Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(O)c1ccc(CCCCO)cn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCCCc1ccc(C(=O)O)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
3.92 g of 5-(4-hydroxybutyl)picolinic acid was dissolved in 20 ml of pyridine, and with stirring under ice cooling, a solution of 4.6 g of carbobenzyloxy chloride in 20 ml of toluene was added dropwise. Under ice cooling, the mixture was reacted for 2 hours. Then, the reaction mixture was poured into ice water, and extracted with toluene. The extract was washed successively with water, 1 N hydrochloric acid and then with water, and the toluene was distilled off to give 5.7 g of 5-(4-carbobenzyloxybutyl)picolinic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
0.28 g of picolic acid (2.32 mmol) and 0.8 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.32 mmol) were dissolved in 30 ml of dichloromethane. After addition of 1.19 g of diisopropylethylamine (9.26 mmol), 0.155 g of hydroxybenzotriazole (HOBt, 1.15 mmol), and 0.487 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.54 mmol) at 0° C., the reaction mixture was stirred for 16 h at room temperature. 0.24 g of N-Ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 5 h. 100 ml of dichloromethane were added. The organic layer was washed twice with water. The dichlormethane phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate as eluent. The residue was re-dissolved in 15 ml of diethylether and treated with 1 N hydrochloric acid in diethyl ether. The precipitate was collected by filtration to yield 0.95 g of the title compound as a hydrochloride salt.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.S(Cl)(Cl)=O.[CH3:24][C@@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26]O>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH2:24][C@@H:25]([CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCC[C@H](C)CO
Solvent: O=S(Cl)Cl
Product: CCCCCC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-Acetoxybiphenyl-4-carboxylic acid (5.80 g) was converted to an acid chloride using thionyl chloride, and the acid chloride was reacted with (S)-2-methyloctanol. The reaction mixture was extracted with diethyl ether, and the ethereal layer was thoroughly dried. Benzylamine was added thereto in small portions at room temperature. Hydrochloric acid was further added thereto, and the mixture was washed with water. The solvent was removed from the reaction mixture by distillation, and the resulting crude product was decolored by passing through a silica gel column (solvent: n-hexane-ethyl acetate mixture) and recrystallized from n-hexane to obtain 6.2 g of (S)-2-methyloctyl 4'-hydroxybiphenyl-4-carboxylate as white crystals having a melting point of 89° C.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH2:23][C:24]#[N:25])=[CH:10][N:11]2C(OC(C)(C)C)=O.C([N-]C(C)C)(C)C.[Li+].CI>O.CO>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:23]([CH3:2])[C:24]#[N:25])=[CH:10][NH:11]2
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2c(Br)cccc21
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CI
Product: CC(C#N)c1c[nH]c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (10 mL) of 1, -dimethylethyl 4-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate [CAS registration number 151726-05-5, Organic Letters 2003, 5(19), 3519-3522] (1.0 g), lithium diisopropylamide (2M tetrahydrofuran solution; 3.4 mL) was added dropwise at −78° C. and the mixture was stirred at the same temperature for one hour. To the mixture, methyl iodide (0.5 mL) was added, followed by stirring for one hour. The mixture was gradually heated to room temperature and methanol (2 mL) was added. The mixture was stirred overnight at room temperature and water was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20 y 70:30) to obtain the titled compound having the following physical properties (0.35 g).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:14])([F:13])[S:9]([OH:12])(=[O:11])=[O:10].O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=1[O:27][CH3:28].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:28][O:27][C:17]1[CH:18]=[C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][C:16]=1[O:10][S:9]([C:8]([F:14])([F:13])[F:7])(=[O:12])=[O:11]
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Yield: 99.9 %

Procedure:
Pyridine (2.10 ml, 25.9 mmol), anhydrous trifluoromethanesulfonic acid (1.61 ml, 9.53 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) were added to a solution of methyl (4-hydroxy-3-methoxyphenyl)acetate (1.70 g, 8.66 mmol) in methylene chloride (20 ml) and the mixture was stirred under ice-cooling for 10 minutes and then stirred at room temperature for 20 minutes. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give methyl (3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (2.84 g, yield: 99%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[CH2:45]([OH:52])[C:46]([NH2:51])([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:51][C:46]([CH2:49][OH:50])([CH2:47][OH:48])[CH2:45][OH:52])=[CH:33][CH:32]=3)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)(CO)CO
Agent: CC(C)(N)CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCCNC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and tris(hydroxymethyl)aminomethane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11](C(OC(C)(C)C)=O)[C:10]=1[C:26]([O:28][CH3:29])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1c(NCCC(=O)c2cccc(F)c2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1cccc(F)c1
Yield: 70 %

