Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([CH3:43])[CH:34]=[CH:33][C:32]([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])=[CH:31][CH:30]=1.[Cl:44][CH2:45][CH2:46][CH2:47][C:48]#[CH:49]>[Au].ClC(Cl)C>[C:29]1([CH3:43])[CH:30]=[CH:31][C:32]([C:35]#[C:36][P:37](=[O:41])([O:42][C:48]([CH2:47][CH2:46][CH2:45][Cl:44])=[CH2:49])[O:38][CH2:39][CH3:40])=[CH:33][CH:34]=1
Reactant: C#CCCCCl
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(CCCCl)OP(=O)(C#Cc1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-chloropent-1-en-2-yl p-tolylethynylphosphonate (68.5 mg, 70%) which is a title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][CH:36]([CH3:42])[CH2:37][CH2:38][C:39](O)=[O:40].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][CH2:37][CH:36]([CH3:42])[CH3:35])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)CCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 4-methylpentanoic acid (37 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-[cis-4-(4-methyl-pentanoylamino)-cyclohexyl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (114 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[N:10]([CH2:13][CH3:14])[CH2:9][CH2:8][NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CCN1CCNc2cc(N)ccc2C1=O
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCNc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc2C1=O
Temperature: 120 °C
Yield: 13.5 %

Procedure:
Into a microwave vial, 8-amino-4-ethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.100 g, 0.000487 mol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.14 g, 0.00046 mol), 10-camphorsulfonic acid (0.22 g, 0.00092 mol) and isopropyl alcohol (1.3 mL, 0.017 mol) were added and heated in the microwave at 120° C. for 40 minutes. The solvent was removed under vacuum. The solid was dissolved in EtOAc and washed with saturated NaHCO3. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via Gilson prep-HPLC to give a TFA salt (30 mg, 13%). 1H-NMR (CDCl3, 400 MHz): δ10.97 (bs, 1H), 9.52 (bs, 1H), 7.75 (s, 1H), 7.70 (bs, 1H), 7.28-7.50 m, 4H), 6.90 (d, 1H), 6.28 (bs, 1H), 3.44-3.65 (m, 7H), 3.01 (d, 1H), 1.25 (t, 3H). LC/MS (ESI+) 484.21 (M+H).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:26][C:27]1[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:30]=[CH:29][C:28]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:23][C:28]3[CH:29]=[CH:30][C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][C:27]=3[F:26])=[O:22])=[CH:19][CH:18]=2)=[N:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCc1ccc(O)c(F)c1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(C(=O)Oc3ccc(CCCCCCCCC)cc3F)cc2)nc1
Reaction time: 4 h

Procedure:
17.0 g of 4-(5-decylpyrimidin-2-yl)-benzoic acid (prepared from 4-(5-decylpyrimidin-2-yl)-benzonitrile by saponification) and 11.1 g of 2-fluoro-4-nonylphenol are introduced into 200 ml of dichloromethane and 11.0 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 4 hours at 20°, the precipitated urea is filtered off under suction, and the filtrate is concentrated to a small volume. After adsorptive filtration of the residue over silica gel using ethyl acetate as eluant, 2-fluoro-4-nonylphenyl 4-(5-decylpyrimidin-2-yl)-benzoate is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[C:42]([O:56][CH3:57])=[N:43][CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:31]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=3[F:29])(=[O:39])=[O:38])[C:42]([O:56][CH3:57])=[N:43][CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 52.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.34 mmol) was treated with 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (280 mg, 0.51 mmol), 2M cesium carbonate (350 μl, 0.70 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 117 mg (50% yield) of the title compound. Purity 97%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH3-]C#N.[Na+].[BH4-].[Na+]>CO.CC(O)=O>[CH:10]1([NH:2][C@H:3]2[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: O[C@H]1CC[C@@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cis-4-aminocyclohexanol hydrochloride (4 mmol) and cyclohexanone (8 mmol) and molecular sieves (3 Å, 1 g) in anhydrous MeOH (10 mL) was stirred under N2 at room temperature for 10 min. The mixture was added NaBH3CN (8 mmol) and glacial AcOH (0.1 mL) and stirred for further 24 h. Addition of NaBH4 (1.3 mmol) followed by stirring for another 10 min. The mixture was filtered and the residue was extracted with MeOH (10 mL) and the combined filtrates were evaporated to dryness. The residue was dissolved in 1 M aqueous HCl (15 mL) and washed with TBME (15 mL). The aqueous phase was added 10% aqueous NaOH until pH 14 and extracted with TBME (15 mL). The organic phase was washed with H2O (10 ml), dried (Na2SO4), and evaporated to dryness under reduced pressure affording crude cyclohexyl-cis-(4-hydroxycyclohexyl)amine which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:2][CH2:3][CH3:4])[C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10]2
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(-c2ccccc2)cc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
1-Bromopropane (0.248 g, 2.015 mmol) was added to a solution of 95A (0.15 g, 0.672 mmol) in DMF (5 mL) followed by cesium carbonate (0.657 g, 2.015 mmol), and the mixture was stirred at 25° C. for 12 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 3% ethyl acetate in hexane as eluent to afford title compound (0.1 g, 56.1%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.54-7.5 (m, 4H), 7.46-7.39 (m, 2H), 7.06 (d, J=2.0 Hz, 1H), 6.8 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.42 (s, 1H), 4.12 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 1.54 (m, 2H), 0.63 (t, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:22]([O:23][CH3:24])=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)=[CH:37][CH:36]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccc(Cl)cc1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 30 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used p-chlorophenyl boronic acid. The title compound (48 mg) was obtained as a white solid, (yield=30%).
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[C:6]([C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH2:1][CH2:2][CH2:3][CH3:4])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:8])[CH3:7]
Reactant: CCCCI
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1ccc(C(C)=O)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 18 h

