Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH3:16][O:17][C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][C:23]=1[CH:30]([OH:32])[CH3:31]
Reactant: COc1ccc(-c2ccncc2)nn1
Reactant: CC=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1C(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 0.93 g 2,2,6,6-tetramethylpiperidine in 30 ml THF is added 4.13 ml (15% solution in toluene) n-butyllithium at −30° C. After being stirred at 0° C. for 30 min, the reaction mixture is cooled to −78° C. and a solution of 1.12 g 3-methoxy-6-pyridin-4-yl-pyridazine in 30 ml THF is added and stirred at −78° C. for 30 min. At this temperature, 3.17 g acetaldehyde are added and stirred for another 2 h. The reaction is quenched by the addition of 24 ml MeOH/THF 1:1 and warmed to ambient temperature. Then, 30 ml saturated aq. NaHCO3 are added and extracted with CH2Cl2. The combined organic layers are washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate 100%) to give 0.91 g (66%) of the desired product as a beige solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][N:31]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cnc(N)nc3)ccn2c1=O
Yield: 80.6 %

Procedure:
Methyl 8-(2-aminopyrimidin-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (90.8 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (96 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(C(F)(F)F)cn2)cc1
Yield: 20.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-bromo-5-(trifluoromethyl)pyridine (0.108 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.51 (t, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.70 (t, J=6.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.4 Hz, 2H), 8.29 (d, J=7.8 Hz, 11-0, 9.00 (s, 1H), 12.75 (br s, 1H). MS (m/z): 459.37 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.CC([O-])(C)C.[K+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Oc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a mixture of 3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (300 mg, 0.96 mmol, 1.0 eq.) and t-BuOK (216 mg, 1.90 mmol, 2.0 eq) in DMF (3 mL) was added dropwise ethyl bromoacetate (193 mg, 128 uL, 1.20 mmol, 1.2 eq) at 0° C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water and neutralized with 1 M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by chromatography (petroleum ether: EtOAc, 4:1) to give the title compound as a colourless oil (200 mg, 52%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][C:16]1([CH2:29][OH:30])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:29]1[C:16]2([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH2:15][CH2:14][O:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCOC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
Diethyl azodicarboxylate (183 μl, 1.16 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate (Description 42, 250 mg, 0.96 mmol) and triphenylphosphine (303 mg, 1.16 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at 0° C. for 90 minutes then at room temperature overnight. The mixture was cooled to 0° C. and further triphenylphosphine (126 mg, 0.48 mmol) and diethyl azodicarboxylate (76 μl, 0.48 mmol) were added. The mixture was stirred at room temperature for 2.5 hours, then the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20), to give the title compound as a colorless oil (150 mg, 65%). m/z (ES+) 186 (M+1-C4H8).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(O[CH:13]1[O:30][C@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C>[Cl-].[Cl-].[Zn+2].C(Cl)Cl>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@@H:29]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:30][C@@H:13]1[O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
8.9 g of p-cresol, 8.9 g of penta-O-acetyl-D-galactopyranose and 0.56 g of ZnCl2 are mixed, heated to 160° C. and kept at this temperature for 30 minutes, according to HELFERICH's method. After cooling to 60° C., the reaction medium is taken up with 400 ml of CH2Cl2 and washed with twice 400 ml of water and then with a solution of sodium hydroxide (≈1N) until the aqueous phase is practically colourless. The organic phase is finally washed with twice 400 ml of water, dried over anhydrous sodium sulfate and then evaporated to dryness in a water bath (temperature: 35°-40° C.) to give a residue of 7.08 g (yield=70%). Chromatography on a column of 60H silica (solvent: hexane/ethyl acetate: 90/10 v/v) gives 2.9 g of the compound 1 (yield=29%) and 1.17 g of its β anomer (yield=12%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([OH:19])[C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.[N+](C)([O-])=O>[O:19]([CH2:8][C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H]([C@@H](O)C(O)Br)C(O)=C1O
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=C1O[C@H]([C@@H](O)COc2ccccc2)C(O)=C1O
Reaction time: 6 h