Procedure:
Dissolve 3-[(m-fluorophenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL) and stir for 4 hours at room temperture. Dilute with ethyl acetate (50 mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dry over magnesium sulfate, filter and concentrate in vacuo. Purify the residue by flash chromatography (30% ethyl acetate/hexane) and recrystallize from ethyl acetate/hexane to yield the title compound (700 mg, 70%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:12][I:13]>>[I-:13].[CH2:1]([N+:5]1([CH3:12])[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCN1CCCC(C)C1
Product: CCCC[N+]1(C)CCCC(C)C1
Product: [I-]

Procedure:
Following this, a second N-substitution was carried out on the 1-butyl-3-methylpiperidine using methyl iodide as an N-alkylating agent to form 1-butyl-1-methyl-3-methylpiperidinium iodide. A slight excess of methyl iodide was added dropwise to 1-butyl-3-methylpiperidine in dichloromethane keeping the temperature below 20° C. by an ice-water bath. The reaction mixture was then allowed to warm to room temperature and stirred until complete conversion of amine (as determined using 1H nmr). Diethyl ether was then added to the reaction mixture and the white precipitate filtered, washed with ether and dried in air. The white solid form 1-butyl-1-methyl-3-methylpiperidinium iodide melted at 204° C. 1H-NMR (300 MHz, CDCl3) δ 1.00 (d, 3H), 1.02 (t, 3H), 1.48 (m, 2H), 1.82 (m, 2H), 2.10 (m, 5H), 3.28 (s, 3H), 3.60 (m, 2H), 3.70 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:21]=[C:22]([CH2:30][CH3:31])[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH2:30]([C:22]1[C:23]2[O:28][CH2:27][O:26][CH2:25][C:24]=2[CH:29]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:21]=1)[CH3:31]
Reactant: NNc1ncccn1
Reactant: CCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc2c1OCOC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 101 mg of [2-(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 21 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(8-ethyl-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>CO>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:1]([CH:2]([CH3:4])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)c1ccccc1
Reactant: COC(=O)NN
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)NN=C(c1ccccc1)C(C)C

Procedure:
To a solution of 44.46 g (0.3 moles) of isobutyrophenone in 200 ml of methanol 3 ml of acetic acid and 27 g of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser, then clarified and evaporated in vacuo to half of its original volume. The residue is cooled and the separated tallow-like product is filtered off. Yield: 64.2 g (97.3%) M.p.: 78°-80° C. The product can be recrystallized from petrol.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:12]=[C:13]([C:16]([Cl:19])=[CH:17][N:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[Cl:19][C:16]1[C:13]([C:14]#[N:15])=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:18][CH:17]=1
Reactant: N#Cc1cc(Cl)ncc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1cc(-c2ccccc2)ncc1Cl

Procedure:
Tetralds(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol) was added to a stirred solution of phenylboronic acid (423 mg, 3.47 mmol), 2,5-dichloro-isonicotinonitrile (550 mg, 2.89 mmol) and sodium carbonate (3.5 mL of 2M aqueous solution) in dimethoxyethane (7 mL) and ethanol (3.5 mL). The resulting suspension was stirred at reflux for 3 hours, concentrated in vacuo and water (25 mL) added. The aqueous solution was extracted with ethyl acetate (×3) and the combined organic extracts were washed with brine, dried and concentrated. Purification by column chromatography using 2% v/v ethyl acetate in hexane as eluent afforded the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:24](=[S:26])=[S:25].Br[CH2:28]Br>CS(C)=O.O>[S:25]1[CH2:28][S:26][C:24]1=[C:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: S=C=S
Reactant: BrCBr
Reactant: COc1cccc(C(=O)Cc2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(C(=O)C(=C2SCS2)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 1-(3-methoxy-phenyl)-2-pyridin-4-yl-ethanone (1 g, 4.40 mmol) in dry DMSO (22 mL) under nitrogen atmosphere solid potassium carbonate (1.8 g, 13.20 mmol, 3 eq) was added at room temperature, followed by carbon disulfide (0.796 mL, 13.20 mmol, 3 eq) and dibromomethane (0.926 mL, 13.20 mmol, 3 eq). The reaction mixture was stirred at room temperature for 3 hour and then poured into stirred iced water (150 mL). The yellow precipitate was filtered, washed with water and dried at 60° C. under reduced pressure for 1 hour to give 1.18 g (83%) of 2-[1,3]dithietan-2-ylidene-1-(3-methoxy-phenyl)-2-pyridin-4-yl-ethanone.
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23]C(=O)OC(C)(C)C)[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:23][C@@H:9]([CH2:8][C@H:5]1[CH2:4][CH2:3][C@@H:2]([F:1])[CH2:7][CH2:6]1)[CH2:10][N:11]([CH3:12])[C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)C[C@H]1CC[C@@H](F)CC1)C(=O)OCc1ccccc1