Procedure:
n-Butyl iodide (13.2 ml, 117 mmol) was added to a mixture of methyl 5-acetylsalicylate (15 g, 77 mmol) and potassium carbonate (16 g, 117 mmol) in acetonitrile (500 ml), and the reaction stirred at 60° C. for 18 hours. TLC analysis showed starting material remaining, so additional n-butyl iodide (26.4 ml, 234 mmol) and potassium carbonate (16 g, 117 mmol) were added and the reaction stirred at 60° C. for a further 72 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The phases were separated, the organic layer washed with brine, dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a yellow oil that crystallised on drying in vacuo, 17.4 g.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=O)=[CH:8][CH:7]=1>CO>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:2][NH2:3])=[O:15])=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (4.7 cm3) was added dropwise to ethyl (4-methoxyphenyl)acetate (3.73 g) and then methanol (20 cm3) was added to form a homogeneous reaction mixture. This mixture was stirred for 18 hours at ambient temperature during which time a white precipitate formed. The precipitate was isolated by filtration and washed with methanol and water, then air-dried to give (4-methoxyphenyl)acetic acid hydrazide (2g). M+ =180; 1H NMR: δ 3.50(2H,s); 380(3H,s); 3.85(2H,br s); 6.70(1H,br s); 6.90(2H,d); 7.20(2H,d); (solid).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCCCCCCc1cccc(I)c1
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
Anhydrous THF (20 ml) was added to a flame-dried 100 ml two-necked flask contain 12-m-iodophenyldodecanoic acid (3.30 g, 8.21 mmol). The solution was cooled in an ice bath before BH3 -THF (15.0 ml, 1 M) was added dropwise. The reaction mixture was allowed to warm to room temperature and to stir under anhydrous conditions for 20 hours. The reaction mixture was again cooled to 0° C. and quenched with H2O. Ether and additional H2O were then added. The ether layer was extracted with H2O, sat. NaHCO3, and more H2O and dried (MgSO4). The solvent was removed under reduced pressure to yield a yellow oil. The crude compound was purified by column chromatography (90 g silica gel, hexanes:ethyl acetate 8:1) to yield a white solid, compound 8, 12-m-iodophenyldodecanol (3.14 g, 98.4% yield).
Reaction SMILES: COC1C=CC(N(OC(C)C(O)C)OC(C)C(O)C)=C(CCC)C=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)Cl)C=CC=CC=1.[CH2:49]([O:53][CH2:54][CH:55]1[CH2:62][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH2:70]CCCCCCCCCCC)=[CH:65][CH:64]=2)[CH2:60][CH:59]([CH2:82][O:83][CH2:84][CH2:85][CH2:86][CH3:87])[O:58][P:57](=[O:94])([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[O:56]1)[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:84]([O:83][CH2:82][CH:59]1[CH2:60][N:61]([C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:62][CH:55]([CH2:54][O:53][CH2:49][CH2:50][CH2:51][CH3:52])[O:56][P:57](=[O:94])([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[O:58]1)[CH2:85][CH2:86][CH3:87]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Agent: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(c2ccccc2)O1
Yield: 24 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1,2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonous dichloride (1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a colourless liquid 0.6 g (24%) and its isomer 0.6 g (24% a colourless liquid).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[CH:29]1[C:34]([CH:35]=O)=[CH:33][C:32]2[O:37][CH2:38][O:39][C:31]=2[CH:30]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl.FC(F)(F)C(O)=O>[O:39]1[C:31]2[CH:30]=[CH:29][C:34]([CH2:35][N:18]([CH2:17][C:9]3[NH:8][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=3)[CH:19]3[C:28]4[N:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:22][CH2:21][CH2:20]3)=[CH:33][C:32]=2[O:37][CH2:38]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(Cc1ccc2c(c1)OCO2)Cc1nc2ccccc2[nH]1
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
