Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1.95 g, 7.73 mmol) in THF (30 mL) was added 3 M HCl (10 mL). The mixture was stirred at 50° C. for 1.5 h, and then poured into EtOAc (50 mL) and aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 60:40 hexane/EtOAc) to give the title compound (1.34 g, 83%) as a colorless solid:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:18]2[CH2:19][CH2:20][C@@H:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:18]2[NH:22][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2]
Reactant: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)c(C#N)c2)=N1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)c(C#N)c2)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
A suspension of methyl (2S)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (D72, 70 mg, 0.198 mmol) and Pt (5% on carbon) in ethyl acetate (10 ml) was stirred at room temperature for 24 hrs. Filtration over celite and subsequent evaporation gave the title compound (64 mg, 91%). The obtained material was used unpurified in the next step. UPLC: Rt=0.55 min, MS: (ES/+) m/z: 355 [MH+], C20H19FN2O3 requires 354.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCC[N+](=O)[O-]
Product: CCC(=Cc1ccc(C(=O)OC)cc1)[N+](=O)[O-]

Procedure:
The title compound was prepared in an identical manner to that described in Description 27 using 4-carbomethoxybenzaldehyde and 1-nitropropane. τ(d6DMSO) 8.8 (3H, t, J=7 Hz), 8.08 (3H, s), 7.19 (2H, q, J=7 Hz), 6.12 (3H, s), 2.38 (2H, d, J=8 Hz), 1.97 (2H, d, J=8 Hz), 1.97 (1H, s).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][C:55]1[CH:60]=[C:59]([N:61]([CH2:63][CH2:64]O)[CH3:62])[CH:58]=[C:57]([CH3:66])[N:56]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(Cl)Cl.CO>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:64][CH2:63][N:61]([C:59]4[CH:58]=[C:57]([CH3:66])[N:56]=[C:55]([CH3:54])[CH:60]=4)[CH3:62])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cc1cc(N(C)CCO)cc(C)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1cc(C)nc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (125 mg, 0.7 mmol) in methylene chloride (5 ml) and the mixture stirred for 2 hours at ambient temperature. Methanol (10 drops) was added and the mixture was poured on to a column of neutral aluminium oxide and the product was separated by elution with methylene chloride/acetonitrile/methanol (60/35/35). The purified solid product was triturated with ether and collected by filtration. The solid was dissolved in methylene chloride/methanol and a solution of 3M ethereal hydrogen chloride (1 ml) was added. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethoxy)-6-methoxyquinazoline (170 mg, 61%).
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[O:31]=[C:12]1[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:33][CH2:32]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C(CO)(c3cc4c(cc3O)OCO4)c3ccccc32)cc1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cc1
Yield: 87 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using methyl 4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 87% yield: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, 2H), 7.38 (d, 2H), 7.18 (t, 2H), 7.02 (t, 1H), 6.72 (d, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.86 (m, 2H), 5.11 (d, 1H), 4.96 (d, 1H), 4.86 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 166.6, 156.0, 149.0, 142.4, 141.8, 140.8, 132.1, 130.3, 129.8, 129.0 127.3, 124.1, 123.7, 119.3, 109.2, 103.0, 102.0, 93.7, 80.5, 58.3, 52.2, 43.9; MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=1.C(N1CCC(OC2C=CC=CN=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C#N)c2)CC1

Procedure:
Prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-2-cyanopyridine using methods substantially equivalent to those described for the synthesis of 1-Boc-4-(pyridin-2-yloxy)piperidine. The product was purified by chromatography over silica gel, eluting with 25% ethyl acetate in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)O)[CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([CH2:8][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1C(O)c1ccc(-c2ccccn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Br)cc1Cc1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
2-(2-Pyridyl)thiophene and 5-bromo-2-methylbenzaldehyde obtained in Reference Example 4 were treated in a manner similar to Reference Example 7-(1) to give 5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol as colorless oil. APCI-Mass m/Z 360/362 (M+H). (2) A solution of the above 5-bromo-2-methylphenyl-5-(2-pyridyl)-2-thienylmethanol (1.59 g) in trifluoroacetic acid (40 ml) was cooled to 0° C., and thereto were added gradually sodium triacetoxyborohydride (4.68 g). The mixture was stirred at room temperature for one hour, and cooled again to 0° C. 10% aqueous sodium hydroxide solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired 5-bromo-2-methyl-1-(5-(2-pyridyl)-2-thienylmethyl)benzene (1.38 g) as a colorless solid. APCI-Mass m/Z 344/346 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.C(OCC)(=O)C.[CH3:31][N:32](C)C=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.[C-]#N.[Zn+2].[C-]#N>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]([C:31]#[N:32])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(C#N)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 160 °C
