Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[CH3:21][CH:22]([OH:24])[CH3:23]>>[Cl:8][C:6]1[CH:7]=[C:2]([O:24][CH:22]([CH3:23])[CH3:21])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:5]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step ii), 3 g) in propan-2-ol (20 ml) was added NaH (0.43 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a pale yellow solid. Yield: 1.8 g
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[I:29]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:29])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH2:16][CH2:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2I)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.000259 mol), N-iodosuccinimide (65.4 mg, 0.000290 mol) and zirconium tetrachloride (9.1 mg, 0.000039 mol) in methylene chloride (2.13 mL, 0.0332 mol) was stirred at rt under Ar in a vial for 3 h. The precipitate was filtered off and the residue was purified with silica gel chromatography eluted is with EtOAc/hexane (0 to 40%) to give (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one as a solid (130 mg, 98%). 1H NMR shows 1.6:1 mixture of 5-iodo and 7-iodo isomers. LCMS: Rf=2.40 min 512.39 ([M-1-1], 30%).
Reaction SMILES: C(O[C:4]([Cl:6])=O)C.[CH2:7]([S:14][C:15]1[S:16][C:17](CN2CCOCC2)=[CH:18][N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([S:14][C:15]1[S:16][C:17]([CH2:4][Cl:6])=[CH:18][N:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CSc2ncc(CN3CCOCC3)s2)cc1
Solvent: C1CCOC1
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C

Procedure:
5.5 ml of chloroformic acid ethyl ester are added to 8.0 g of 4-(2-benzylsulfanyl-thiazol-5-ylmethyl)-morpholine in 60 ml of tetrahydrofuran, and the mixture is heated at reflux for 5 hours. The mixture is then cooled to room temperature, the solvent is removed by evaporation in vacuo and the residue is purified by chromatography on silica gel with ether-hexane 1:2. 2-Benzylsulfanyl-5-chloromethylthiazole having a melting point of 57-59° C. is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH2:23][CH3:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)[C:11](=[O:27])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH2:23]([C:21]1[N:20]([CH3:25])[C:19]2[CH:26]=[C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:27])[CH:16]=[CH:17][C:18]=2[N:22]=1)[CH3:24]
Reactant: CCc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61012.9 %

Procedure:
A mixture of 4-(benzyloxy)-1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (3.5 mg), Pd/C (10%, 700 mg) and MeOH (10 ml) was stirred under H2 atmosphere at room temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (1.6 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:39]1([CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH2:40][CH2:41]1
Reactant: Nc1cccc(S(=O)(=O)NCC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-cyclopropylmethyl-benzenesulfonamide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 582.1 [(M−H)−]; mp 234° C.
Reaction SMILES: [Na].C(=O)(O)O.[NH2:6][C:7]([NH2:9])=[NH:8].[NH:10]([CH:17]=[C:18]([C:33]#N)[CH2:19][C:20]1[CH:28]=[C:27]([O:29][CH3:30])[C:23]([NH:24]C=O)=[C:22]([O:31][CH3:32])[CH:21]=1)C1C=CC=CC=1>O>[NH2:8][C:7]1[N:9]=[C:17]([NH2:10])[C:18]([CH2:19][C:20]2[CH:21]=[C:22]([O:31][CH3:32])[C:23]([NH2:24])=[C:27]([O:29][CH3:30])[CH:28]=2)=[CH:33][N:6]=1
Reactant: N=C(N)N
Reactant: COc1cc(CC(C#N)=CNc2ccccc2)cc(OC)c1NC=O
Agent: O=C(O)O
Agent: [Na]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reaction time: 2 h

