Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29].[OH-].[Na+]>O>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]
Reactant: O=C(O)CCCCCCCCCC=Cc1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCCCCCCCCC=Cc1cccs1

Procedure:
To a stirred slurry of 18.1 g. lithium aluminum hydride in 460 ml. ether is added dropwise a solution of 61.3 g. 12-(2-thienyl)-11-dodecenoic acid in 140 ml. ether at a rate such that gentle reflux is maintained. After four additional hours at reflux, the solution is cooled in ice and treated sequentially with 18.1 ml. water, 18.1 ml. 15% sodium hydroxide, solution and 54.3 ml. water. The precipitate is filtered and washed several times with ether. The combined ether fractions are washed with brine, dried, and evaporated. Distillation of the residual yields 12-(2-thienyl)-11-dodecenol as a semicrystalline mass.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-piperidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=215.2: AtRet=2.90.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:2][NH2:3])=[O:17]
Reactant: COC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Temperature: 60 °C
Yield: 92 %

Procedure:
Hydrazine hydrate (2 ml) is added dropwise to a suspension of methyl 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoate (227.1 mg, .73 mmol) in 10 ml of methanol. The reaction mixture is heated at 60° C for seven hours under an atmosphere of nitrogen and then allowed to cool to room temperature overnight. The now clear colorless solution is concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (gradient of 1:2 to 1:1), providing 208.6 mg (92%) of a white solid, mp 158°-160° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>Cl.O>[ClH:22].[C:13]1([N:6]([CH2:5][CH:4]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(CN(c1ccccc1)c1ccccc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CN(c1ccccc1)c1ccccc1)NCC2
Yield: 35.4 %

Procedure:
N,N-diphenylaminoacetaldehyde diethyl acetal (3.5 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.1 g) were added to a mixture of n-butyl alcohol (35 ml), water (5 ml) and conc. hydrochloric acid (2 drops) and then the mixture was refluxed for 6.5 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was washed with acetone and collected by filtration to recover the starting material, 3,4-dihydroxyphenethylamine (1.2 g). The filtrate was concentrated to give 1-(N,N-diphenylaminomethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.5 g), oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]([OH:15])CO)[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:15])[C:8]([C@@H:16]([N:18]1[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]1=[O:28])[CH3:17])=[CH:7]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1C(O)CO)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1cc2cccc(Cl)c2nc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-((S)-1-(8-chloro-2-(1,2-dihydroxyethyl)quinolin-3-yl)-ethyl)isoindoline-1,3-dione (170 mg, 0.43 mmol) in THF (4.0 mL) and water (1.0 mL) was added sodium periodate (91.6 mg, 0.43 mmol). The reaction was stirred at room temperature for 3 hours and then it was diluted with water (50 mL). The separated aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to give (S)-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-quinoline-2-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ ppm 10.36 (1H, s), 8.59 (1H, s), 7.89-7.91 (1H, m), 7.82-7.86 (3H, m), 7.71-7.73 (2H, m), 7.57-7.61 (1H, m), 6.67 (1H, q, J=7.0 Hz), 2.00 (3H, d, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1.C(N(CC)CC)C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (470 mg, 1.91 mmol) was added tert-butyl piperidin-4-ylmethylcarbamate (410 mg, 1.91 mmol) followed by triethylamine (0.267 mL, 1.91 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and the organic portion washed with 1N HCl, H2O, and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude residue was purified by flash chromatography on a 24 g silica gel cartridge using 0 to 100% ethyl acetate in hexane over 15 minutes, then 0 to 20% MeOH in DCM over 15 min. to provide Intermediate 3A (800 mg, 1.890 mmol, 99% yield). HPLC/MS (Method M) RT=1.58 min, [M+1]+ 324.1.
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][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:31][C@@H:30]1[C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. After the reaction the material was purified using chiral preparatory HPLC (Chiralcel AS column, 5% EtOH in hexanes, 42 minute run). The first enantiomer to come off of the column is Enantiomer A.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10]CC2C=CC(OC)=CC=2)[CH2:7][C@H:6]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:4])=[O:3].C([SiH](CC)CC)C>>[CH3:1][S:2]([N:5]1[C@H:6]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][C@@H:8]([SH:10])[CH2:9]1)(=[O:3])=[O:4]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](COc3ccccc3)N(S(C)(=O)=O)C2)cc1
Agent: CC[SiH](CC)CC
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COc1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
(Method 2): A solution of 102 mg (0.25 mmol) (2S,4R)-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-2-phenoxymethyl-pyrrolidine and 0.4 ml (2.5 mmol) triethylsilane was heated for 1 min at 80° C., cooled to room temperature and evaporated. Crystallization from Et2O/pentane gave 39 mg (54%) of (3R,5S)-1-methanesulfonyl-5-phenoxymethyl-pyrrolidine-3-thiol, mp 78-79° C., MS: 288 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH3:27][C@H:28]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:29]O>C(Cl)Cl>[I:20][CH2:29][C@H:28]([CH3:27])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: II
Reactant: CC(C)CCC[C@@H](C)CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CI
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of supported triphenyl phosphine (6.55 g, 19.67 mmol) in CH2Cl2 at 0° C. was added iodine (4.99 g, 19.67 mmol) and imidazole (1.33 g, 19.67 mmol). The mixture was warmed to ambient temperature, stirred for 1 h and cooled to 0° C. for the dropwise addition of (R)-2,6-dimethyl heptan-1-ol in CH2Cl2 (5 mL). The mixture was allowed to reach ambient temperature and stirred for 1 h, at which time it was filtered through a pad of celite and the solids were washed with CH2Cl2. The filtrated was concentrated, and the crude product was purified via silica gel chromatography to give (R)-1-iodo-2,6-dimethyl heptane (2.44 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.[F-].[K+]>>[F:11][C:9]1[CH:10]=[C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Agent: [F-]
Agent: [K+]
Product: Cn1c(C#N)ccc1-c1cc(F)c2c(c1)C(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.4 %

