Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:14]#[C:15]Br>>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C@@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)=[CH:12][CH:11]=1
Reactant: N[C@@H](CO)CCc1ccc(F)cc1
Reactant: N#CBr
Product: NC1=N[C@H](CCc2ccc(F)cc2)CO1

Procedure:
In analogy to example 1b (R)-2-amino-4-(4-fluoro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (R)-4-[2-(4-fluoro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 209.3 ([M+H]+))
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OCC)(=O)C>[Cl-].[Na+].O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O-:3])=[O:2]
Reactant: CCCCCCCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCNc1ccccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
157.6 g (1 mol) of 2-nitrochlorobenzene and 280 g (2.2 mol) of octylamine were mixed. The reaction mixture was heated to a temperature of 150° C. for 3 hours to undergo reaction, and then allowed to stand overnight. To the reaction solution was then added a mixture of ethyl acetate and saturated brine. The reaction solution was then subjected to separation. The organic phase thus extracted was dried and concentrated to obtain 235 g (0.93 mol) of the desired aniline derivative (yield: 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([O:8][CH3:17])=[O:7]
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N)cc1O
Temperature: 0 °C

Procedure:
4-Amino-5-chlorosalicylic acid (24 g) is added to a stirred solution of thionyl chloride (30 ml) in methanol (300 ml) cooled to 0° C., and the mixture is stirred under reflux for 18 hours. The reaction mixture is evaporated and the residue is recrystallized from EtOH-H2O to give methyl 4-amino-5-chlorosalicylate which is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:15](O)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[C:15]([C:14]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]([F:11])[CH:13]=1)=[O:16]
Reactant: COc1cccc(Br)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Product: COc1ccc(C(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c(Br)c1

Procedure:
Synthesized from 3-bromoanisole (1.1 ml) and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (3.3 g) according to an analogous synthetic method to Preparation Example 66, the title compound (1.6 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)C(=O)C.[OH-].[Na+]>CO>[CH3:1][NH:2][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(N(C)C(C)=O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1ccc(/C=C/C(=O)O)cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a solution of methyl (E)-3-[6-(N-methyl-N-acetylamino)pyridin-3-yl]acrylate (110 mg) in methanol (3 ml) was added 1N sodium hydroxide solution (1.1 ml) at ambient temperature and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was evaporated in vacuo and was dissolved in water. The solution was adjusted to pH 6 with 1N hydrochloric acid, and the precipitate was cooled by vacuum filtration to give (E)-3-[6-(methylamino)pyridin-3-yl]acrylic acid (72 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:14]O.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>C(Cl)Cl>[Cl:27][CH2:14][C:3]1[C:2]([CH3:1])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CO)cccc1N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CCl)cccc1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(2-methyl-3-morpholinophenyl)methanol (0.468 g, 2.26 mmol) was dissolved in dry DCM (14 mL) with triethylamine (0.669 mL, 4.82 mmol) and this stirred solution was cooled at 0° C. in an ice bath. Mesyl chloride (0.415 g, 3.62 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was diluted in DCM (25 mL), washed with water (20 mL) and the water re-extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed under vacuum to afford 4-(3-(chloromethyl)-2-methylphenyl)morpholine as a crude oil (0.5 g, 98% yield).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>>[C:1]([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: BrCCCOC1CCCCO1
Reactant: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Product: CCCCCC(=O)Nc1ccc2ccn(CCCOC3CCCCO3)c2c1
Yield: 81 %

Procedure:
6-Hexanamidoindole was alkylated with 2-(3-bromopropoxy)tetrahyro-2H-pyran using a similar procedure to that described in Example 23 to give 2-[3-(6-hexanamidoindol-1-yl)propoxy]tetrahydro-2H-pyran in 81% yield as an oil, which was used without characterisation.
Reaction SMILES: Cl.C(O[CH:5](OCC)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Br:17])[CH:10]=1)C.[C:21]([S-:23])#[N:22].[K+]>O.C(O)C.Cl>[Br:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH2:8][N:7]1[CH:6]=[CH:5][N:22]=[C:21]1[SH:23]
Reactant: CCOC(CNCc1ccc(OC)c(Br)c1)OCC
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2ccnc2S)cc1Br