Procedure:
A solution of 1.84 g. of sodium in 200 ml. of absolute alcohol was treated with 14.4 g. of guanidine carbonate and 8.9 g. of 4'-(3-anilino-2-cyano-allyl)-2',6'-dimethoxy-formanilide and refluxed for 20 hours. Then, 200 ml. of water were added and the alcohol was removed under vacuum. After standing at room temperature for 2 hours, the crystals formed were removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine having a melting point of 215°-216° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([C:12]1[CH:29]=[CH:28][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[C:14]([CH2:30][CH2:31][CH3:32])[C:13]=1[O:33][CH3:34])(=[O:11])[CH3:10].N(CCO)(CCO)CCO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C:5]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:28]=[CH:29][C:12]([C:9](=[O:11])[CH3:10])=[C:13]([O:33][CH3:34])[C:14]=2[CH2:30][CH2:31][CH3:32])[CH:22]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2cccc(N)c2)ccc(C(C)=O)c1OC
Solvent: ClCCl
Solvent: OCCN(CCO)CCO
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2)ccc(C(C)=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 10 minutes a solution of 3.45 ml of chloro-oxalic acid ethyl ester in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-aniline and 4.3 ml of triethanolamine in 90 ml of methylene chloride. After stirring for 5 hours at room temperature the mixture is poured onto water and extracted with methylene chloride. Concentration of the extracts by evaporation and recrystallisation of the residue from ether yields N-{3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-phenyl}-oxamic acid ethyl ester having a melting point of 91°-92°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.CO.O.C([O-])(=O)C.[NH4+]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Clc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A 100 mL round bottom flask was charged with commerically available 6-chloropyrimidin-4-amine (300 mg, 2.316 mmol) and 2-bromo-1-phenylethanone (922 mg, 4.63 mmol). The mixture was suspended in acetonitrile (23.2 mL) and the flask was fitted with a reflux condenser and heated to reflux via heating mantle. The reaction mixture was let stir overnight. After 17 hours, LCMS showed a major peak consistent with desired by mass (m/z=230 [M+H]+); (Methanol/Water/Ammonium Acetate/Phenomenex Luna C18, 30×2 mm, 3μ ES+/−). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude solid was diluted with ethyl acetate and a saturated solution of sodium bicarbonate. The contents of the flask were transferred into a separatory funnel where the aqueous was extracted with ethyl acetate (×3), analyzed for product, and subsequently discarded. The combined organics were transferred into a 125 mL Erlenemyer flask and heated using a heat gun to dissolve the remaining crude. The solution was transferred back into a separatory funnel and the organic was washed with brine (×2), dried with magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography: (40 g SiO2, equilibrated with hexanes, loaded with dichloromethane, initial waste: 125 mL, fraction size: 12 mL 16×100 mm, and eluted with ethyl acetate in hexanes 0% [100 mL], 10% [250 mL], 20% [1000 mL]). Collected product containing fractions to give 7-chloro-2-phenylimidazo[1,2-c]pyrimidine (206 mg, 0.897 mmol, 38.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J=1.3 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 8.06-7.99 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.54-7.45 (m, 2H), 7.44-7.37 (m, 1H). Mass found 230 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[O:21][CH:22]=1>>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1/[CH:24]=[CH:23]/[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: ClCc1coc(/C=C/c2ccco2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)co1)\c1ccco1
Yield: 70 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-(2-furyl)ethenyl]oxazole to give 2-[(E)-2-(2-furyl)ethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 70%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 122-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[NH:9][N:8]=[CH:7]2)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[NH2:13])[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cc2cn[nH]c2cc1N
Yield: 67.5 %

Procedure:
By referring to the Step 2 of Example 7, 5,6-dinitroindazole (5.0 g, 24.0 mmol), 10% Pd/C (1 g), were used to obtain a product (2.4 g, 66.7%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)C>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([F:13])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)c1nc(F)cc(CCl)n1

