Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:25])=O>ClCCl.CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([Cl:25])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cn1cccc1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (4 mmol) of 1-methyl-2-pyrrolecarboxylic acid in 5 ml of dichloromethane are introduced into a round-bottomed flask and under a nitrogen stream. There are added, dropwise, 790 μI (4 mmol) of dicyclohexylamine and, 30 minutes later, 290 μl (4 mmol) of thionyl chloride. The medium is stirred for 1 hour at room temperature and then heated for 2 hours at 50° C. The mixture is then diluted with ether and the precipitate is filtered off. The filtrate is evaporated off and a brown oil is obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=S)[NH2:14])(=[O:3])[CH3:2].[C:16]([NH:21][NH2:22])(=O)[CH2:17][CH2:18][CH3:19]>C(O)CCC>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:14]=[C:16]([CH2:17][CH2:18][CH3:19])[NH:21][N:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(N)=S
Reactant: CCCC(=O)NN
Solvent: CCCCO
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)n[nH]1
Reaction time: 0.17 h

Procedure:
A suspension of intermediate (13) (0.0102 mole) in n-butanol (200 ml) was treated with butanoic acid hydrazide (0.0254 mole), stirred for 10 minutes, and then heated to reflux for 10 days. The reaction was cooled, concentrated in vacuo, distributed between DCM and distilled water. The concentrated organic phase was subjected to reverse phase preparatory column chromatography to give 1-acetyl-2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole (compound 91).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14]C)[CH2:12]C)=[O:7])=[C:4]([O:19]C)[CH:3]=1.NC1C(Cl)=CC(C(NCCN(C)C)=O)=C(OC)C=1>>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:14])[CH3:12])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: COc1cc(N)c(Cl)cc1C(=O)NCCN(C)C
Product: CN(C)CCNC(=O)c1cc(Cl)c(N)cc1O
Yield: 89 %

Procedure:
The general procedure of Preparation 1A was repeated except that the 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide utilized therein was replaced by 4-amino-5-chloro-N-[2-(dimethylamino)ethyl]-2-methoxybenzamide (prepared according to U.K. Pat. No. 1,793,771). The solvent (DMF) was removed in vacuo, and the residue treated with water and methylene chloride saturated with carbon dioxide, concentrated, and the crude product isolated in 89% yield by extraction with ethanol. A sample was chromatographed on a silica gel column usimg methylene chloride (97), methanol (3), ammonia (0.3) solvent system. The appropriate fractions were combined and concentrated in vacuo. The residue was crystallized from methanol to give the title compound as a colorless solid, mp. 163°-165°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:19][C:11]3=[N:12][CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>CN1C(=O)CCC1>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[CH:7]=[C:6]([C:8]2[NH:19][C:11]3=[N:12][CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COCCCN
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccnc(Cl)c3)nc2c1
Solvent: CN1CCCC1=O
Product: COCCCNc1cc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)ccn1
Yield: 33.6 %

Procedure:
1.20 g (4.35 mmol) 2-(2-Chloro-pyridin-4-yl)-6-nitro-3H-imidazo[4,5-b]pyridine in 12 ml dry NMP and 1.18 g (13 mmol) 3-methoxypropylamine were heated to 200° C. in a closed vessel in a microwave reactor for 30 min. The solvent was removed under vacuum and the residue dissolved in a mixture of 20 ml ethyl acetate and 30 ml 5% aqueous HCl. The HCl phase was separated and brought to alkaline pH by addition of conc. ammonia. The alkaline aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried. Evaporation and chromatography of the residue on silica in ethyl acetate/methanol mixtures gave 480 mg of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[O:8][C:4]=2[CH:3]=1.Cl.C(OCC)(=O)C.O>O1CCCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[O:12][CH2:13][C:14]([OH:16])=[O:15])[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl [3-(6-bromobenzoxazol-2-yl)phenoxy]acetate (Compound of Example 279) (2.22 g) in tetrahydrofuran (10 ml) was added 4 N hydrochloric acid-ethyl acetate (50 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain [3-(6-bromobenzoxazol-2-yl)phenoxy]acetic acid (1.27 g, 66%). The crystals were recrystallized from tetrahydrofuran-ethyl acetate.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2].I[CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]3)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C(C)C
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a solution of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide (300 mg, 0.88 mmol, step 4 in preparation 3) in N,N-dimethylformamide (30 mL), tert-butyl 4-(iodomethyl)piperidine-1-caroxylate (343 mg, 1.05 mmol, Villalobos Anabella et al., J. Med. Chem., 1994, 37, 2721) and potassium carbonate (610 mg, 4.4 mmol) were added at room temperature. The mixture was heated at 80° C. overnight. After cooled to room temperature, water (30 mL) was added and extracted with diethyl ether (50 mL×2). The combined organic layer was washed with water (20 mL×2), brine (20 mL), dried over magnesium sulfate and concentrated in vacuo gave yellow oil, which was chromatographed on a column of silica gel eluting with ethyl 25% ammonium oxide/methanol/dichloromethane (3:30:1000) to give 154 mg (32%) of the title compound as a clear colorless oil.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1>O1CCOCC1>[CH:27]([N:26]1[C:22]([C:17]2[N:18]=[C:19]3[C:20]4[CH:21]=[C:8]([CH:6]([N:30]5[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:12][CH2:13][CH2:14][N:15]3[CH:16]=2)=[N:23][CH:24]=[N:25]1)([CH3:29])[CH3:28]
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Reactant: CC(C)(O)C1CCNCC1
Solvent: C1COCCO1
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCC(C(C)(C)O)CC1
Temperature: 90 °C

