Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]5[CH:24]=[C:23]([CH2:25][C@H:26]([OH:29])[CH2:27][OH:28])[N:22]=[N:21]5)[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:3])[CH3:2].CC1(C)O[C@H](CC#C)CO1>>[C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]5[CH:24]=[C:23]([CH2:25][C@@H:26]([OH:29])[CH2:27][OH:28])[N:22]=[N:21]5)[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1-n1cc(C[C@H](O)CO)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: C#CC[C@@H]1COC(C)(C)O1
Product: COc1cc2c(cc1-n1cc(C[C@@H](O)CO)nn1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3

Procedure:
The other enantiomer 20g was prepared analogous to 20f, starting from (R)-2,2-dimethyl-4-(prop-2-ynyl)-1,3-dioxolane.
Reaction SMILES: C[Si](Cl)(C)C.BrCCBr.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>CC(N(C)C)=O.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:26][CH:27]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of Zn (21.6 g, 330 mmol) in DMA (53 mL). A 7:5 v/v mixture of TMSCl/1,2-dibromoethane (5.8 mL) was added to the mixture drop-wise at a rate to maintain the temperature below 65° C. The mixture was stirred for an additional 10 min, then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (68.7 g, 220 mmol) in DMA (122 mL) was added drop-wise at 40-45° C. and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to room temperature and stirring was ceased to allow for the zinc powder to settle. Into another 500-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 4-bromobenzonitrile (20 g, 110 mmol), CuI (2.1 g, 11 mmol), Pd(dppf)Cl2 (4.51 g, 5.5 mmol) and DMA (100 mL). The freshly prepared zinc reagent solution was decanted into an addition funnel and added drop-wise to the mixture at room temperature. The resulting mixture was stirred at 85° C. for 4 h, then cooled to 20° C. and diluted with methyl tert-butyl ether (500 mL) and carefully quenched with 1 M ammonium chloride (500 mL). The mixture was stirred at room temperature for 30 min and then filtered to remove solids. The organic layer was washed with saturated aqueous ammonium chloride (100 mL), followed by brine (3×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:10) as the eluent to yield the title compound as a brown oil (20 g, crude) and used in the next step without additional purification.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:24].CO>>[ClH:24].[ClH:24].[NH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(N)=O)C1
Agent: Cl
Solvent: CO
Product: NC(=O)C1CNCCN1
Yield: 100 %

Procedure:
A mixture of di-tert-butyl 2-carbamoylpiperazine-1,4-dicarboxylate (7.5 g, 22.79 mmol), in HCl/MeOH (75 mL, 2.86; N) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to yield the product (4.58 g, 100% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6](O)[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[ClH:21]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:21])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Reactant: Cl
Solvent: CCOCC
Product: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 3-methoxy-α-(1-naphthyl)benzyl alcohol (2.5 g, 9.5 mmol) in diethyl ether (5 mL) was added 35% hydrochloric acid (10 mL) at 0° C. The reaction mixture was warmed to r.t. in 1 h, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with aqueous NH4Cl solution and brine, dried over MgSO4. Evaporation of solvents gave 3-methoxy-α-(1-naphthyl)benzyl chloride (1.94 g, 72%). GC-MS (Rt =10.30 min) 282 (M+), 247, 232, 215, 202, 189, 163, 151, 139, 123, 101.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[C:37]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)[CH:38]=1)[NH2:35]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:35][C:34]2[CH:36]=[C:37]([N:39]3[CH:43]=[N:42][N:41]=[N:40]3)[CH:38]=[C:32]([O:31][CH3:30])[CH:33]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: COc1cc(N)cc(-n2cnnn2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: COc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)cc(-n2cnnn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-methoxy-5-(1H-tetrazol-1-yl)aniline in step 1. MS: 425.4 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[C:35]([CH3:52])[CH:34]=2)[N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(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.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[C:35]([CH3:52])[CH:34]=2)[N:25]=1
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.103 g, 0.589 mmol) in DMF (1.5 mL) and Et3N (0.273 mL, 1.96 mmol) were added to a suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A40) (0.231 g, 0.491 mmol), PdCl2(PPh3)2 (0.052 g, 0.074 mmol), CuI (0.014 g, 0.074 mmol) and PPh3 (0.013 g, 0.049 mmol) in DMF (2 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (60 mL). The filtrate was washed with water (50 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried (Na2SO4). The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A41 as a yellow oil (0.248 g, 83%); 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.68 (dd, J=7.6, 0.9 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.45-7.40 (m, 1H), 7.39-7.29 (m, 4H), 7.18 (d, J=8.4 Hz, 1H), 4.38-4.21 (m, 2H), 3.96 (s, 2H), 3.70 (s, 3H), 2.92-2.71 (m, 3H), 2.38 (s, 3H), 1.75 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, peak obscured), 1.49 (s, 9H). LCMS-A: rt 6.992 min; m/z 609.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:33]=[CH:34]/C)[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH:33]=[CH2:34])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 1 (0.040 g, 0.082 mmol) in THF/MeOH (2/1) (1.5 mL) was added a 1 M solution of LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford 19 (0.022 g, 59% yield). MS ESI (neg.) m/e: 461.2 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[NH+:3]1[O-:13]>C(O)C.O=[Pt]=O>[OH:13][N:3]1[C:2]([CH3:14])([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1([CH3:12])[CH3:11]
Reactant: CC1(C)c2ccccc2C(C)(C)[NH+]1[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC1(C)c2ccccc2C(C)(C)N1O
Yield: 77.7 %