Procedure:
5-Bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one (5.16 g, 20.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (5.4 g, 36 mmol), KF (3.83 g, 66 mmol), and Pd2(dba)3 monochloroform adduct (516 mg, 0.500 mmol) were added to a 200 mL round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 min. THF (50 mL) was added and the mixture was purged with nitrogen for an additional 5 min. A solution of tri-t-butylphosphine (10% wt in hexanes) (2.97 mL, 1.00 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 5 h. The mixture was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed through with 200 mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification by flash chromatography (20% acetone/hexane) afforded the title compound (4.5 g, 80%) as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[CH:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4]>C(OCC)(=O)C>[NH2:5][C@H:3]([CH3:4])[C@@H:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)[OH:1]
Reactant: COc1cc([C@@H](O)C(C)NC(=O)OC(C)(C)C)ccc1SC
Solvent: CCOC(C)=O
Product: COc1cc([C@@H](O)[C@@H](C)N)ccc1SC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
t-Butyl (R)-1-hydroxy-1-(3-methoxy-4-(methylthio)phenyl)propan-2-ylcarbamate (308c, 44 μg, 130 μmol) was dissolved in a solution of HC in ethyl acetate (1M, 5 mL) and stirred at 60° C. for 2 h. The solvent was evaporated, and the diastereomers were separated by HPLC (XBridge column). The subtitle compound is the first eluted product, 17 mg (55%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:40]=2)O1>O1CCOCC1.O.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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[CH:40]=2)[CH:7]=1
Reactant: Cc1nc(NC(=O)NC(=O)C(C)C)ccc1Oc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)NC(=O)C(C)C)ccc1Oc1ccnc(-c2ccnc(N3CCOCC3)c2)c1
Temperature: 95 °C
Yield: 28 %

Procedure:
A mixture of N-((5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide (0.136 g, 0.390 mmol), K2CO3 (0.108 g, 0.780 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.136 g, 0.468 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.045 g, 0.039 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration through a pad of diatomaceous earth and Na2SO4. The filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was purified twice more via silica gel chromatography (MeOH/EtOAc). The resulting material was treated with Et2O, sonicated and the solid collected via filtration to afford N-((6-methyl-5-((2′-morpholino-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (52 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.84 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.30 (dd, J=5.2, 1.3 Hz, 1H), 6.80 (dd, J=5.6, 2.4 Hz, 1H), 3.70 (m, 4H), 3.51 (m, 4H), 2.66 (m, 1H), 2.27 (s, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 477.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH2:22]([NH2:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:22]([NH:34][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
At 0° C., to a solution of 4-nitro-benzoyl chloride (12.664 g, 68.25 mmol) and DIEA (9.7 g, 75.05 mmol) in anhydrous DCM (200 mL) was added dropwise a solution of dodecylamine (12.650 g, 68.25 mmol in 50 mL of DCM). The reaction mixture was stirred at 0° C. for 30 min, then 1.5 h at rt. The solvents were evaporated and the residue dissolved in boiling AcOEt, washed with water, a 10% aqueous solution of HCl, water, dried over MgSO4 and filtered. The solvents were evaporated to give a yellow solid (23.02 g). This residue was washed twice with diethylether (50 mL) to give after evaporation of the solvent the title compound as a pale yellow powder (20.31 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (t, 1H, J=5.5 Hz), 8.30 (d, 2H, J=9.0 Hz), 8.04 (d, 2H, J=9.0 Hz), 3.25 (q, 2H, J=6.3 Hz), 1.43-1.58 (m, 2H), 1.12-1.35 (m, 18H), 0.83 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 6.55 min (HPLC purity: 93.2%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].O.[F-].C([N+](CC)(CC)CC)C.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.O>CN(C=O)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[CH:9][C:6]=1[CH2:7][OH:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Reactant: ClCc1ccc2ccccc2n1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.3 %