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate from Example 146 (123 mg, 0.295 mmol) in dioxane (15 mL) was added 2-(piperidin-4-yl)propan-2-ol (422 mg, 2.95 mmol). The mixture was heated at 90° C. overnight. The solvent was removed and the residue was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 152. The enantiomers were separated by chiral SFC (OD-H column, 15% EtOH isocratic) to give: 17.6 mg of one enantiomer and 13.0 mg of the other (22% total yield)
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C[C:11]([N:13](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:11]#[N:13])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)cnc1Br
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)cnc1C#N
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218 mmol), zinc cyanide (8.30 mL, 131 mmol), tris(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in dimethylacetamide (40 mL) was heated to 110° C. for 4 hours. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate. The organic phase obtained was concentrated under reduced pressure and residue purified by chromatography on silica gel using ISCO eluting with 0-60% EtOAc/hex to afford the title compound 5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76% yield). LC/MS (ESI+) m/z=153.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([SH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].I[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH3:14])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(S)c(F)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)c(Br)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 4-bromo-2-fluoro-5-methylbenzenethiol (2.28 g, 10.3 mmol) in 25 mL of DMF at RT was treated with NaH (0.284 g, 12.4 mmol). After 15 minutes the solution was cooled to 0° C. and iodomethane (0.772 mL, 12.4 mmol) was added. The reaction mixture was allowed to warm up to RT and stirred overnight. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.40 g, 99% yield) as an orange oil. The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc(OC)c2sc(-c3ccc([N+](=O)[O-])cc3)nc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c2sc(-c3ccc(N)cc3)nc2c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filtered, washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene to this lawessons reagent (4.6 g, 11.5 mmol) is added and refluxed at 110° C. for 8h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 116 mg, 0.698 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6d as a brown solid (63%).
Reaction SMILES: [CH3:1][O-].[Na+].[F:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:16][N:15]=1.C=O.[BH4-].[Na+]>CO.O.ClCCl>[F:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:1])=[CH:24][CH:23]=2)=[CH:16][N:15]=1
Reactant: C[O-]
Reactant: Nc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
Sodium methoxide (1M in methanol, 0.23 ml) was added to a solution of compound 5 (15.8 mg, 0.046 mmol) in methanol (5 ml) followed by the addition of paraformaldehyde (6.6 mg, 0.23 mmol). The reaction mixture was refluxed for 1.5 hour then cooled to 0° C. with an ice bath. Sodium borohydride (10.4 mg, 0.27 mmol) was added with caution. The mixture was refluxed again for 1 hour and cooled down. Dichloromethane and water was added. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (3% MeOH in DCM as developing solvent) to give product 6 (12 mg, Yield: 73%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.2 Hz), 7.76 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.35 (2H, d, J=8.6 Hz), 6.92 (1H, d, J=16.4 Hz), 6.80 (1H, d, J=16.4 Hz), 6.76 (2H, d, J=8.6 Hz), 4.53 (2H, d, t, J1=47.6 Hz, J2=4.2 Hz), 4.49 (2H, t, J=4.8 Hz), 3.85 (3H, m), 3.70 (5H, m), 2.88 (3H, s). HRMS (EI) m/z calcd. for [C20H25FN2O3]+ 360.1849.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:19](=[O:34])[N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([O:11][CH2:10][C@@H:9]([NH:7][CH3:6])[C:19]([N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
N-((R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)N-methylcarbamic acid tert-butyl ester (0.23 g; 0.476 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 10 min at room temperature. Methylene chloride (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.182 g of (2R)-3-Benzyloxy-N-methyl-2-(methylamino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Br[C:6]1[N:10]([C@@H:11]2[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1>C(Cl)Cl>[Cl:23][C:21]1[C:20]([Cl:24])=[CH:19][C:9]2[N:10]([C@@H:11]3[O:17][C@H:16]([CH3:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:6]([NH:4][CH2:1][CH:2]=[CH2:3])=[N:7][C:8]=2[CH:22]=1
Reactant: C=CCN
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: C=CCNc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 83.1 %