Procedure:
6.6 g (0.035 mol) of 1,1,3,3-tetramethyl-1,3-dihydroisoindole N-oxide are hydrogenated to saturation in 66 ml of ethanol over 0.12 g of PtO2 at atmospheric pressure. The catalyst is filtered off and the solvent is evaporated on a rotary evaporator, after which the crystalline residue is recrystallized from a little dichloromethane. This gives 5.2 g (78%) of N-hydroxy-1,1,3,3-tetramethyl-1,3-dihydroisoindole which is obtained in the form of colourless crystals; melting point: 128–130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43].ClCCCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:42]([S:46]([NH:49][C:24]([C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=3[CH:17]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25])(=[O:48])=[O:47])([CH3:45])([CH3:44])[CH3:43]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)C(C)(C)C)c3)cc12
Yield: 30.6 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and tert-butylsulfonamide (37 mg, 0.27 mmol). 1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was concentrated, filtered, purified by prep HPLC, and concentrated on a speedvac to give 14 mg (31% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (s, 1H) 7.97 (s, 1H) 7.91 (dd, J=8.55, 5.19 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.79 (d, J=7.32 Hz, 1H) 7.46-7.59 (m, 3H) 7.19 (t, J=8.55 Hz, 2H) 6.04 (br. s., 1H) 2.99 (d, J=4.58 Hz, 3H) 1.54 (s, 9H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.71 min, (ES+) m/z (MH+)=509. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=16.49 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=100%.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 170 mg (0.58 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 124 mg (0.70 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.31 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 295 mg of resultant crude imine are cyclized in the same way as in Example 1 at −20° C. using 2.6 ml (2.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 25 mg of product.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=1)[CH3:3]>CCO.[Pd]>[CH:2]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)c1cccc(C(=O)OCC)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(C(C)C)n1
Yield: 93 %

Procedure:
To ethyl 6-(prop-1-en-2-yl)picolinate (4.63 g, 24.2 mmol) in EtOH (50 mL) was added Pd/C (0.61 g, 0.573 mmol). The reaction mixture was purged with nitrogen and hydrogen three times each. A hydrogen balloon was applied to the reaction for three hours. The reaction was then purged with nitrogen, filtered through Celite® and washed with EtOH (100 mL). Solvent was removed under reduced pressure to give the desired product (93%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20])(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH3:6][NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnccc1N1CCCCC1C