Procedure:
To a stirred solution of 7.44 g (0.06 mol) sodium carbonate in 25 ml of water was added 4.76 g (0.02 mol) of 6-bromo-L-ascorbic acid in small portions, followed by 3.8 g (0.04 mol) of phenol. The solution thickened to a white mobile paste, gradually turning yellow after stirring 6 hours under a nitrogen atmosphere. The reaction mixture was then adjusted to pH 0.5 with 6 N aqueous hydrochloric acid the aqueous solution extracted with ethyl acetate (3×100 ml), the ethyl acetate layer washed with water, brine and dried over anhydrous magnesium sulfate. On removal of solvent in vacuo the residue was triturated with benzene, the resulting crystals collected by filtration and dried under vacuum overnight affording 1.54 g of crude title compound. A sample for analysis was obtained by recrystallization from nitromethane followed by drying under vacuum overnight: mp 160°-161°; VmaxKBr 5.68 (s) 6.00 (s); 1H-nmr (D2O): 7.54-6.75 (m, 5, arom.), 4.93 (broad s, l), 7.20 (m, 3, --CH2 --O and --CH--OH); mass spectrum (70 eV): m/e 252.0563 (parent, C12H12O6, 136 (--O--CH2 --C+H--OH), 116 ##STR4## 107 (--O+ =CH2), 94 (base, --OH); [α]D24 79.3° (C 1.09, CH3OH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.Br[CH2:32][CH2:33][CH2:34]Br>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:34][CH2:33][CH2:32][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCCO2
Temperature: 60 °C
Yield: 89.9 %

Procedure:
Potassium carbonate (818 mg, 5.92 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 1.00 g, 2.69 mmol) and 1,3-dibromopropane (597 mg, 2.96 mmol) in N,N-dimethylformamide (17 mL), and the suspension was heated at 60° C. for 5 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 9-(5-chloro-2-methoxybenzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylic acid methyl ester (996 mg, 90%). White solid, MS (ISP)=412.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[C:14]=2[CH3:23])(=[O:12])=[O:11])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[S:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[C:14]=2[CH3:23])(=[O:12])=[O:11])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCN(C)CC1
Solvent: ClCCCl
Product: Cc1c(S(=O)(=O)Nc2ccc(O)c(N3CCN(C)CC3)c2)sc2ccc(Cl)cc12

Procedure:
To a suspension of boron tribromide dimethyl sulphide complex (620 mg, 2 mmol) in 1,2 dichloroethane (30 ml) under argon was added 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]amide (E17) (0.2 mmol). The reaction mixture was heated to reflux for 12 hrs, cooled, quenched by the addition of water (20 ml) and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title compound (E113). Found MH+ 452/454
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1.[CH:30](=O)[CH3:31].N>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:30]([CH3:31])=[N:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2NC(C(=NO)N2CCOCC2)C1
Reactant: CC=O
Agent: N
Solvent: CC(=O)O
Product: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=[N+]([O-])C2

Procedure:
A mixture of 4.2 g (0.01 mole) of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine 4-oxide, 50 ml of glacial acetic acid and 4 ml of acetaldehyde was heated to reflux for 5 minutes. The cooled reaction mixture was poured on ice, made alkaline with ammonia and extracted with methylene chloride. The extracts were dried and evaporated and the residue was crystallized from ether/2-propanol to yield yellow crystals.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:8][OH:9])[CH2:6][O:7][CH2:13][O:5][CH2:4]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CO)(CO)CO
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CO)COCOC1
Reaction time: 3 h

Procedure:
In a one-liter three neck flask were placed 405 grams of 2-ethyl-2-hydroxymethyl-1,3-propanediol, 90 grams of paraformaldehyde, 0.9 grams of p-toluene sulfonic acid monohydrate and 150 ml of toluene. The flask was equipped with a Dean-stark trap and a condenser. The reaction mixture was stirred at a bath temperature of 120° C. to 170° C. for three hours. The toluene-water was collected, and after removing the toluene, the crude product was distilled under vacuum at 10-11 mm Hg and 115° C. to 117° C. 410 grams of 5-ethyl-5-hydroxymethyl-1,3-dioxane (EHMDO) were collected. The product was then dried by molecular sieve and had a water content of about 350 ppm. NMR spectra confirmed that EHMDO was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[F:8][C:4]1[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cccc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Fc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
12.27 g (70.2 mmol, 1 eq.) of 1-bromo-3-fluorobenzene and 44.7 g (210.5 mmol, 3 eq.) of K3PO4 are added to a solution of 12.83 g (105.3 mmol, 1.5 eq.) of phenylboronic acid in 200 ml of isopropanol. The mixture is stirred at room temperature for 4 hours. 0.0021 g (14.8 μmol, 0.0021 mol %) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is subsequently added, and the reaction mixture is stirred at room temperature for 20 hours, giving 3-fluorobiphenyl quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[F:34][C:35]([F:49])([F:48])[C@:36]([O:46][CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:37](=[O:38])[C@@:36]([O:46][CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:35]([F:48])([F:49])[F:34])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@](C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To racemic 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (obtained as described in Example 1, Procedure 1) (55 mg, 0.14 mmol) in DCM (1 mL) was added pyridine (56 μL, 55 mmol) and (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (52 μL, 0.22 mmol). The reaction was stirred at room temperature for 14 h and the reaction mixture filtered through a silica plug elution with DCM. (S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide was crystallized from ether heptane.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (140 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (83 mg, 0.54 mmol) and 1,1′-dimethyltriethylamine (190 μL, 1.1 mmol) in n-butanol (3 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: LC-MS (ESI) m/z 378.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(#N)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1)([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCCN2CCOCC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(OCCN2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A resealable tube was charged with 4-[2-(4-iodo-phenoxy)-ethyl]-morpholine 100b (2.00 g, 6.00 mmol), acetonitrile (40 mL), and triethylamine (5 mL). Dichlorobis(triphenylphosphine)palladium (II) (0.211 g, 0.30 mmol), copper (I) iodide (0.057 g, 0.30 mmol), and (trimethylsilyl)acetylene (0.766 g, 1.10 mL, 7.80 mmol) were added. The system was purged with argon, the tube was sealed, and the mixture stirred at 60° C. for 16 h. The reaction mixture was concentrated to afford 4-[2-(4-trimethylsilanylethynyl-phenoxy)-ethyl]-morpholine 101b as a dark brown solid which was used without purification. MS (MH+) 304.2; Calculated 303 for C17H25NO2Si.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:22])=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.[I-:23].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(=O)CC.C(OCC)(=O)C>[CH2:16]([O:15][P:13]([CH2:12][C:11]1[C:2]([I:23])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:21])=[C:6]([CH3:22])[CH:5]=2)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: [I-]
Reactant: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1Cl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1I)OCC
Yield: 55.2 %

