Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>CN(C=O)C.CCOC(C)=O>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#Cc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NCCc2cccc(C#N)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 56.8 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 3-(2-Aminoethyl)benzonitrile (78 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (118 mg, 56.3%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 2.60 (t, 2H), 3.17 (q, 2H), 4.37-4.46 (m, 1H), 5.49 (bs, 1H), 6.88 (s, 1H), 7.02 (d, 1H), 7.30-7.34 (m, 1H), 7.47-7.57 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 20.38, 35.75, 44.70, 47.90, 107.72, 113.00, 118.70, 125.17, 129.19, 129.67, 130.36, 130.77, 131.95, 132.20, 133.23, 135.11, 139.03, 158.60; Mass Spectrum: M+H+ 396.1.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([C:15]1[S:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)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>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[S:19][C:15]([C:12](=[O:14])[CH3:13])=[CH:16][CH:17]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: Fc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1

Procedure:
A mixture of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (620 mg, 2.9 mmol), 5-acetyl-2-thiopheneboronic acid [206551-43-1] (634 mg, 3.7 mmol), potassium carbonate [584-08-7] (792 mg, 5.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (100 mg, 0.1 mmol) was suspended in a microwave reaction vial with a 25% (v/v) solution of water in acetonitrile (4.5 mL) then stirred and irradiated to an internal temperature of 145° C. for 15 minutes. The cooled reaction mixture was diluted with ethyl acetate, filtered, and partitioned between 1N aqueous sodium hydroxide and additional ethyl acetate. The organic extract was flash chromatographed (silica gel, eluted with 20% (v/v) ethyl acetate/hexanes) to provide 1-[5-(6-fluoro-imidazo[1,2-b]pyridazin-3-yl)-thiophen-2-yl]-ethanone as 300 mg of yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (s, 3H) 7.00 (d, J=9.35 Hz, 1H) 7.75 (d, J=4.04 Hz, 1H) 7.83 (d, J=4.04 Hz, 1H) 8.13 (dd, J=9.60, 7.07 Hz, 1H) 8.21 (s, 1H). LRMS (ESI) m/z 262.1 [(M+H)]+, calc'd for C12H8FN30S: 261.28.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].O>C(N(CC)C=O)C>[OH:1][CH:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)C(Br)C(C)(C)C
Reactant: [OH-]
Agent: CCN(C=O)CC
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)C(O)C(C)(C)C
Temperature: 110 °C

Procedure:
5 g (0.125 mol) of sodium hydroxide powder was added to 11.6 g (0.05 mol) of 4-Bromo-2,2,5,5-tetramethyl-3-hexanone in 10 g of dry diethylformamide. This reaction mixture was heated to 110° C. for 2 hours, cooled to room temperature and 600 mL of water and 200 mL of hexanes added. The hexane layer was collected and the aqueous layer was washed three times with 50 ml of additional hexanes. The hexanes fractions were then combined, washed three times with 50 ml water, then dried with MgSO4. The product was collected as a crystalline solid after hexanes removal by atmospheric distillation.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[O:7][N:6]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:1].[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[O:7][N:6]=2)[CH2:18][CH2:17]1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCCc2noc3cc(F)ccc23)CC1
Product: Cl

Procedure:
A mixture of 5 g of 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole, 2.9 g of 4-methylpiperidine, 10 g of potassium carbonate and a few crystals potassium iodide in 50 ml of dimethylformamide was stirred at 65°-70° C. for four hrs. The mixture was cooled, filtered and concentrated to an oil. The oil was stirred with water and extracted with ether. The organic extracts were washed with water (2x), saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with ethereal hydrogen chloride to give 4 g (55%) or product, mp 180°-182° C. Recrystallization from ethyl acetate/methanol gave the analytical sample, 189°-190° C.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:13][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.0 ml of a 30% ethanolic solution of methylamine were added dropwise to a mixture of 29.0 g of 2,6-dichloro-3-nitropyridine, 300 ml of ethanol and 36.6 g of sodium carbonate, whilst cooling with ice, and the resulting mixture was stirred at room temperature for 8 hours. At the end of this time, the reaction mixture was freed from ethanol by distillation. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 22.3 g of the title compound, melting at 114° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:29]1[CH:44]=[CH:43][C:32]([C:33](ON2C(=O)CCC2=O)=[O:34])=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:34])=[CH:43][CH:44]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-[p-(2,2,2-trifluoro-N-hexadecylacetamido)benzoyloxy]succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid, m.p. 190°-220° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.C([Li])CCCCC.CCCCCC.[Cl:23][CH2:24][C:25]([CH2:27][Cl:28])=[O:26]>C(OCC)C>[Cl:23][CH2:24][C:25]([C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1)([OH:26])[CH2:27][Cl:28]
Reactant: O=C(CCl)CCl
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [Li]CCCCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(CCl)(CCl)c1cc(F)cc(Cl)c1

