Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].I[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:20]([O:19][C:17]([C:16]1[CH:22]=[CH:23][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 65 °C
Yield: 46.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (604 mg), ethyl 4-iodobenzoate (1.1 g), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and anhydrous triethylamine (4 ml) and anhydrous dimethylformamide (8 ml) was stirred under an atmosphere of argon. The reaction mixture was heated at 65° C. for 18 hours. The reaction mixture was cooled and the triethylamine and dimethylformamide removed by evaporation. To the residue was added 2M sodium hydroxide (25 ml) and the mixture extracted with dichloromethane. The organic phase was washed with water, saturated brine and dried (MgSO4). Evaporation gave a solid which was crystallised from acetonitrile to give 3-[2-(4-ethoxycarbonylphenyl)ethynyl]-3-hydroxyquinuclidine (553 mg) as a colourless solid, m.p. 176°-177° C.; microanalysis, found: C, 72.2; H, 7.3; N, 4.8%; C18H21NO3 requires: C, 72.2; H, 7.07; N, 4.68%; NMR (DMSO-d6): 1.32(3H, t), 1.49-2.01(5H, m), 2.68(4H, t), 2.78-3.14(2H, d of d), 4.32(2H, q), 5.66(1H, br.s), 7.49-7.58(2H, d) and 7.90-7.98(2H, d); m/Z 300 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ncccc1Br
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Br)ccc[n+]1[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromopicolinonitrile (1.0 eq.) in chloroform (0.3 M) was added 77% meta-chloroperbenzoic acid (mCPBA) (1.8 eq.) and heated at 60° C. for 2 days. After cooling to room temperature, Ca(OH)2 (2.5 eq.) was added, and the resulting precipitate was stirred for 30 minutes. The precipitate was filtered and washed with 5% methanol in dichloromethane. The filtrate was washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted several times with 3% methanol in dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated en vacuo. The crude product was stirred in hot hexane/ethyl acetate (1:1), filtered, and dried to give the desired product as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@@H:11]([Cl:13])[C@H:10]2[O:14][CH2:15][C@@H:16]([OH:17])[C@H:9]12)=[O:7])(C)(C)C.C(Cl)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:46]([NH:53][C@H:54](C(O)=O)[CH2:55][CH:56]([CH3:58])[CH3:57])([O:48]C(C)(C)C)=O.Cl.[F:63][C:64]1[CH:65]=[C:66]([CH:70]=[CH:71][C:72]=1[C:73]1[N:74]=[C:75]([N:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)[S:76][CH:77]=1)C(O)=O>CO>[Cl:13][C@@H:11]1[CH2:12][N:8]([C:6]([C@@H:54]([NH:53][C:46](=[O:48])[C:66]2[CH:70]=[CH:71][C:72]([C:73]3[N:74]=[C:75]([N:78]4[CH2:79][CH2:80][N:81]([CH3:84])[CH2:82][CH2:83]4)[S:76][CH:77]=3)=[C:64]([F:63])[CH:65]=2)[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:7])[C@H:9]2[C@H:16]([OH:17])[CH2:15][O:14][C@H:10]12
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Cl)[C@H]2OC[C@@H](O)[C@@H]21
Reactant: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3F)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)c1ccc(-c2csc(N3CCN(C)CC3)n2)c(F)c1)C(=O)N1C[C@@H](Cl)[C@H]2OC[C@@H](O)[C@@H]21

