Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:11])CC.C(N(CCCC)CCCC)CCC.CN([CH:28]=[O:29])C>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>[CH3:28][O:29][C:8]([N:4]1[CH:3]=[CH:2][CH:7]=[N:6][CH2:5]1)=[O:11]
Reactant: CN(C)C=O
Reactant: CCCO
Reactant: Brc1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)N1C=CC=NC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 52 %

Procedure:
A mixture of 5-bromopyrimidine (1.59 g, 10 mmol), 1-propanol (1.5 mL, 20 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.50 mmol) and tributylamine (3.72 g, 20 mmol) in DMF was stirred at 90° C. under a carbon monoxide balloon for 10 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with potassium dihydrogenphosphate (1.0 M, 20 mL, twice), water, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was then purified by column chromatography (50:50:10 hexane-dichloromethane-ether) to give 3-pyrimidinecarboxylic acid methyl ester (715 mg, 52%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][SH:9].[Cl:10][C:11]([Cl:38])([Cl:37])[CH2:12][O:13][C:14]([C:16]1[N:21]2[C:22](=[O:34])[C@@H:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:20]2[S:19][CH2:18][C:17]=1[CH2:35]Br)=[O:15].C(O)C>CN(C)C=O>[CH3:8][S:9][CH2:35][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:34])[N:21]2[C:16]=1[C:14]([O:13][CH2:12][C:11]([Cl:38])([Cl:37])[Cl:10])=[O:15]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Reactant: CS
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
Triethylamine (0.70 ml, 5 mmole) and a solution of methanethiol (2.8 ml, ca. 10 equiv.) in dimethylformamide (10 ml,), previously cooled to -30°, were added to a solution of 2,2,2-trichloroethyl-3-bromomethyl-7β-phenylacetamidoceph-3-em-4-carboxylate, 1β-oxide (2.79 g, 5 mmole) in dimethylformamide (40 ml) cooled to -30°. The reaction solution was allowed to warm to 20° and then stirred at this temperature for 30 minutes then dilution of an aliquot with ethanol gave a solution with λmax. 274 nm. Nitrogen was passed through the dimethylformamide solution for 45 minutes to remove the excess of thiol and potassium iodide (5 g.) and acetyl chloride (5 ml.) were added. After 4 hours at 20°, t.l.c. (acetone-methylene chloride, 1:15) showed that reduction was complete. The solution was cooled in an ice-bath, and 0.1 N-sodium thiosulphate solution was added until the solution became pale-yellow. Methylene chloride and water (80 ml of each) were added and the aqueous layer was separated and reextracted with methylene chloride (100 ml.). The combined methylene chloride layers were washed with water (3 × 100 ml.), dried and evaporated to give the title ester as a solvated yellow gelatinous solid (2.76 g), λmax. 268 nm (E1cm1% 133).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(Cl)=[S:19].[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH:27]([NH:30][C:18]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:19])[CH2:26][CH2:25]1
Reactant: S=C(Cl)Cl
Reactant: NCCCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C1(c2ccccc2)CCC(NC(=S)NCCCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
Phenylpropylamine (285 μl, 2 mmole) was dissolved in dry chloroform (15 ml) and combined with triethylamine (555 μl, 4 mmole). Thiophosgene (153 μl, 2 mmole) was added to this mixture. After a reaction time of 16 h, the diastereoisomer mixture of N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was added and stirring was continued for a further 16 h at RT. Working up was performed by extracting the batch with saturated NaHCO3 solution (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers and could be purified by column chromatography [silica gel 60 (50 g); methanol (500 ml)]. The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-(3-phenyl-propyl)-thiourea was obtained as a colorless foam in a yield of 205 mg (25%). The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-(3-phenyl-propyl)-thiourea was obtained as a colorless foam in a yield of 410 mg (50%).
Reaction SMILES: [C:1]1([Mg][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[C:14]1([S:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br>C1C=CC=CC=1>[Br-:8].[C:1]1([S+:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: c1ccccc1
Product: [Br-]
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
A 3.0 M solution of phenylmagnesium bromide in diethyl ether (83 ml, 0.25 mole) was distilled under vacuum with slow heating from 20° to 80° C. Benzene (140 ml) was added, the resulting mixture was stirred and a solution of diphenylsulfoxide 10.1 g, (0.050 mol), in benzene (60 ml) was added during 1 hour at 80° C. The mixture was stirred for 18 hours and cooled to room temperature. An 25% aqueous hydrobromic acid solution (180 ml) was slowly added to the reaction mixture (exotherm-). The layers were separated and the organic layer was extracted twice with 5% aqueous hydrobromic acid (2×30 ml). The combined aqueous extracts were extracted three times with dichloromethane (3×250 ml). The dichloromethane extracts were dried over magnesium sulfate, filtered and the organic solvent evaporated to leave triphenylsulfonium bromide (7.7 g, 45%).
Reaction SMILES: [CH:1]1[C:13]([NH2:14])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH:1]1[C:13]([NH:14][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Yield: 7.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine (0.13 g, 0.55 mmol), hexanoyl chloride (0.076 mL, 0.55 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-ylhexanamide (14 mg). MS (ES) m/z 325.1; HPLC purity 100% at 210-370 nm, 11.0 min.; 98.9% at 250 nm, 11.0 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2289.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]1([C:10]([C@H:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)[CH2:9][CH2:8]1>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:7]1([C:10]([C@H:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH2:1])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)C2CC2)COC1(C)C
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: C=C(C1CC1)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a suspension of potassium tert-butoxide (9.29 g, 82.80 mmol) in ether (250 mL) at room temperature was added methyltriphenylphosphonium bromide (29.6 g, 82.80 mmol). The mixture turned bright yellow and was heated to 40° C. for 1 hour. The mixture was cooled to room temperature and a solution of (R)-tert-butyl 4-(cyclopropanecarbonyl)-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 231, 11.15 g, 41.40 mmol) in ether (30 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous was extracted once with ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound as a colorless oil (9.84 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:4]=2[N:3]=1.C([O-])(=O)C.[NH4+:20]>[NH4+].[OH-].CO>[CH3:1][C:2]1[NH:20][C:13](=[O:15])[C:12]2[C:4](=[C:5]([C:6]([OH:7])=[O:8])[CH:9]=[CH:10][CH:11]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Cc1nc2c(C(=O)O)cccc2c(=O)o1
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(C(=O)O)cccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 16325.3 %