Procedure:
A solution of 10.74 g (0.029 mole) of N-(3-bromo-4-methoxybenzyl)aminoacetaldehyde diethyl acetal hydrochloride and 3.37 g (0.35 mole) of KSCN in 50 ml of H2O, 50 ml of ethanol and 5 ml of 3N HCl was refluxed for 4.5 hr. One hundred ml of H2O was added and the mixture was cooled. A solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(3-bromo-4-methoxybenzyl)-2-mercaptoimidazole, 6.3 g (72%), mp 188°.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: C1CNCCN1
Product: c1cncc(-c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)c1
Yield: 78 %

Procedure:
Following the procedures of Example 143, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperazine were reacted and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 42 mg (78%) of 162. ESI MS m/z 358.1 (M+1). 1H NMR (400 MHz, DMSO): 9.24 (d, J=8.1 Hz, 1H), 8.90 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.56 (d, J=6.7 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 3.82 (s, 2H), 3.17 (s, 2H)
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)=[O:20])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:4]=1)#[CH:2].C[Si]([N:41]=[N+:42]=[N-:43])(C)C>CN(C)C=O.CO>[NH:41]1[C:1]([C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=5)=[O:20])=[CH:16][CH:17]=4)=[CH:9][CH:10]=3)[N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[N:4]=2)=[CH:2][N:43]=[N:42]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc12
Solvent: CN(C)C=O
Solvent: CO
Product: C[Si](C)(C)CCOCn1nc(-c2cnn[nH]2)c2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of Example 21C (90 mg, 0.180 mmol) in N,N-dimethylformamide (4 ml) and methanol (0.7 ml) under argon was treated with Cu(I)I (5.00 mg, 0.026 mmol) and trimethylsilyl azide (0.249 ml, 1.798 mmol), then heated at 100° C. in an oil bath in a sealed tube for 3 hours. An additional amount of trimethylsilyl azide (0.5 ml) was added and the vial was recapped and heated at 100° C. for 4 hours and then stirred at room temperature for 16 hours. The resulting mixture was partitioned between ethyl acetate and brine, and the organic extract was dried with MgSO4, concentrated and the residue was purified on a 12 gram Silicycle column eluting with 2 to 3% methanol in CH2Cl2 to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1NCC(=O)O
Temperature: 25 °C
Yield: 106.2 %

Procedure:
A mixture of 3-[3-(ethoxycarbonylmethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (40 mg, 0.0.084 mmol), potassium carbonate (23 mg, 0.167 mmol), methanol (5 mL) and water (1 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 40 mg (99%) of 3-[3-(carboxymethyl-amino)-4-methyl-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2].Cl.[CH3:14]N(C)CCCN=C=NCC>CO.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
4-Cyano-3-fluorobenzoic acid (Carbocore, 1 g; 6.06 mmol) was dissolved in MeOH (12.50 mL) to which 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.39 g; 7.27 mmol) followed by 4-dimethylaminopyridine (0.07 g; 0.61 mmol) were added. The mixture was stirred at RT overnight after which it was concentrated, taken up in EtOAc and washed with 0.1N HCl, 0.1 N NaOH and brine (2×50 mL each) and dried over MgSO4 to give the title compound as an off-white solid (0.95 g; 87%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.16 (dd, J=6.40 Hz, J=7.91 Hz, 1H), 8.02 (dd, J=1.50 Hz, J=9.80 Hz, 1H), 7.97 (dd. J=1.50 Hz, J=7.91, 1H), 3.95 (s, 3H). GC/MS (M+·): 179 (EI). HPLC (Method A) Rt 3.17 min (Purity: 87.3%).
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[F:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: Nc1ccccc1F
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 75 °C