Procedure:
This compound was prepared from N—[(S)-1-((3S,3aS,6R,6aS)-6-chloro-3-hydroxy-hexahydro-furo[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester by a series of deprotection (acetyl chloride, MeOH) and HATU-mediated coupling steps with Boc-leucine initially, and finally 3-fluoro-4-[2-(4-methylpiperazin-1-yl)-thiazol-4-yl]benzoic acid HCl salt prepared as described in Example 9.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH3:12][O:13][C:14]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[C:27]1[CH2:28][CH2:29][CH2:30][C:25]1=[O:9]
Reactant: COc1cccc(C=O)c1OC
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Agent: Cl
Product: COc1cccc(C=C2CCCC2=O)c1OC
Temperature: 30 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 2,3-dimethoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 80.3%.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])(=O)=O)(C)C.C[Li].[Cl:32][C:33]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:34]=1[CH:35]=[O:36]>O1CCCC1>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH:35]([C:34]2[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:33]=2[Cl:32])[OH:36])=[CH2:22])=[CH:24][CH:25]=1
Reactant: CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccc(C)cc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)C(O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(4-methylphenyl)ethanone-2,4,6-triisopropylbenzenesulfonylhydrazone (6.54 g) in tetrahydrofuran (80 ml) at -70° C. was dropwise added a solution of methyl lithium (25 ml, 1.3M in ether) while stirring and maintaining the temperature of the mixture below -60° C. After 10 minutes the reaction mixture was allowed to warm to room temperature. When evolution of nitrogen from the reaction mixture ceased, a solution of 2,4-dichlorobenzaldehyde (3.48 g) in tetrahydrofuran (10 ml) was rapidly added. After stirring for 1 hour at room temperature the reaction was quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil. The oil was chromatographed on silica gel eluting with ethyl acetate-hexane (3:97) to yield α-[1-(4-methylphenyl)ethenyl]-2,4-dichlorobenzenemethanol δ (CDCl3): 1.86 (1H,d, J=5 Hz), 2.64-2.78 (1H, dd, J=13.5 Hz, J=10 Hz), 2.92-3.04 (1H,dd, J=15 Hz, J=5 Hz), 4.8 (1H,m), 5.38 (2H,d, J=6 Hz) and 7.16-7.5 (10H,m) as a yellow oil (2.1 g) having the formula: ##STR13##
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:31])[NH:22][C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH3:24])=[O:31])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (S)-{4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(1-phenyl-ethylcarbamoyl)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester (80 mg) in dichloromethane (1.6 mL) was added trifluoroacetic acid [TFA] (0.40 mL) dropwise at room temperature and the mixture was stirred at room temperature for 1 hour. The reaction mixture was portioned between AcOEt and aqueous K2CO3. The organic layer was separated, washed with H2O and brine, dried over MgSO4, and evaporated to pale yellow amorphous, which was solidified by trituration in i-Pr2O. The resulting solid was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as yellow crystal (57 mg, 85%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 1.45 (d, J=7.3 Hz, 3H), 3.23 (septet, J=7.0 Hz, 1H), 5.15 (quintet, J=7.3 Hz, 1H), 5.58 (s, 2H), 6.62 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.5 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.16-7.25 (m, 1H), 7.25-7.40 (m, 4H), 7.63 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.5, 1.8 Hz, 1H), 7.88 (d, J=1.8 Hz, 1H), 8.57 (s, 1H), 8.75 (d, J=7.3 Hz, 1H), 8.87 (d, J=8.5 Hz, 1H), 10.12 (s, 1H) MS ESI+ m/z: 535 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH2:34][CH3:35].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH2:33][CH2:34][CH3:35])=[N:8][C:7]=2[N:26]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (153 mg), 1M aqueous sodium hydrogen carbonate solution (439 μl), 1-iodopropane (117 μl) and N,N-dimethylformamide (3 ml) was stirred at 80° C. for 10 min. The reaction mixture was allowed to be cooled, and water (20 ml) was added thereto. The white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (10 ml). The solution was diluted with ethyl acetate (20 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethyl acetate/heptane to give the title compound (114 mg) as cotton-like needle crystals.
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>CN1CCCC1=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([C:2]#[N:3])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)c(C(C)C)cc1OC
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1OC
Temperature: 0 °C
Yield: 74.8 %

Procedure:
Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) in N-methyl-2-pyrrolidinone (30 ml). The mixture was stirred under argon and boiled under reflux for 4 h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[CH:34]1[CH2:36][CH2:35]1)CCC>>[Cl:13][C:11]1[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([CH:34]2[CH2:36][CH2:35]2)[CH:12]=1
Reactant: Nc1nnc(-c2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Product: Nc1nnc(-c2cc(Cl)cc(C3CC3)c2)c(-c2ccccc2)n1
Yield: 6.7 %

Procedure:
6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethane-sulfonate (0.40 g, 0.93 mmol) and tri-n-butyl(cyclopropyl) tin (0.37 g, 1.11 mmol) according to the general procedure for Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)=[CH:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1nccs1
Reactant: COc1ccc(Cc2ccc(N)cc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2ccc(Nc3nccs3)cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 90 °C
Yield: 45 %

Procedure:
(P-443): In an 8 mL vial equipped with a stir bar was placed 4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenylamine (I-35) synthesized above (100 mg, 0.293 mmol), 2-bromothiazole (52.1 μL, 0.585 mmol), 10% aqueous ethanol (1.5 mL) and concentrated hydrochloric acid (48.8 μL, 0.585 mmol). The mixture was heated to 90° C. for 18 hours and then cooled to room temperature. After water (30 mL) and 5% aqueous potassium carbonate (30 mL) were added, the aqueous portion was extracted with ethyl acetate (2×35 mL) and the organic portions were combined, washed brine (30 mL), dried (magnesium sulfate) and concentrated. The crude material was purified by column chromatography utilizing 3% acetone/dichloromethane as the eluent to produce 57 mg of [4-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-thiazol-2-yl-amine. (P-443) as white solid in 45% yield. 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.94 (s, 2H), 6.62 (d, J=4 Hz, 1H), 6.70 (dd, J=8, 1 Hz, 1H), 7.10 (t, J=9 Hz, 1H), 7.20-7.22 (m, 2H), 7.26-7.40 (m, 8H) ppm; MS (APCI+): 425.0 (M+1), LC-MS: 89%
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[C:22](=[O:24])=[O:23].[K+].[Br-]>C1COCC1>[C:22]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1)([OH:24])=[O:23]
Reactant: Brc1ccc2c(c1)COCC2
Reactant: O=C=O
Agent: [Br-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=C(O)c1ccc2c(c1)COCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 7-bromoisochroman (7 g; 32.86 mmol) in THF (100 ml) was cooled to -78° C. and treated with 40.6 ml of a 1.7M solution of tert-butyllithium in pentane (69 mmol; 2.1 eq). Powdered dry ice (excess) was added to the red anion solution within 45 seconds. The reaction mixture was stirred for 30 minutes at -78° C. and 1 hour at room temperature. The reaction was quenched with 60 ml of 1N HCl and extracted with 3×70 ml of ether. The ether layers were combined and washed with brine until the pH was neutral, dried with MgSO4, and concentrated in vacuo. The product was obtained as a white solid, mp 140°-142° C. (5.7 g; 82%). 1H NMR (CDCl3): δ2.95 (t, 2H); 4.03 (t, 2H); 4.83 (s, 2H); 7.24 (t, 1H); 7.89 (s, 1H); 7.92 (d, 1H). IR (KBr): 2954, 2561, 1684, 1427, 1293, 1108 cm-1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][NH:29][CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:32](Cl)[Cl:33].[CH3:35][C:36](O)=O>CC(C)=O>[ClH:33].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:30][N:29]([CH:36]([CH3:35])[CH3:32])[CH2:28][CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Reactant: ClCCl
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)N1CCCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Yield: 38 %