Procedure:
Following General Procedure V, allylamine (Aldrich, 5 mL, 66.64 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:25 methanol:CH2Cl2 gave the title compound (195 mg, 0.54 mmol, 84%); MS (EI): m/z (rel. intensity) 358 (0.05, M+); 1H NMR (DMSO-d6) δ7.41 (s, 1H, Ar—H), 7.36 (s, 1H, Ar—H), 7.10 (t, 1H, NH, J=11.2 Hz), 5.94 (m, 1H, CH), 5.70 (d, 1H, CH, J=6.5 Hz), 5.25 (m, 3H, overlapping OH and CH2), 5.09 (d, 1H, OH, J=8.8 Hz), 4.35 (m, 1H, CH), 3.98 (m, 2H, CH2), 3.92 (m, 1H, CH), 3.81 (m, 1H, CH), 1.38 (d, 3H, CH3, J=6.5 Hz).
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:8]>>[C:2]([OH:8])(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: c1ccccc1
Reactant: O
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
A publication in J. Amer. Chem. Soc. 70 (1948), 1,629-1,632 discloses that the reaction can also be carried out with the free base in the absence of hydrochloric acid, at from 180° to 220° C.; as shown by the description and all the Examples, the reaction is intended to be carried out with a molar ratio of the reactants of 1:1, and in the presence of benzene in the reaction mixture. During the reaction, an azeotropic mixture of benzene and water is distilled off. In spite of this special procedure, substantial amounts of a high-boiling by-product are always found alongside the imidazoline. The publication describes, and shows with Examples, that the yield of this by-product increases with the number of carbon atoms in the alkanecarboxylic acid molecule; for example, reactions with acetic acid give a 32.7 percent yield, and those with myristic and a 92.5 percent yield, of high-boiling by-product. In the case of stearic acid, only the by-product is obtained, the yield being virtually quantitative. The yields of imidazoline are 26.6 percent in the case of acetic acid, 13.3 percent in the case of formic acid, 12.9 percent in the case of propionic acid and 15.4 percent in the case of caproic acid. The yields for longer-chain carboxylic acids are not stated. The recovery of a part of the imidazoline from the by-product is only possible by laborious methods, for example by treatment with aqueous sodium hydroxide solution, extraction with ether, drying the ether extract over solid potassium hydroxide, evaporation of the ether and fractional distillation.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=[O:34])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:22]([CH3:23])[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([OH:6])=[O:34])=[O:35])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCOc1ccccc1C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 124.1 %

Procedure:
A solution of sodium chlorite (2.85 g; 31.5 mmol; 5.5 eq.) and sodium dihydrogenphosphate (2.47 g; 20.6 mmol; 3.6 eq.) in water (25 mL) was added dropwise to a mixture of 2-methyl-2-butene (5.7 mL) and [2-(2-formyl-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.6 g; 5.73 mmol; 1 eq.) in 1,4-dioxane (25 mL). The reaction mixture was stirred at room temperature for 1.5 hour. After dilution with EA, the solution was washed with 1M HCl, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.1 g, 93%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.59 (dd, J=7.7, 1.8 Hz, 1H), 7.52-7.42 (m, OH), 7.16-7.10 (d, J=8.4 Hz, 1H), 7.03-6.94 (td, J=7.5, 1.0 Hz, 1H), 4.18-4.07 (m, 1H), 3.54-3.48 (t, J=5.4 Hz, 2H), 2.96-2.86 (d, J=11.7 Hz, 3H), 1.42-1.31 (m, 9H).
Reaction SMILES: C1(C)C=CC=CC=1.CSC.B.[Br:12][CH2:13][CH2:14][CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][C:19](=[O:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[Br:12][CH2:13][CH2:14][CH:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][C@@H:19]([OH:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]1=2
Reactant: O=C1Cc2ccccc2C(=CCCBr)c2ccccc21
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H]1Cc2ccccc2C(=CCCBr)c2ccccc21
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
In a dry 40 mL vial with a septum cap, S-CBS catalyst, 1 M in toluene (3.98 mL, 3.98 mmol), 2.0 M borane-dimethyl sulfide in tetrahydrofuran (1.69 mL, 3.37 mmol), and 10 mL dry tetrahydrofuran were premixed. The premix was cooled to −20° C. in an acetonitrile/dry ice bath. A tetrahydrofuran solution of 5-(3-Bromo-propylidene)-5,11-dihydro-dibenzo[a,d]cyclohepten-10-one (6) (1.00 g, 3.06 mmol) which had been stored over molecular sieves was then added dropwise. The reaction was allowed to slowly come to room temperature over ˜90 minutes. When complete, the reaction was cooled to 0° C. and 1 mL methanol added to quench the reaction. After 15 minutes of further stirring, 1 mL saturated sodium bicarbonate was added. The reaction mixture was then evaporated and the residue is separated between water (50 mL) and dichloromethane (50 mL). The organic layer was then separated, evaporated, and the crude residue was purified by silica gel chromatography using a 5-25% hexanes:ethyl acetate gradient. 0.86 g (85%) (S)-5-(3-bromo-propylidene)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ol (7b) was obtained as a faintly yellow oil. ESI MS m/z 623.3 (2(M−H2O)+H)+. 1H NMR (CDCl3, 250 MHz): 7.48 (1H, d), 7.33-7.12 (7H, m), 5.91 (1H, t), 5.12-4.70 (1H, 2×m), 3.65 (1H, d), 3.44 (1H, t) 3.06 (1H, dd), 2.73 (2H, m), 1.61 (2H, m).