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester (60 mg, 0.20 mmol) was stirred in a solution of TFA (300 μL) and CH2Cl2 (2 mL) for 1 h after which all volatiles were removed under reduced pressure. The resulting compound was pure enough to be used directly in the next step without further purification.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1C=O.[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:25])[CH:45]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1nc(-c2ccccn2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Agent: O=Cc1ccccn1
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2nc(-c3ccccn3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-2-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 3-amino-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 3-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carbonyl]-amino}-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.18 (1H, br s), 9.84 (1H, br s), 8.63 (1H, d), 8.48 (1H, s), 8.23 (1H, d), 8.00 (1H, d), 7.93 (1H, td), 7.63 (1H, d), 7.42 (2H, m), 2.99 (2H, m), 1.95 (3H, br s), 1.65 (6H, m), 1.54 (6H, s), 1.42 (2H, m). The product was converted to the L-tartaric acid salt and lyophilised from water/dioxan. Found: C, 58.35; H, 6.11; N, 8.80%. C32H36N4O9.2.0 mols H2O requires: C, 58.23; H, 6.14; N, 8.53%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].C[N+]1([O-])CC[O:32]CC1.OS([O-])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:32])[CH3:8])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1)c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5-(trifluoromethyl)benzamide (0.86 g, 1.9 mmol) in acetone (45 mL) were added OsO4 (2.5% in t-butyl alcohol, 0.49 mL, 0.039 mmol) and 4-methylmorpholine-4-oxide (0.41 g, 3.5 mmol). The solution was stirred under nitrogen at RT overnight and then an aqueous solution of NaHSO3 (39%, 45 mL) was added. The mixture was stirred for 2 h, diluted with water and then extracted twice with methylene chloride. The combined organic solutions were separated by means of a phase separator column and the solvent was removed by evaporation. The residue (1.08 g) was dissolved in THF (18 mL) and water (4.5 mL) and to the resultant solution was added NaIO4 (0.73 g, 3.4 mmol). The mixture was stirred under nitrogen overnight at RT. The mixture was partitioned between methylene chloride and water. The aqueous phase was extracted with methylene chloride and then the combined organic solutions were washed with brine and separated by means of a phase separator column. The solvent was removed by evaporation. There was obtained 0.78 g (90%) of the title compound. 1H NMR (500 MHz, CDCl3): 2.4-4.4 (cm, 8H), 6.2-8.2 (cm, 7H), 9.8 (s, 1H); LCMS: m/z 447 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O-:18].[Na+].Cl>CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][O:18][CH3:17])[C:7]=2[CH:8]=1
Reactant: COC(=O)c1oc2ccc(F)cc2c1CBr
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1c(C(=O)OC)oc2ccc(F)cc12
Yield: 63 %

Procedure:
To a solution (50 mL) of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.87 g) synthesized above in methanol was added 28% solution (8.33 mL) of sodium methoxide in methanol, and the mixture was stirred with heating under reflux for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (3.04 g, 63%) as a white solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1NCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCC1NCCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.2 %

Procedure:
To 10% palladium-carbon (50 mg), a solution of tert-butyl (2-((3-((benzyloxycarbonyl)amino)propyl)amino)cyclohexyl)carbamate (C39, 137 mg) in methanol (5 mL) was added at room temperature, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((3-aminopropyl)amino)cyclohexyl)carbamate (C40, 101 mg).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.Cl>C1(C)C=CC=CC=1.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>[C:20]([C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)(=[O:22])[CH3:21]
Reactant: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A slurry of N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (1.30 g, 5.04 mmol) and dichlorobis(triphenylphosphine)palladium(II) (35.3 mg, 0.05 mmol) in toluene (10 mL) was treated with tributyl(1-ethoxyvinyl)tin (2.00 g, 5.54 mmol). The reaction slurry was then heated under reflux, resulting in a homogeneous yellow solution. After heating under reflux for 15 h, the resulting black reaction mixture was allowed to cool to 25° C. and then was cooled to 0° C. with an ice-water bath. The cooled reaction mixture was treated slowly with a 5% aqueous hydrochloric acid solution (8.4 mL). The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 24 h. The resulting two layers were separated, and the organic layer was further diluted with ethyl acetate (100 mL). The organic layer was then diluted with a 10% aqueous ammonium fluoride solution (100 mL), and the resulting mixture was stirred at 25° C. for 5 h. The solids were then filtered, and the filtrate layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 15% ethyl acetate/hexanes) afforded N-(5-acetyl-pyrazin-2-yl)-2,2-dimethyl-propionamide (1.07 g, 96%) as a white solid: mp 173–174° C.; (ES)+-HRMS m/e calcd for C11H15N3O2 (M+H)+ 222.1237, found 222.1240.