Procedure:
Acetone (2.81 mL) and picoline borane complex (59 mg, 0.55 mmol) were added to a suspension of 4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (80 mg, 0.18 mmol) in 10:1 CH2Cl2/AcOH (3.1 mL) and the resulting solution was stirred at reflux for 18 h. Acetone (1.0 mL) and picoline borane complex (50 mg, 0.46 mmol) were added to the solution and the resulting mixture was stirred for 48 h. The mixture was partitioned with H2O (5 mL) and CH2Cl2 (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes) followed by preparative TLC (Analtech, 20×20 cm, 1000 microns, 50:50 (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH) provided a white solid that upon concentration with 1.25 M HCl in MeOH (2.0 mL) afforded the title compound (33 mg, 38%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.92 (br s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72 (s, 3H), 3.57-3.47 (m, 3H), 3.11 (t, J=6.0 Hz, 2H), 2.24-2.07 (m, 2H), 1.34-1.30 (m, 6H); ESI MS m/z 442 [M+H]+; HPLC (Method A, 223 nm) 98.4% (AUC), tR=15.7 min.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CCN)CCCCC1.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: NCCC1CCCCC1
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(O)CSc1cnc(NC(=O)N(CCC2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 2-cyclohexylethylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=O.Cl.[C:22]([NH:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[NH:24])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][NH:25][C:22]1[N:23]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:4]([C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[CH:3][N:24]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCNC(=N)N
Reactant: CN(C)/C=C(/C(=O)c1ccc(C#N)cc1)c1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(C#N)cc2)n1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
[4-[(2E)-3-(dimethylamino)-2-imidazolylprop-2-enoyl]benzenecarbonitrile (8.0 g, 30.0 mmol) in NMP (5 ml) was added to a stirred mixture of N-[2-(amidinoamino)ethyl](tert-butoxy)carboxamide, hydrochloride (13.8 g, 45 mmol)) and Cs2CO3 (11.72, 36.0 mmol) in NMP (15 ml). The reaction was heated to 100° C. for 48 hours. The reaction was followed by HPLC. Upon completion, the reaction was partitioned with water (50 ml) and dichloromethane (250 ml). The organic layer was separated and washed with water (2×50 ml), brine (50 ml), dried Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography eluting with 10% methanol in dichloromethane. After stripping off the solvents and drying in vacuo, 10.08 g of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)carboxamide was obtained as a dark red glass in 83% yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][O:24][CH3:25])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[CH2:40].Cl>O1CCOCC1.O>[F:16][C:14]([F:17])([F:15])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[CH2:40])[CH:46]=2)=[C:8]([CH2:26][CH2:27][CH3:28])[CH:9]=1)([O:22][CH2:23][O:24][CH3:25])[C:18]([F:20])([F:19])[F:21]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1cccc(B(O)O)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cccc(-c2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Yield: 81.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenyl trifluoromethanesulfonate (238 mg, 497 μmol) in 1,4-dioxan, potassium phosphate (401 mg), 3-vinylphenylboronic acid (88 mg), and tetrakis triphenylphosphine palladium complex (57 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl aceate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (175 mg, yield 81%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1.[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][C:17]=2[F:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)nc(N)c1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Temperature: 100 °C
Yield: 36.3 %

Procedure:
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (1.11 g, 5 mmol, see WO 2007/082076 A1 for preparation), 4-chloro-2-fluorophenylboronic acid (1.13 g, 6.5 mmol), bis(triphenylphosphine)-palladium(II) dichloride (350 mg, 0.5 mmol), and cesium fluoride (1.52 g, 10 mmol) were combined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The product was purified by column chromatography (methylene chloride/ethyl acetate gradient) then purified again by column chromatography (ethyl acetate/hexane gradient) to yield the title compound (574 mg, 40.8% yield): mp 194-196° C.; 1H NMR (CDCl3): δ 7.96 (m, 1H), 7.2 (m, 2H), 5.64 (br s, 2H), 4.01 (s, 3H).