecenoate (686 mg, 1.65 mmol, described in example 4) and 3-chloroperbenzoic acid (5.7 g of 55% grade, 18.2 mmol) were heated under reflux in dichloromethane (15 ml) for 24 h. The mixture was cooled and poured into aqueous NaHCO3 /Na2SO3. This mixture was stirred for 10 min, then extracted with dichloromethane. The extracts were washed with aqueous NaHC3, water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum, and the residue purified by chromatography on silica gel (20-40% ether/petroleum ether 40-60%) to give the title compound (369 mg, 52%) as an oil.