Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:28]=[N+:29]=[N-:30])[CH2:7][N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.4 g, 36.09 mmol) in dry N,N-dimethylformamide (50 mL) was added sodium azide (4.7 g, 72.18 mmol) and the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude which was purified by column chromatography (15% ethyl acetate in hexane as eluent) to give (2S,4S)-4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (7.8 g, 80% yield) as a light brown liquid. MS calcd. for C11H19N4O4 [(M+H)+] 271.0, obsd. 271.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].O.S(=O)(=O)(O)O>C(OCC)C>[CH2:7]([C@H:12]1[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@H]1CC[C@H](CCC(=O)OCC)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCO)CC1
Reaction time: 0.83 h
Yield: 100.1 %

Procedure:
250 ml of absolute diethyl ether were placed in a sulphonation flask under nitrogen gasification and treated cautiously with 3.9 g of lithium aluminium hydride. A solution of 46.9 g of ethyl β-(trans-4-pentylcyclohexyl)propionate in 200 ml of absolute diethyl ether was added dropwise thereto within 50 minutes. A further 250 ml of absolute diethyl ether were then added thereto and the mixture was stirred overnight. Subsequently, there were added dropwise to the mixture within 10 minutes 21 ml of water and then 210 ml of 10% sulphuric acid. The aqueous phase was separated and extracted twice with diethyl ether. The combined organic phases were washed once with water and once with saturated sodium chloride solution, dried over sodium sulphate and evaporated. 39.2 g of 3-(trans-4-pentylcyclohexyl)-1-propanol were obtained as a colourless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2cc(C=O)ccc2F)n1
Temperature: 120 °C

Procedure:
To a solution of methyl 6-bromopicolinate (1.0 equiv.) in DME (0.03 M) in a microwave vial was added Pd(dppf)Cl2-DCM (0.05 equiv.), 2-fluoro-5-formylphenylboronic acid (1.5 equiv.) and 2M Na2CO3 (2 equiv.). The reagents were heated to 120° C. for 20 min. A mixture of the desired product and the corresponding carboxylic acid was detected by LC/MS, the reaction was diluted with ethyl acetate, washed with HCl (pH=5), the acidic phase was extracted with ethyl acetate, the combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to provide a light brown solid. The solid was dissolved in MeOH and treated with 3 equiv. of TMS-diazomethane at room temperature. Upon complete conversion of the carboxylic acid to the corresponding methyl ester, the reaction was concentrated in vacuo and the crude material was purified via silica gel column chromatography (ISCO) eluting with 30% ethyl acetate in hexanes to provide methyl 6-(2-fluoro-5-formylphenyl)picolinate as a yellow solid in 58% yield. LC/MS=260.0 (M+H), Rt=0.70 min.
Reaction SMILES: P(Br)(Br)Br.[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([CH2:14][CH3:15])[N+:7]=1[O-].[OH-].[Na+]>C(Cl)Cl>[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([CH2:14][CH3:15])[N:7]=1
Reactant: CCc1ccc(OC)c(Br)[n+]1[O-]
Agent: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1ccc(OC)c(Br)n1
Temperature: 50 °C

Procedure:
Phosphorous tribromide (1.3 mL) was added to a solution of 2-bromo-6-ethyl-3-methoxy-pyridine 1-oxide (0.3 g, 1.3 mmol, from step 4 of example A(2)) dissolved in CH2Cl2 (10 mL). The reaction mixture was heated to 50° C. for 1 hour. After cooling to room temperature the mixture was poured into ice and made basic with 15% NaOH and extracted with CH2Cl2. The organic extracts were dried over Na2SO4 and concentrated to a clear oil (0.28 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.27 (t, J=7.6 Hz, 3 H), 2.76 (d, J=7.6 Hz, 2 H), 3.89 (s, 3 H), 7.06 (d, J=8.1 Hz, 1 H), 7.09 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:24](O)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43](Cl)[CH:42]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][C:41]([NH:40][C:24](=[O:25])[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ccnc(Cl)c1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ccncc1
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine (4.40 g) was dissolved in dry tetrahydrofuran (100 ml) and triethylamine (1.80 ml) was added under ice-cooling, followed by stirring for 15 minutes. To this solution was added ethyl chlorocarbonate (1.44 g) and the mixture was stirred for 30 minutes. After adding 4-amino-2-chloropyridine (1.54 g), the reaction was carried out at room temperature for 10 hours. Thereafter, the solid was filtered off and the filtrate was concentrated under a reduced pressure. The residue was extracted with ethyl acetate. The extract was purified with a column chromatography (hexane/ethyl acetate=3/1) to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-(2-chloro)pyridylamide (I) (0.60 g), which was confirmed by the following NMR analysis, in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:27])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH:40]1[CH:41]=[CH:42]C2N(O)N=[N:46][C:44]=2[CH:45]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:27])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](=[O:23])[N:46]3[CH2:42][CH2:41][CH2:40][CH2:45][CH2:44]3)[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](C(=O)O)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a solution of (2S)-2{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.020 g) in DCM (2 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.011 g), HOBT (0.007 g) and triethylamine (0.020 ml) and the mixture was stirred at room temperature for 30 min. Piperidine (0.006 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.002 g) as a colourless gum.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[O-]CC.[Na+].C(O)C>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([Cl:18])[N:13]=1
Reactant: O=CNc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Yield: 73.4 %