Procedure:
Preparation according to Preparation 1: 1-bromo-3-chloro-5-fluorobenzene (5 g, 23.9 mmol), dry diethyl ether (100 mL), n-hexyllithium in hexane (2.3 M, 10.4 ml, 23.9 mmol) and 1,3-dichloroacetone (3.03 g, 23.9 mol). Yield: 4.49 g (73%). MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 209 (65), 207 (bp), 211 (11), 143 (28).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH2:3]1.[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14].[CH3:18][CH2:19][O:20][CH2:21][CH3:22]>C(OC(=O)C)(=O)C.C(O)C>[C:12]([O-:17])(=[O:16])[C:13]([O-:15])=[O:14].[CH3:1][NH+:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[N:9]=[C:18]([CH3:19])[O:11][N:10]=2)[CH2:3]1.[CH3:1][NH+:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[N:10]=[C:21]([CH3:22])[O:20][N:9]=2)[CH2:3]1
Reactant: O=C(O)C(=O)O
Reactant: CCOCC
Reactant: CN1CCC=C(C(N)=NO)C1
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: Cc1nc(C2=CCC[NH+](C)C2)no1
Product: O=C([O-])C(=O)[O-]
Yield: 52 %

Procedure:
A solution of 1-methyl-1,2,5,6-tetrahydropyridin-3-carboxamide oxime (200 mg; 1.29 mmol) in acetic anhydride (5 ml) was heated at 80° C. for 24 hours. After evaporation in vacuo the residue was dissolved in 4N NaOH (5 ml) and extracted with ether (3×25 ml). The ether phases were dried (MgSO4), filtered, and evaporated in vacuo. The residue was dissolved in ethanol (99.9%)(5 ml) and added to a solution of oxalic acid (100 mg; 1.1 mmol) in ethanol (99.9%)(5 ml). Addition of ether gave the title compound in a yield of 52%. M.P. 173°-174° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:39]=[CH:40][C:41]=1[F:42])[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[CH:20][C:21]=2[O:23][CH2:24][C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2C(OC(C)(C)C)=O)[N:16]=[CH:15][N:14]=1.N>CO>[Cl:8][C:9]1[CH:10]=[C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:37][CH3:38])=[CH:20][C:21]=3[O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[N:16]=[CH:15][N:14]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COc1cc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (25 ml) was added in one portion to tert-butyl (2S)-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (1.6 g) and the solution was stirred at room temperature for 1 hour 30 minutes. The solution was then concentrated in vacuo and azeotroped three times with ether to leave an orange oil. 7N Ammonia in methanol (5 ml) was added and the mixture was stirred for 10 minutes. The mixture was then concentrated in vacuo to leave an orange oil and purified by column chromatography using 0-10% methanol in DCM as eluent to give N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine as a light yellow solid (1.15 g, 75% over two steps); Mass spectrum MH+ 403.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17]([Cl:18])=[C:16]([S:19][CH3:20])[C:15](Cl)=[N:14][CH:13]3[NH2:22])[CH:10]=2)[N:5]=C(C)[CH:3]=1.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[N:28]=[C:27]([CH3:36])[CH:26]=1.[CH2:37](O)[CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17]([Cl:18])=[C:16]([S:19][CH3:20])[CH:15]([NH2:14])[N:35]([C:32]4[CH:33]=[C:34]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([CH3:36])[CH:26]=[C:25]5[NH2:24])[CH:13]3[NH2:22])[CH:10]=2)[N:5]=[C:37]([CH3:38])[CH:3]=1
Reactant: CCO
Reactant: CSC1=C(Cl)N(c2ccc3nc(C)cc(N)c3c2)C(N)N=C1Cl
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Product: CSC1=C(Cl)N(c2ccc3nc(C)cc(N)c3c2)C(N)N(c2ccc3nc(C)cc(N)c3c2)C1N
Reaction time: 16 h

Procedure:
A mixture of 43 mg of N-(4-amino-2-methyl-6-quinolyl)-2-amino-4,6-dichloro-5-methylsulfanylpyrimidine and 55 mg of 4,6-diamino-2-methylquinoline in 5 mL of ethanol is heated under reflux for about 3 hours, left at a temperature in the region of 20° C. for about 16 hours and then filtered. The filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40° C., and then the residue obtained is purified by HPLC (column: C18 Waters, 5 M, 50×19 mm; eluent: elution gradient water-acetonitrile-TFA (0.07%) from 95-5 to 5-95 over 30 minutes). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. to obtain 12 mg of N,N′-bis(4-amino-2-methyl-6-quinolyl)-2,4-diamino-6-chloro-5-methylsulfanyl-pyrimidine in the form of a beige colored solid.
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16](C(=O)C)=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[F:12].S(=O)(O)[O-].[Na+].[O:27]1[CH2:32]COCC1>O>[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]=1[C:32]([OH:27])=[O:1]
Reactant: CC(=O)c1ccc(-c2ccc(F)c(F)c2)cc1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)ccc(F)c1F
Temperature: 50 °C