Procedure:
2-Methyl-4-oxo-4H-3,1-benzoxazine-8-carboxylic acid (51.5 g; 251.26 mmol) was dissolved in NH4OH (360.0 ml; 6.98 V; 28% solution). Ammonium acetate (77.5 g; 1.005 mmol) was added, and the reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with MeOH (40 mL) then heated for 72 h at 80° C. in a pressure bottle. The reaction mixture was concentrated on the rotary evaporator then cooled on ice and filtered. The solid was dried under vacuum to provide the desired product (33.5 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]I
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(1-methyl-1H-indazol-5-yl)methanone (410 mg, 1.32 mmol) in 10 mL THF was added methylmagnesium iodide (0.88 mL, 2.63 mmol) at 0° C. After stirring at 0° C. for 3 hour, the reaction was quenched with saturated NH4Cl and concentrated under resdue pressure. The residue was extracted with DCM three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the title compound as a white solid (430.0 mg, 95%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 5.98 (s, 1H), 3.99 (s, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+=328, tR=4.55 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1.[CH2:20](Br)[CH:21]([CH3:23])[CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](C(C)C)CS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@@H](C(C)C)N1CC(C)C

Procedure:
(1R)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-Methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4R)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl -4-nitrophenylimino)-4-isopropyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C:6]([CH2:9][NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[N:7][O:8][C:4]=2[CH:3]=1.[CH:18]1([CH2:21][NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:20]C1.[C:40](=O)([O-])[O-].[Na+].[Na+]>CC(O)C.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>[CH:21]1([NH:22][C:23](=[O:39])[C:24]2[CH:25]=[CH:26][C:27]([CH3:40])=[C:28]([C:2]3[CH:17]=[CH:16][C:5]4[C:6]([CH2:9][NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[N:7][O:8][C:4]=4[CH:3]=3)[CH:29]=2)[CH2:18][CH2:20]1
Reactant: OCC(CO)NCc1noc2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2cccc(C(=O)NCC3CC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(CNC(CO)CO)noc2c1
Reaction time: 18 h