Procedure:
2-Chloro-3-diethylphosphonomethyl-6,7-dimethylquinoline (0.40 g, 1.17 mmol), prepared as described in Example 4 was dissolved in 2-butanone (20 ml) and treated with sodium iodide (0.39 g, 2.6 mmol) and p-toluenesulfonic acid (0.11 g, 0.58 mmol). The mixture was refluxed for 10 hours. Ethyl acetate and saturated sodium hydrogen carbonate were added. The organic phase was separated and filtered through a pad of silica gel. Evaporation of solvents gave 0.28 g of 3-diethylphosphonomethyl-6,7-dimethyl-2-iodoquinoline.
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)C1=O)=CCC.Cl>O>[CH:15]1[CH:14]=[N:13][CH:12]=[C:11]([C:10]2[CH2:7][CH2:8][CH2:9][N:5]=2)[CH:16]=1
Reactant: CCC=CN1CCC(C(=O)c2cccnc2)C1=O
Agent: Cl
Solvent: O
Product: c1cncc(C2=NCCC2)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A mixture of 1-(but-1-enyl)-3-nicotinoylpyrrolidin-2-one (II), (40 g, 0.1639 mol), 50 ml water and 85 ml HCl were refluxed together for 12 hrs. The reaction mixture was cooled to room temperature, washed with 50 ml×2 ethyl acetate, further cooled to 0° C. and pH adjusted to >13 using NaOH. The reaction mixture was extracted with 100 ml×3 of dichloromethane and the extract dried over Na2SO4. After removing the solvent under reduced pressure, the crude solid obtained was purified by high vacuum distillation to give colorless solid myosmine (16.75 g, 70%). 1H NMR (CDCl3): δ 2.05 (2H, m), 2.94 (2H, t), 4.06 (2H,t), 7.34 (1H, dd), 8.18 (1H,dt), 8.64 (1H, dd), and 8.99 (1H, d). 13C-NMR(CDCl3): δ 170.56, 151.1, 149.1, 134.6, 130.0, 123.3, 61.5, 34.7, and 22.5. 1R: 2961, 1620, and 1590 Cm−1.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]2[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(CCC2CCC(C#N)CC2)cc1
Yield: 81.8 %

Procedure:
956 mg of the 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile obtained were dissolved in 50 ml of toluene in a sulphonation flask, treated with 150 mg of palladium/carbon (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill (about 30 minutes). Filtration of the mixture (rinsing with toluene), concentration of the filtrate and low-pressure chromatography (0.4 bar) of the residue (890 mg) on silica gel with 5% ethyl acetate/petroleum ether gave 788 mg (82%) of 4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile as a viscous colourless oil. Although in the thin-layer chromatogram using different solvent systems as the eluant only a single spot appeared, according to gas chromatographic and NMR spectroscopic analysis this material was a cis/trans isomer mixture (about 1:3). Two-fold crystallization of this material from pentane at -20° C. finally yielded trans-4-[2-(p-pentylphenyl)ethyl]cyclohexanecarbonitrile of sufficient purity (according to gas chromatographic analysis 98.8% of trans compound and 1.2% of cis compound); m.p. 22.4° C., cl.p. (N-I) -14.1° C.