Procedure:
A mixture of 5-hydroxy-2-nitrobenzyl alcohol (5.1 g, 30 mmol), tetraethylammonium fluoride hydrate (8.94 g, 60 mmol) and 2-chloromethylquinoline (5.31 g, 30 mmol) in DMF (90 ml) was stirred at room temperature for 72 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated in vacuo. To the residue was added methylene chloride (25 ml) and the solid was filtered to provide 3.1 g of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F-:12].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [F-]
Reactant: N#Cc1cc(F)c(Cl)cc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)cc1Cl
Temperature: 0 °C
Yield: 68.6 %

Procedure:
A mixture comprising 5.70 g (0.03 mol) of 2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KF and 30 ml of dimethylsulfoxide, was reacted at a temperature of from 140° to 150° C. for 3.5 hours in a glass reactor. After completion of the reaction, the mixture was poured into ice water (50 ml) and extracted with chloroform. The chloroform extract was washed five times with water and then dried. Then chloroform was distilled off. The residue was distilled under reduced pressure to obtain 3.57 g (yield: 68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107° C./37 mmHg; melting point: 35°-37° C.
Reaction SMILES: [CH3:1][C:2]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH3:20])[C:15]([CH:18]=O)=[N:16][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH3:20])[C:15]([CH2:18][NH:10][C:2]([CH3:3])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: CC(C)(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CNC(C)(C)c1ccccn1

Procedure:
Using General Procedure B: Reaction of 1-methyl-1-pyridin-2-yl-ethylamine and 5-chloro-3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave (5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amine as a beige oil. 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.19 (s, 3H), 3.62 (s, 2H), 4.66 (s, 1H), 7.11-7.15 (m, 1H), 7.38 (s, 1H), 7.48 (d, 1H, J=6.0 Hz), 7.62-7.67 (m, 1H), 8.37 (s, 1H), 8.58 (d, 1H, J=6.0 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:33][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CCCC(Oc3ccc(-n4ccnc4)cc3)C2)c2ccccc12
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1–2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10–2.30 (m, 3), 1.80 (m, 1), 1.40–1.70 (m, 2) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[C:10](=[O:15])[O:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl.Cl.[CH2:20]([O:22][C:23]([C@@:25]1([NH2:30])[CH2:27][C@H:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.O>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][C@@H:12]([OH:11])[CH2:14][C@H:9]1[C:10](=[O:15])[NH:30][C@:25]1([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:27][C@H:26]1[CH:28]=[CH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CC2CC1C(=O)O2
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 88.7 %

Procedure:
Compound 146 (56 mg, 0.264 mmol) was dissolved in dioxane/water 1:1 (5 mL) and the mixture was cooled to 0° C. 1 M lithium hydroxide (0.52 mL, 0.520 mmol) was added and the mixture was stirred at 0° C. for 45 minutes, after which the mixture was neutralized with 1M hydrochloric acid and evaporated and coevaporated with toluene. The crystalline residue was dissolved in DMF (5 mL) and (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid ethyl ester hydrochloride (60 mg, 0.313 mmol) and diisopropylethylamine (DIEA) (138 μL, 0.792 mmol) were added and the solution was cooled to 0° C. HATU (120 mg, 0.316 mmol) was added and the mixture was stirred for 0.5 h at 0° C. and for an additional 2 h at room temperature. The mixture was then evaporated and extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification by flash column chromatography (toluene/EtOAc 1:1) provided the title compound (86 mg, 89%) as a colourless oil. The afforded oil was crystallised from ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].C1COCC1.[CH2:17]([NH2:20])[CH2:18][NH2:19].Cl>O>[NH2:19][CH2:18][CH2:17][NH:20][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: NCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=S)Nc1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 2,6-dichlorophenyl isothiocyanate (500 mg) and THF (5 ml) was added dropwise under argon within 20 minutes to a solution of ethylenediamine (3.68 g) and abs. THF (4 ml). After stirring for a further 30 min, the mixture was added to water, acidified with 10% HCl and extracted three times with ethyl acetate. The aqueous phase was made basic using saturated potassium carbonate solution, and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvent was removed under reduced pressure and the residue was co-evaporated twice with toluene. After drying in high vacuum, the desired product was obtained as a white solid (532 mg).