Procedure:
A mixture of 2-[(6-bromo-1,2-benzisoxazol-3-yl)methyl]amino-1,3-propanediol (Intermediate 2, 8 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5, 10 mg) aqueous sodium carbonate (1M, 0.1 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in 2-propanol (0.2 ml) was stirred at 80° under nitrogen for 18 h. The solvent was evaporated and the residue was purified on a Varian Bond-Elut SPE cartridge (silica, 500 mg) using a dichloromethane-methanol elution gradient (19:1 to 9:1) to give the title compound as an oil (3 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of (2S,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. (2S,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.CCN(CC)CC.[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[F:23][C:24]([F:32])([F:31])[C:25]1[CH:29]=[C:28]([NH:30][C:13]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=2)=[O:15])[NH:27][N:26]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (100 mg, 0.350 mmol) in dry NMP (2 ml) was added NEt3 (0.097 ml, 0.699 mmol) followed by 3-(trifluoromethyl)-1H-pyrazol-5-amine (48.0 mg, 0.318 mmol). The mixture was stirred at RT for 5 minutes, before treating with HATU (133 mg, 0.350 mmol). The resulting orange solution was stirred at RT for 10 minutes and then partitioned between EtOAc (50 ml) and 1M NaOH (30 ml). The organic portion was separated and washed with 1M NaOH (20 ml), water (20 ml), dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane/EtOAc (gradient of 0 to 50% EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[C:10](Cl)(=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:2]1[NH:1][CH:5]=[C:4]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1)=[O:7]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
To a solution (5 ml) of 1.25 g (10 mmol) of methyl pyrrole -2-carboxylate in benzene was added 2.71 g (11 mmol) of tetradecanoyl chloride under ice-cooling, followed by adding 1.73 ml) (15 mmol) of stannic chloride dropwise thereto. The mixture was stirred for 2 hours at room temperature, treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the product was purified by subjecting it to column chromatography over silica gel (ethyl acetate/hexane=1/7) to obtain 1.80 g (54% yield) of methyl-4-tetradecanoylpyrrole-2-carboxylate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.C(#N)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:22]=[CH2:23])[N:7]=1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (prepared from 5-bromo-2-chloroquinoline and 2-methoxy-benzylamine as described in example 3, step A, 1 g, 2.9 mmol) was dissolved in 30 mL toluene. Vinyltributyltin (952 mg, 3.0 mmol) and tetrakis(triphenylphosphin)palladium (67 mg, 0.058 mmol) was added. The reaction mixture was refluxed overnight. The mixture was diluted with 100 mL acetonitrile and extracted three times with heptane (100 mL each). The acetonitrile phase was dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a yellow oil (544 mg, 64%), MS: m/e=291.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[CH3:7][C:8]1[N:9]=[C:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[S:11][CH:12]=1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]([C:10]2[S:11][CH:12]=[C:8]([CH3:7])[N:9]=2)([OH:18])[C:14]([F:17])([F:16])[F:15])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: Cc1csc(C(=O)C(F)(F)F)n1
Solvent: C1CCOC1
Product: Cc1csc(C(O)(c2nc(C)cs2)C(F)(F)F)n1

Procedure:
From 4-methylthiazole and 4-methyl-2-trifluoroacetylthiazole and using anhydrous tetrahydrofuran as solvent.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)N
Reactant: O=c1[nH]nc2c(Cl)nc(Br)cn12
Solvent: C1CCOC1
Product: CC(C)Nc1nc(Br)cn2c(=O)[nH]nc12

Procedure:
A solution of 0.50 g of the product of Step D and 0.59 g of isopropylamine in THF (20 mL) was heated to reflux. After one h, the reaction was concentrated and the residue partitioned between EtOAc and water. The layers were separated and the organic phase was washed with sat sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to provide 6-bromo-8-isopropylamino-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a light tan solid. MS (M+H−)=271.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CCOCC>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:6][CH2:5]2
Reactant: NCCCn1ccnc1
Reactant: O=C1CCc2cc(Cl)ccc21
Solvent: CCOCC
Product: Cl
Product: Clc1ccc2c(c1)CCC2NCCCn1ccnc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloroindanone (10.2 g, supplied by Lancaster Chemicals) and 1-(3-aminopropyl)imidazole (7.62 g) was heated at 90° C., while bubbling nitrogen through the molten mixture, for 2 hours. The mixture was cooled and dissolved in absolute ethanol (140 ml). Sodium borohydride (4.63 g) was added to the solution and the mixture boiled under reflux for 7 hours. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate to give an oil which was dissolved in ether and filtered. The filtrate was treated with ethereal hydrogen chloride to give a solid which was collected and recrystallised from propan-2-ol/ethanol/water (150 ml/150 ml/trace) (with a charcoal hot filtration) to give N-(5-chloroindan-1-yl)-3-(imidazol-1-yl)propylamine dihydrochloride, m.p. 251-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]5[CH2:70][CH2:69][O:68][CH2:67][CH2:66]5)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (28 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (24.6 mg). LCMS-ESI+: calc'd for C46H54N8O7: 830.97 (M+); Found: 831.33 (M+H+).