Procedure:
To a sealed tube were added 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) (0.010 g, 0.045 mmol), 2-fluoroaniline (0.0050 g, 0.045 mmol), Cs2CO3 (0.022 g, 0.067 mmol), chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(11) (0.0050 g, 0.0056 mmol), and dioxane (0.5 mL). The reaction vessel was purged with argon, sealed and warmed to 75° C. for 8 hours with stirring. The reaction was cooled and diluted with dioxane (1.0 mL) and was passed through a syringe filter. The collected eluent was concentrated in vacuo to afford 4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a crude residue. MS ESI calc'd. for C26H24ClFN6 [M+H]+ 475. found 475.
Reaction SMILES: [Sn].[CH3:2][N:3]([CH3:26])[C:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][C:7]([C:10]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:11]=2[CH3:19])=[CH:6][CH2:5]1>Br>[CH3:26][N:3]([CH3:2])[C:4]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:5][CH2:6][CH:7]([C:10]2[NH:18][C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[C:11]=2[CH3:19])[CH2:8][CH2:9]1
Reactant: Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccncc12
Agent: Br
Agent: [Sn]
Product: Cc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Tin powder (3.00 g, 45 mmol) was added to N,N-Dimethyl-N-[4-(3-methyl-1H-pyrrolo[3.2-c]pyridin-2-yl)-1-phenylcyclohex-3-enyl]amine (525 mg, 1.58 mmol) in HBr/glacial acetic acid (33 per cent strength; 30 ml) in the course of 150 min (vigorous evolution of gas). The reaction mixture became dark brown in colour. The mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness in vacuo and 5 N sodium hydroxide solution (20 ml) was added to the residue. Methylene chloride (20 ml) was added to the pale-coloured suspension and the mixture was stirred for 10 min. Insoluble grey powder was then filtered off. Thereafter, the phases of the filtrate were separated. The aqueous phase was extracted with methylene chloride (2×20 ml) and trichloromethane/ethanol (2×20 ml; 1:1). The combined organic phases were dried with sodium sulfate and the volatile constituents were then removed completely in vacuo. The residue (250 mg of pale yellow powder) was separated by chromatography [silica gel 60 (100 g), ethyl acetate/methanol 1:1 (500 ml); methanol (1,000 ml)]. 20 mg (0.06 mmol; 4%) of N,N-dimethyl-4-(3-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-1-phenylcyclohexanamine (non-polar diastereoisomer) and 78 mg (0.41 mmol; 15%) of the polar diastereoisomer were isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([S:15][CH2:16][C:17](=O)[CH3:18])[CH2:9]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[C:11]2[C:17]([CH3:18])=[CH:16][S:15][C:10]=2[CH2:9]1
Reactant: CC(=O)CSC1=CC(=O)CC(c2ccccc2Cl)C1
Solvent: Cc1ccccc1C
Product: Cc1csc2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 7.5 %