Procedure:
A solution of 9-benzyloxy-6-chloro-2-formamidopurine (3.0g; 9.88mmol) in 0.05M sodium ethoxide in ethanol was heated at reflux temperature for 11/2h and then cooled. Acetic acid (0.5ml) was then added and the solvent removed under vacuo. The residue was purified by column chromatography eluting with chloroform: methanol (50:1) to afford the title compound (2.0g; 73%). υmax (KBr) 3397, 3312, 3205, 1634, 1558, 1505, and 1468cm-1 ; δH [(CD3)2SO] 5.45 (2H, s, CH2Ar), 7.20 (2H, br.s, D2O exchangeable, NH2), 7.50 (5H, s, Ph), 8.15 (1H, s, H-8). (Found: C, 52.74; H, 3.70; N, 25.62%, C12H10N5OCl requires: C, 52.27; H, 3.66; N, 25.41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9]OS(C)(=O)=O.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.C(OCC)(=O)C.C(OCC)C>[C:15]([N:22]1[CH2:23][CH2:24][N:25]([CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])[CH2:26][CH2:27]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CS(=O)(=O)OCCc1ccncc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccncc2F)CC1
Temperature: 55 °C
Yield: 84.6 %

Procedure:
3-Fluoro-4-(2-methanesulfonyloxyethyl)pyridine (5.2 g, 23.7 mmol) was dissolved in DMF (65 mL). 1-Boc-piperazine (8.85 g, 47.4 mmol), K2CO3 (3.3 g, 23.7 mmol), NaI (3.6 g, 23.7 mmol) and Cs2CO3 (7.7 g, 23.7 mmol) were added, and the mixture heated to 55° C. for 18 h. The mixture was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated, and the water layer extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum to provide a solution of product and DMF. The residue was dissolved in diethyl ether and water. The layers were separated, and the water layer extracted with diethyl ether. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography (SiO2, 15:1-6:1 CH2Cl2:CMA) to give 1-Boc-4-[2-(3-fluoropyridin-4-yl)ethyl]piperazine (6.2 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]([OH:32])[C:8]5[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=5)[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: COc1ccccn1
Product: COc1ncccc1C(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 75.2 %

Procedure:
2-Methoxypyridine (0.3 ml) and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.5 g) were treated in accordance with the method described in J. Org. Chem., 1367 (1988). to give the title compound (0.493 g) as a pale yellow oil (yield: 75.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:15])[C:11]=1[O:12]CC)[CH:7]=[O:8])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:15])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(F)c1OCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(C=O)cc(F)c1O
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To the solution of 3,4-diethoxy-5-fluorobenzaldehyde (300 mg, 1.4 mmol) in DCM (50 mL) was added AlCl3 (207 mg, 1.55 mmol), and at 0° C., pyridine (230 mg, 2.8 mmol) was added, and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temperature, poured into ice water solution, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography on silica gel to give 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde (160 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[Cl:12][C:13](=[CH2:22])[CH2:14][CH:15]([CH2:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17].C(I)C>C1COCC1>[Cl:12][C:13](=[CH2:22])[CH2:14][C:15]([CH2:1][CH3:2])([CH2:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17]
Reactant: C=C(Cl)CC(CC)C(=O)OC
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCI
Product: C=C(Cl)CC(CC)(CC)C(=O)OC
Reaction time: 0.75 h