Using General Procedure B: To a solution of [1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (125 mg, 0.33 mmol), piperonal (50 mg, 0.33 mmol) and AcOH (0.02 mL, 0.33 mmol) in THF (3.3 mL) was added NaBH(OAc)3 (210 mg, 0.99 mmol) and the resultant suspension stirred at room temperature for 16 h. The crude product was dissolved in a mixture of CH2Cl2 (˜2 mL) and trifluoroacetic acid (˜2 mL). After 1.5 h, the reaction mixture was concentrated, redissolved in H2O (˜2 mL), and basified with 1N NaOH. The aqueous solution was extracted with CH2Cl2 (3×50 mL) and the combined organic extracts were dried over MgSO4 and concentrated to a yellow syrup. The product was purified by column chromatography on silica gel (100:1:1—EtOAc:MeOH:NH4OH) to give the titled compound as a white foam (45 mg, 33%). 1H NMR (300 MHz, CDCl3) δ 8.69 (d, 1H, J=3.3 Hz), 7.58 (br s, 2H), 7.43 (d, 1H, J=7.2 Hz), 7.21-7.16 (m, 3H), 6.99 (d, 1H, J=1.5 Hz), 6.79 (dd, 1H, J=8.1, 1.5 Hz), 6.65 (d, 1H, J=7.8 Hz), 5.86-5.85 (m, 2H), 4.15 (d, 1H, J=16.5 Hz), 4.09-4.06 (m, 1H), 3.98 (d, 1H, J=16.8 Hz), 3.64 (s, 2H), 2.91-2.80 (m, 1H), 2.74-2.67 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.64 (m, 2H), 1.75-1.64 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 159.2, 158.0, 149.4, 148.7, 148.5, 139.0, 136.5, 135.0, 124.0, 123.5, 123.3, 110.7, 109.5, 102.5, 61.8, 55.5, 49.9, 31.0, 25.0, 23.1. ES-MS m/z 413.3 (M+H). Anal Calcd for (C25H24N4O2).0.8 (H2O): C, 70.34; H, 6.04; N, 13.12. Found: C, 70.29; H, 5.99; N, 12.75.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@@H:5]([CH3:17])[O:6][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].[OH-].[K+].[OH:20]S(O)(=O)=O>O1CCOCC1.O.CCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:20][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@@H:5]([CH3:17])[O:6][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1O[C@H](C)Cc2c(Br)cccc21
Reactant: O=S(=O)(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1O[C@H](C)Cc2c(O)cccc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (3R)-ethyl 5bromo-3-methylisochroman-1-carboxylate (2.0 g, 5.95 mmol) in dioxane (50 ml) and water (10 ml) was added KOH (1.37 g, 35.7 mmol), tetramethyl dit-butyl XPhos (0.28 g, 0.06 mmol) and Pd2(dba)3 (0.06 g, 0.06 mmol) at room temperature. Then, reaction mixture was degassed three times with N2 and stirred at 100° C. for 16 h. The reaction mixture was quenched with MeOH and concentrated under reduced pressure to afford crude compound. The crude was dissolved in EtOH (80 ml) added H2SO4 (1.0 ml) then stirred at 80° C. for 5 h. The solvent was removed by evaporation to get the crude compound. The title compound was purified by separation methods A and E. (Yield 100 mg).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(F)ccc(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(CCl)c1F

Procedure:
To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice cooling with stirring, and the mixture is stirred at room temperature overnight. To the mixture is added triethylamine (10 ml), and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g), as colorless oil, b.p. 63;L ° C. (13 mmHg).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7]([N+:14]([O-])=O)=[C:8]([CH:10]=[CH:11][C:12]=1[Cl:13])[NH2:9].O.O.[Sn](Cl)Cl.N#N>CO>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:8]([NH2:9])[C:7]=1[NH2:14]
Reactant: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1N
Temperature: 75 °C
Reaction time: 11 h

Procedure:
3-(3-bromo-2,5-dichlorophenoxy)-4-chloro-2-nitroaniline (2.68 g, 6.50 mmol) and tin(II) chloride dihydrate (7.33 g, 32.5 mmol) were suspended in MeOH (50 mL) and heated to 75° C. under a reflux condenser and N2. After 11 hours, the reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (150 mL), after which 10% aqueous sodium carbonate (250 mL) was added with vigorous stirring until the pH was 10. The resulting suspension was filtered through celite, the filtrate was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to yield the title compound. LRMS (M+1)=382.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNCC(C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-(2-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.