Yield: 32 %

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.100 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (O) (0.30 g, 0.03 mmol), and zinc cyanide (0.036 g, 0.31 mmol) in N,N-dimethylformamide (2 mL) was heated with microwave irradiation for 30 min at 160° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (10 mL), washed with water (3×2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:8, ethyl acetate/petroleum ether) to afford (5)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile (0.27 g, 32%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 0.74-0.82 (m, 1H), 0.90-1.10 (m, 2H), 1.10-1.18 (m, 3H), 1.28-1.39 (m, 1H), 1.49-1.61 (m, 1H), 1.80-1.91 (m, 1H), 2.10-2.22 (m, 1H), 2.39-2.51 (m, 1H), 2.67-2.80 (m, 1H), 4.71-4.89 (m, 1H), 6.85 (d, J=8.10 Hz, 2H), 7.08 (t, J=7.50 Hz, 1H), 7.28-7.38 (m, 2H), 7.40-7.47 (m, 1H), 7.49-7.55 (m, 1H). MS (ESI, pos. ion) m/z 333 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C>CS(C)=O>[CH:2]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:1]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C=O)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1-Methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-hydroxymethyl-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (0.328 g, 0.82 mmol) was added to 6 mL of dry DMSO. Triethylamine (0.46 mL, 3.28 mmol) was added followed by sulfur trioxide pyridine complex (0.52 g, 3.28 mmol) and the mixture was stirred at room temperature for a half hour. The mixture was poured into 100 mL of ice water and extracted twice with ethyl acetate. The ethyl acetate extracts were rinsed twice with a 10% citric acid solution, twice with water and once with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Concentration in vacuo gave 0.311 g (0.78 mmol) of 1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-formyl-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@@H:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][OH:31]>>[OH:31][CH2:30][C@@H:29]([NH:28][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[CH:27][CH:26]=1)=[O:24])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)[C@H](N)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@H](CO)C(C)C)cc2)CC1
Yield: 80 %

Procedure:
By the same procedure as described in the example 30, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using (S)-(+)-2-amino-3-methyl-1-butanol. Then, the product was recrystallized using ethanol and isopropyl ether to give a desired compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:19][C:20]([C:22]1[NH:31][C:25]2=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=[C:24]2[CH:23]=1)=[O:21])[C@@H:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([NH:19][C:20]([C:22]1[NH:31][C:25]2=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=[C:24]2[CH:23]=1)=[O:21])[C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cc2cc(Cl)ncc2[nH]1)[C@@H](O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(tert-butyldimethylsilanyloxymethyl)-2-(S)-hydroxy-2-phenylethyl]amide (Preparation 100, 304 mg, 0.661 mmol) in dry DCM (10 mL) was added Dess-Martin periodinane (342 mg, 0.806 mmol). After stirring for 3 h at room temperature alkaline sodium thiosulfate solution was added (5.4 g Na2SO3 dissolved in 20 mL saturated NaHCO3 solution) and the emulsion vigorously stirred for an additional 30 min. Ethyl acetate (150 ml) was added and the aqueous layer removed. The organic layer was washed with brine (50 ml), dried (MgSO4) and concentrated to a residue which was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate: 50/50) to give the title compound as colourless solid. m/z (ES+)=458.34 [M+H]+; RT=4.32 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13](OS(C)(=O)=O)[CH2:12][CH2:11][N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8].[C-:27]#[N:28].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:27]([C@@H:13]1[CH2:12][CH2:11][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:14]1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C[C@@H]1c1ccc(F)c(F)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A mixture of (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.72 g, 1.8 mmol), and potassium cyanide (0.33 g, 3.7 mmol) in N,N-dimethylformamide (3.3 mL) was stirred at 90° C. for 18 hours. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), washed twice with 5% lithium chloride solution (30 mL), then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-1,1-dimethylethyl (2R,4R)-4-cyano-2-(3,4-difluorophenyl)piperidine-1-carboxylate (165 mg, 30% yield). MS (EI) for C17H23F2N2O2: 323 (MH+).