Procedure:
A mixture of 0.8 g (0.0039 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61), 0.51 g (0.0089 mol) of anhydrous potassium fluoride and 0.14 g (0.0004 mol) of 18-crown-6 in 7 ml of acetonitrile is heated at reflux temperature for 48 hours. The mixture is then taken up in diethyl ether and the solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. The 4-chloromethyl-6-fluoro-2-isopropyl-pyrimidine is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.32 (d, CH(CH3)2), 3.18 (m, CH(CH3)2), 4.62 (s, CH2Cl), 6.99 (d, CH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:53])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([F:24])([F:23])[CH2:21][OH:22])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:54](Cl)(Cl)=[O:55]>ClCCl.C(#N)C>[Br:53][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:52])[C:10](=[O:11])[CH:12]([NH:26][C:27]1[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[C:45](=[O:46])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:32][CH:31]=[CH:30]3)[C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([C:20]([F:23])([F:24])[CH2:21][O:22][C:54](=[O:55])[NH:1]2)=[C:17]([CH3:19])[CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2Br)cc(C)c1C(F)(F)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2cc(C)c1C(F)(F)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To a solution of 4A (289 mg, 0.362 mmol) in dichloromethane (5 mL) and acetonitrile (5.00 mL) at 0° C., was added phosgene (20% in toluene) (0.242 mL, 0.488 mmol). The reaction mixture was stirred at 0° C. for 15 min. Nitrogen was bubbled though the mixture for 0.5 h, then DMPU (˜0.4 mL) was added. The resulting solution was added dropwise via a syringe pump into a solution of TEA (0.353 mL, 2.53 mmol) in dichloromethane (90 mL) at rt over 4 h, stirred for an additional 15 min and then evaporated. The crude product was purified by flash chromatography to give 4B (177 mg, 0.215 mmol, 59.3% yield) as a white solid. MS and 1H NMR are consistent with the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5].[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]1([CH3:56])[C:45]([CH3:47])([CH3:46])[O:44][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH:51]=O)[O:42]1.O>C1COCC1>[CH3:46][C:45]1([CH3:47])[C:41]([CH3:40])([CH3:56])[O:42][B:43]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)/[CH:51]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:31][CH:30]=2)[O:44]1
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A solution of (4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (2.9 g, 6 mmol) in 50 mL of THF was added dropwise via syringe to a solution of LDA (5 mL, 10 mmol) in THF at −78° C. under N2 atmosphere. After 30 min at this temperature 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.4 g, 6 mmol) in 50 mL of THF was added dropwise via syringe and then stirred at this temperature for 30 min and then allow warm to room temperature over 4 hours, and stirred overnight. The mixture was poured into H2O (300 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=50:1) to give (E)-methyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)styryl)benzoate (0.9 g, 41%) as a colorless oil. LC-MS: 365 [M+H]+, tR=1.98 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13].[C:18]([O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([N+:34]([O-:36])=[O:35])[CH:27]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]([OH:31])[C:13]#[C:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[C:28]([N+:34]([O-:36])=[O:35])[CH:27]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
A 1.0 M solution (9.49 ml) of lithium bistrimethylsilylamide in tetrahydrofuran was added to tetrahydrofuran (20.0 ml) at -78° C. under an argon atmosphere, and the mixture was stirred for 30 min. A solution of ethyl propiolate (0.78 ml, 8.62 mmol) in tetrahydrofuran (2.0 ml) was added thereto, and the mixture was stirred for 30 min. A solution of 4-t-butoxycarbonylamino-2-nitrobenzaldehyde (1.53 g, 5.75 mmol) in tetrahydrofuran (20 ml) was then added thereto, and the temperature was raised to -60° C., followed by stirring for 30 min. This reaction mixture was poured into an ice-cold 10% aqueous ammonium chloride solution, and the mixture was vigorously stirred for 5 min. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4-(4-t-butoxycarbonylamino-2-nitrophenyl)-4-hydroxy-2-butynoate as an oil (693 mg, 33%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].[NH4+].[Cl-]>CCO>[OH:2][CH2:1][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:12])=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: Cc1nc2ccc(C=O)nc2s1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1nc2ccc(CO)nc2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of the product of Step 5 (3.733 g, 21 mmol) in 200 mL of EtOH at 0° C. was added NaBH4 (800 mg, 21 mmol) and the mixture was stirred at 0° C. for 5 min. Saturated aq. NH4Cl was then added slowly and the product was extracted in EtOAc:THF 1:1, dried over Na2SO4, and purified by flash chromatography on silica with acetone: toluene 30:70; yield: 3.49 g, (92%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.C(N(CC)CC)C.[C:30]([Cl:33])(=[O:32])[CH3:31]>CN(C=O)C>[ClH:33].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:32])[CH3:31])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 are dissolved in 5 ml DMF, 71.4 mg (705 μmol) triethylamine and 20.3 mg (259 μmol) acetyl chloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>>[CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1C=C(C(=O)O)C2C
Product: Cc1cccc2c1C=C(C(=O)Cl)C2C
Yield: 100 %

Procedure:
1,4-Dimethyl-indene-2-carboxylic acid is converted to its acid chloride by treatment with thionyl chloride. Yield 100%.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(N(CC)CC)C>CN(C=O)C>[NH2:9][C:6]1[C:5]([CH2:10][NH:17][C@H:16]([CH3:18])[C:15]([O:14][CH3:13])=[O:19])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COC(=O)[C@@H](C)N
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2.5 g, 7.3 mmol) in DMF (10 mL) was added D-alanine methyl ester hydrochloride (1.67 g, 10.9 mmol) and triethylamine (5 mL, 36 mmol) and the reaction was stirred at room temperature overnight. The reaction is quenched with water (20 mL) and the product was extracted with ethyl acetate (4×20 mL), the combined organic layers dried over sodium sulfate and concentrated. The crude reaction mixture was purified using a silica gel column eluting with ethyl acetate to give the final product as a white solid (1 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.35 (s, 1H), 5.54 (bs, 2H), 3.73 (d, 1H, J=13.2 Hz), 3.54 (d, 1H, J=13.2 Hz), 3.36-3.34 (m, 1H), 2.96 (s, 3H), 1.35 (d, 3H, J=6.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O.C1COCC1.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:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13]
Reactant: COC(=O)c1cc(Cl)nc(C=O)c1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)nc(-c2ccco2)c1
Temperature: 55 °C
Reaction time: 14 h
Yield: 42.5 %

Procedure:
To a degassed mixture of 205 mg (1.027 mmol) of methyl 2-chloro-6-formylisonicotinate, 183 mg (1.64 mmol) of 2-furanboronic acid, and 316 mg (2.98 mmol) of Na2CO3 in 2 mL of H2O and 4 mL of THF was added 263 mg (0.227 mmol) of Pd(PPh3)4. The mixture was stirred at 55° C. for 14 h, and EtOAc and H2O were added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided methyl 2-formyl-6-(furan-2-yl)isonicotinate as a yellow solid (101 mg) in 43% yield. The desired 6-(furan-2-yl)-4-(methoxycarbonyl)picolinic acid was synthesized from the aldehyde (methyl 2-formyl-6-(furan-2-yl)isonicotinate) following the general procedures as described herein.