Procedure:
A solution of 5-(2-chlorophenyl)-3-(2-oxopropylthio)-2-cyclohexen-1-one (1.0 g) in xylene (10 ml) was refluxed for 7.5 days and cooled, and the reaction solution was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzothiophene-4-one (0.07 g).
Reaction SMILES: Cl.[CH2:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]#[C:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[C:36]3[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)[CH:25]=1)[CH:3]([CH3:5])[CH3:4]>O1CCOCC1>[CH2:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][C:15]=1[C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[C:36]3[N:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[S:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)[CH:25]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4C#CC4CCCCN4CC(C)C)ncn3)cccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4CCC4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
A solution of N-(4-(6-(2-(2-(1-isobutylpiperidin-2-yl)ethynyl)-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide hydrochloride, Example 15(c), (221 mg, 0.37 mmol) in dioxane (5 mL) was hydrogenated under the conditions of Example 12(a) to provide the title compound as a tan solid. MS (ESI, pos. ion) m/z: 598 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:25])[CH3:24])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(NC(C)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
(S)-Ethyl-2-tert-butyloxycarbonylamino-3-(4-aminophenyl)propionate (0.10 g, 0.31 mmol) was dissolved in ethyl acetate (4 mL). Acetic anhydride (1 eq, 0.31 mmol, 0.030 mL) was added and the pale peach solution was heated to reflux, stirring at this temperature for 6.5 hours. The heating bath was removed and the flask allowed to cool to room temperature overnight. The solution was then poured into aqueous saturated NaHCO3 and extracted. The organic portion was washed again with sat. NaHCO3, then it was dried over MgSO4, filtered, and concentrated. Trituration with diethyl ether induced precipitation of a pale pink solid (0.09 g, 84%).
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:3]=[CH:4]/[CH:5]=[O:6].CC(=CC)C.[O-:24]Cl=O.[Na+]>CC(O)(C)C.O>[O:1]=[C:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:3]=[CH:4]/[C:5]([OH:24])=[O:6]
Reactant: CCCCCCCCCCCCC(=O)/C=C/C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCCCCCCCCCC(=O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of (E)-4-oxohexadec-2-enal (400 mg, 1.58 mmol) and 2-methyl-2-butene (1.69 ml, 15.8 mmol) in t-BuOH (20 ml) was treated with NaH2PO4 (2.00 g, 16.7 mmol) and NaClO2 (181 mg, purity 80%, 1.89 mmol), both dissolved in H2O (10 ml), and the resulting mixture was stirred for 2 h at RT. Most of the solvent was removed under reduced pressure, and EtOAc (50 ml) and a saturated NaCl solution (10 ml) were added to the residue. The aqueous phase was acidified to a pH of 1 by dropwise addition of 1 N HCl. The organic phase was then separated off and the aqueous phase was extracted with EtOAC (2×50 ml). The combined organic phases were dried over NaSO4 and concentrated under reduced pressure to give the product as a whitish-yellow solid (350 mg, 1.31 mmol, 83%), melting point 98±0.5° C. 1H NMR (400 MHz, CD3CD2OD) δ 1H ppm: 0.87 (t, 3H, J=7.0 Hz, H-16), 1.08-1.34 (m, 18H), 1.56-1.63 (m, 2H), 2.68 (t, 2H, J=7.0 Hz, H-5), 6.65 (d, 1H, J=16.2 Hz, H-2), 7.01 (d, 1H, J=16.2 Hz, H-3); 13C NMR (100.5 MHz, CD3CD2OD) δ 13C ppm: 15.5 (C-16), 24.6, 25.7, 26.2, 31.0, 31.3, 31.4, 31.5, 31.6, 31.6, 33.9, 43.0 (C-5), 133.7 (C-2), 141.3 (C-3), 169.4 (C-1), 202.8 (C-4); (−)-ESI-CID-MS: m/z 267 [M−H]−, 535 [2M−H]−; (−)-ESI-CID-MS: m/z 269 [M−H]; ESI-FT-ICR-MS: m/z 267.19633 (calculated for C16H27O3−, m/z 267.19633).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([NH:40][C:41](=[O:46])[CH2:42][CH2:43][CH2:44]Cl)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:46])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)CCCCl)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCCC3=O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(4-chlorobutyrylamino)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (283 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto is added sodium hydride (18 mg) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution and the mixture is extracted with ether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→1:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-oxopyrrolidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (132 mg). MS (m/z): 667 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[O:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[CH:7]=3)=[CH:22][CH:21]=2)[O:16]1
Reactant: BrCc1cc2ccccc2o1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCc3cc4ccccc4o3)cc2)OC1(C)C
Temperature: 70 °C
Yield: 63 %

Procedure:
To 2-Bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.56 g, 7.1 mmol, 1 eq.), potassium carbonate (1.96 g, 14.2 mmol, 2 eq.) was dissolved in acetonitrile (50 mL) under argon and heated at 70° C. for 16 hours. After work-up and flash column chromatography, 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran is obtained. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.3 (m, 1 H) 7.6 (m, 4 H).