Reaction SMILES: [N:1]([C:4]([CH3:15])([CH3:14])[CH2:5][C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:15][C:4]([NH2:1])([CH3:14])[CH2:5][CH2:6][NH:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: CC(C)(CC(=O)NCC(F)(F)F)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(N)CCNCC(F)(F)F
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
3-Azido-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (10.9 g, 48.4 mmol) was dissolved into anhydrous THF (50 mL) and added dropwise to a suspension of LAH (3.67 g, 2.0 equiv, 96.8 mmol) in anhydrous THF (200 mL) to maintain the reaction at reflux (30 min). After complete addition, the flask was fitted with a condenser and the reaction heated in a 70° C. oil bath for 8 h. The reaction mixture was cooled in an ice bath and water (4 mL) was added dropwise over 20 min. Then 15% NaOH solution (4 mL) was added dropwise over 10 min. The suspension was stirred for a further 10 min and water (4 mL) was added in one portion and the mixture stirred for 30 min to a give fine white suspension. The suspension was filtered through a pad of Celite® and washed with isopropyl alcohol (2×200 mL). Aqueous acid (6 N HCl, 10.0 mL) was added to the combined filtrate and concentrated on a rotovap to an oily residue. The residue was partitioned between DCM (100 mL) and water (100 mL). The aqueous layer was adjusted to pH ˜14 and the organic layer was separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic layers were combined and dried over anhydrous MgSO4, filtered and concentrated with a bath temperature between 10-13° C. to an orange liquid (8.84 g, quant). 1H NMR (CDCl3, 400 MHz): δ 1.15 (s, 6H), 1.55-1.62 (t, J=7.2, 2H), 2.81-2.86 (t, J=7.2, 2H) 3.15-3.22 (q, J=9.6, 2H). LRMS (ESI+) for C7H15F3N2 (184.1); Found: 185 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C@@H:10]([C:9]([OH:31])=[O:8])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)C[C@H](C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](C(=O)O)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
N-(t-butyloxycarbonyl)methyl-N-t-butyloxycarbonyl-D-leucine benzyl ester (2.1 g) was dissolved in methanol (25 ml), and 10% palladium-carbon (210 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless oil (1.66 g, 96%), which was directly used for the next reaction.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.[Cl-].[Na+].O>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:21]2[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: Fc1cncc(F)c1
Reactant: Nc1cc(O)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2cncc(F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) and potassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirred overnight at RT. The dark solution was treated with the 3,5-difluoropyridine (2.73 g, 23.7 mmol) and powdered potassium carbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80° C. and stirred for 24 h. The resulting black mixture was cooled to RT, diluted with brine (100 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated in vacuo and purified via column chromatography to yield 2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which was used without further purification. 1H-NMR (DMSO-d6): δ 5.57 (br s, 2H), 6.26-6.30 (dd, 1H), 6.50 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H), 8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m/z: 239.0 (M+H+).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:11]([C:8]1([CH2:6][OH:5])[CH2:10][CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the title B compound, 1-benzyl-cyclopropanecarboxylic acid tert-butyl ester (0.232 g, 1 mmol) in THF (8 mL) under nitrogen is added drop wise at −50° C. LiAlH4 (3 mL, 3 mmol, 1 m in THF). The resulting mixture is further stirred for 1 h at −50° C., then slowly allowed to reach room temperature and poured into a saturated NaHCO3 aqueous solution. The aqueous layer is extracted twice with EtOAc. and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1 to 1/1) to afford the title compound: TLC, Rf (hexane/AcOEt 1/1)=0.52. MS 180.0 [M+18]. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 4.95 min.