Procedure:
A solution of tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (550 mg, 1.3 mmol) in TFA/CH2Cl2 (20 mL, v/v 20%) was stirred for 1 h at rt, quenched with satd aq NaHCO3 until no further gas evolution was visible and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and condensed under reduced pressure to obtain benzyl (S)-2-amino-3-(cis-4-fluorocyclohexyl)propylmethylcarbamate (400 mg, yield 95%). 1H NMR (CDCl3, 400 MHz) δ 1.42(m, 4 H), 1.64(m, 4 H), 2.98(d, 3 H), 3.21(m, 1 H), 3.50(m, 1 H), 3.90(m, 1 H), 5.13(d, 2 H), 7.33(m, 5 H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:54]1[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=1)CCC>CN(C)C=O.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>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 84.9 %

Procedure:
To a solution containing the product from Example 92D (0.50 g, 0.70 mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150 g, 0.214 mmol), and 4-tributylstannylpyridine (0.776 g, 2.11 mmol), and the mixture was heated to 100° C. for 18 hours. The reaction was filtered, diluted with ethyl acetate and washed with water, and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in acetonitrile and washed twice with hexanes, and the acetonitrile layer was evaporated to give the title compound (0.422 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1.C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:9][C:8]([CH2:10][CH2:11][CH3:12])=[N:7][C:6]=2[CH:13]=1
Reactant: CCCc1nc2cc(Br)cc(C)c2[nH]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc2cc(-c3ccco3)cc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 72 h
Yield: 30.1 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-4-methyl-2-propylbenzimidazole (WO2004082621; 200 mg, 0.83 mmol) was dissolved in toluene (4 mL), tributyl(2-furanyl)tin (0.78 mL, 2.49 mmol) and tetrakis(triphenylphosphine)palladium (288 mg, 0.25 mmol) were added, and the mixture was stirred at 100° C. for 3 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/2 to 1/9) to give the title compound (60 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.[Cl-].[Na+].O>[C:15]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:9][CH2:10]1)(=[O:17])[CH3:16]
Reactant: OC1CCN(c2ccc(Br)cn2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1CCN(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)piperidin-4-ol (200 mg, 0.78 mmol), acetic anhydride (0.16 mL, 1.7 mmol), DMAP (10 mg, 0.08 mmol), and Et3N (0.24 mL, 1.7 mmol) in CH2Cl2 (4 mL) was stirred at rt for 17 h. Brine was added and extracted with CH2Cl2, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with water and the title compound was collected by vacuum filtration (203 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=2.2 Hz, 1H), 7.52 (dd, J=9.0 Hz, 2.5 Hz, 1H), 6.57 (d, 9.0 Hz, 1H), 5.01-4.95 (m, 1H), 3.9-3.85 (m, 2H), 3.35-3.28 (m, 2H), 2.07 (s, 3H), 1.99-1.92 (m, 2H), 1.74-1.65 (m, 2H); MS ESI 300.9 [M+H]+, calcd for [C12H15BrN2O2+H]+ 299.03.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(#N)C.C(N(CC)CC)C.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27]>O>[CH3:24][C:25]([CH3:30])([CH3:29])[C:26]([N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1)=[O:27]
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)N(c1ccccn1)c1ccccn1
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a flask were added 2.0 g of 2,2′-dipyridylamine and 35 ml of acetonitrile. The solution was stirred under nitrogen and cooled to 5 C, when 1.5 g of triethylamine were added, followed by 1.5 g of trimethylacetyl chloride and the mixture was allowed to warm to 22 C. After 1 hour, 50 ml of water were added and the acetonitrile was removed. The product was extracted with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using 50% ethyl acetate in hexane, resulting in 1.8 g of an oil that solidified on standing.