Procedure:
(0.80 mL, 5.7 mmol) in THF (5 mL) was added a 1.6M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) over a 5 minute period and stirring was continued for an additional 45 min. Then a solution of methyl 4-chloro-2-ethyl-4-pentenoate (800 mg, 5 mmol) from Example 27, Step A, in THF (2 mL) was added and the reaction was stirred at 0° C. for another 30 minutes. Then ethyl iodide (440 μL, 5.5 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with NH4OAc buffer (50 mL of 25% w/v) and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude product was purified by Kugelrohr distillation (b.p. 120° C. at 0.1 mm Hg) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:28][CH3:29])[CH3:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:16]1[N:15]=[C:14]2[NH:13][C:12](=[O:24])[N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH2:20][C:19]2=[CH:18][N:17]=1)[CH3:26]
Reactant: CCN(CC)CCCCN
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Product: CCN(CC)CCCCNc1ncc2c(n1)NC(=O)N(c1cc(OC)cc(OC)c1)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A suspension of 0.2261 g (0.65 mmol) of 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.103 g (0.71 mmol) of diethylaminobutylamine in 10 mL of dry dioxane was warmed to 60° C. and stirred overnight. To the reaction mixture was added 0.306 g (2.13 mmol) of diethylaminobutylamine and 0.1658 g (0.71 mmol) of camphorsulfonic acid. The reaction mixture was stirred for another 18 hours at 60° C. The reaction solution was concentrated in vacuo, and the residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The ethyl acetate layer was washed with a saturated solution of sodium bicarbonate, then with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed down silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) to give 0.173 g (62%) of the title compound: mp 203-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22]O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>O1CCCC1>[Br:50][CH2:22][C:19]1[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[N:17][CH:18]=1
Reactant: BrC(Br)(Br)Br
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CO)cn2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyrazin-2-yl)-propionamide (457.1 mg, 1.04 mmol) in tetrahydrofuran (10 mL) was treated with triphenylphosphine (573.5 mg, 2.19 mmol) and carbon tetrabromide (726.2 mg, 2.19 mmol). The reaction solution was stirred at 25° C. for 6 h and then was concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (337.2 mg, 65%) as a purple foam: mp 98–103° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H23BrClN3O3S (M+H)+ 500.0405, found 500.0410.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[O:35]=[C:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:37](=[O:38])[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:35])[CH2:31][CH2:30]1)=[O:28]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.9 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (311 mg, 0.65 mmol), 2-oxo-2-phenylacetic acid (900 mg, 6 mmol), DIPEA (2 ml, 11.6 mmol), and HATU (1010 mg, 2.65 mmol) were mixed in DMF (50 ml), the resulting reaction mixture was stirred at room temperature for 4 days until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml)). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was firstly purified by column chromatography on silica gel (DCM:MeOH=100:1) and re-purified by preparative TLC (DCM:MeOH=40:1) to afford the desired product (110 mg, 32.9%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[S:29][C:30]([CH2:33]Cl)=[CH:31][N:32]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:33][C:30]3[S:29][C:28]([Cl:27])=[N:32][CH:31]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: ClCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cnc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
500 mg (1.63 mmol) of the compound from Example 5A and 449 mg (3.25 mmol) of potassium carbonate were dissolved in 4 ml of acetonitrile, and 287 mg (1.71 mmol) of 2-chloro-5-(chloromethyl)-1,3-thiazole were added. The mixture was stirred at 80° C. for 1.5 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1, then 1:1). This gave 619 mg (87% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[O:13][CH3:14].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(N)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(N)cc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To methyl 4-amino-6-bromo-3-methoxypyridine-2-carboxylate (0.300 g, 1.15 mmol) in 10 mL of methanol was added 1N NaOH (1.15 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 1 hr and concentrated to dryness in vacuo. Diethyl ether and H2O were added. The aqueous layer was acidified with 1N HCl until pH=2 and concentrated to dryness. Methanol (50 mL) was added to the white solid. The mixture was filtered and the filtrate concentrated to dryness. Triturating with 5% diethyl ether/pet ether gave 0.180 g of a light pink solid. 1H NMR(DMSO): δ 3.60 (s, 3H); 6.80 (S, 1H).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[C:7]([F:14])[C:8]([O:12][CH3:13])=[C:9]([F:11])[CH:10]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:31][N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1>CN(C=O)C.[Cu]I>[F:11][C:9]1[CH:10]=[C:5](/[C:3](/[CH3:4])=[CH:2]/[N:36]2[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]3[CH2:33][N:32]([CH3:31])[CH2:45][CH2:44][C:35]2=3)[CH:6]=[C:7]([F:14])[C:8]=1[O:12][CH3:13]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1c(F)cc(C(C)=CBr)cc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1c(F)cc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 85 °C
Reaction time: 8 h

Procedure:
5-(1-Bromoprop-1-en-2-yl)-1,3-difluoro-2-methoxybenzene (223 mg, 1.2 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. Yield: 63 mg. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.32 (s, 1H), 7.30 (s, 2H), 7.08 (m, 3H), 4.72 (m, 1H), 4.39 (m, 1H), 4.0 (s, 3H), 3.82 (m, 1H), 3.60 (m, 1H), 3.20-3.10 (m, 5H), 2.42 (s, 3H), 1.90 (s, 3H).