Procedure:
Next, to a mixture in which 530 g of ice and 125 g of water were added to 126 g of sodium hydroxide was gradually added dropwise 125 g of bromine. After completion of dropwise addition, a solution of the previously obtained 45 g of 3,4-difluoro-4'-acetylbiphenyl dissolved in 230 ml of dioxane was added dropwise to the mixture at a temperature of 20° C. or lower. After completion of the dropwise addition, the mixture was heated to 50° C. and reacted for 1 hour. After the reaction, 100 ml of a 40% aqueous sodium bisulfite solution was added to precipitate crystals. The crystals were collected by filtration, washed well with methanol and purified by recrystallization to obtain 36 g of 3,4-difluorobiphenyl carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1([S:6]([NH:9][C:10]([C@@:12]2([NH:17][C:18]([C@@H:20]3[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]3[C:26](=[O:40])[C@@H:27]([NH:32][C:33]([O:35][C:36](C)([CH3:38])[CH3:37])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:19])[CH2:14][C@H:13]2[CH:15]=[CH2:16])=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].ClC(OC(C)C)=O.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:36]([O:35][C:33](=[O:34])[NH:32][C@H:27]([C:26]([N:21]1[CH2:22][CH:23]([OH:25])[CH2:24][C@H:20]1[C:18](=[O:19])[NH:17][C@:12]1([C:10]([NH:9][S:6]([C:3]2([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:8])=[O:7])=[O:11])[CH2:14][C@H:13]1[CH:15]=[CH2:16])=[O:40])[C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:37])[CH3:38]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1(CC)CC1
Agent: CC(C)OC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1CC(O)CN1C(=O)[C@@H](NC(=O)OC(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1(CC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A solution of 2(S)-[1 (R)-(1-ethyl-cyclopropanesulfonylaminocarbonyl)-2(S)-vinyl-cyclopropylcarbamoyl]-N-[N-Boc-amino-(S)-t-butyl-acetyl]-4(R)-hydroxy-pyrrolidine (585 mg, 1.0 mmol) in TFA (2 ml) and CH2Cl2 (2 ml) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (5 ml) and isopropyl chloroformate (1.0M in toluene, 1.0 ml, 1.0 mmol), DIPEA (0.5 ml) were added. The resulting mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The crude product was purified by flash column chromatograph (Biotage Flash 40M) eluted with EtOAc to provide the title compound (180 mg, 32%). MS 571 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][NH:12][C:11]1=[S:15].[I:16]I.[I-].[K+]>CO.O>[IH:16].[NH:12]1[CH2:13][CH2:14][N:10]=[C:11]1[S:15][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: S=C1NCCN1
Reactant: c1ccc2[nH]ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: I
Product: c1ccc2c(SC3=NCCN3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 11.7 g indole in 100 ml methanol and 10.2 g 2-imidazolidinethione in 150 ml methanol is added to a well-stirred solution of 25.4 g iodine and 50 g potassium iodide in 100 ml water. The mixture is stirred for 2 hours at room temperature. The clear solution is concentrated in vacuo to one third of the original volume and cooled. The solid which separates is filtered off, dried and recrystallised from alcohol-ether to give 3-(2-imidazolin-2-ylthio)-indole hydriodide of the formula ##SPC9##
Reaction SMILES: CN/[C:3](=C\C)/[C:4]([O:6][CH3:7])=[O:5].C([N:12]([CH2:15][CH3:16])[CH2:13]C)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]([C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:15]([NH:12][CH3:13])[CH3:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: C/C=C(\NC)C(=O)OC
Solvent: Cc1ccccc1
Product: CNC(C)=C(C(=O)OC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
193.5 g (1.5 moles) of methyl methylaminocrotonate is dissolved in 450 ml of toluene, and 166.7 g (1.65 moles) of triethylamine is added; while cooling at 0° to 5° C., 211 g (1.5 moles) (=174 ml) of benzoyl chloride is then dripped into this mixture. After the mixture has been stirred for 12 hours at 25° C., the precipitated triethylamine hydrochloride is filtered off and the toluene solution is extracted with water. After the toluene phase has been dried with Na2SO4, the residue is evaporated under reduced pressure and the solid which is obtained is recrystallized from a 4:1 mixture of ligroin and toluene. There is obtained 217 g (62%) of a white solid; m.p.: 75°-77° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:37][CH3:36])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3S,4R)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.7 g, 5.48 mmol) in MeOH (containing 2% AcOH, 25 mL), methylamine (13.7 mL, 27.41 mmol, 2M in MeOH) is added. The solution is stirred at RT for 1 h under nitrogen atmosphere and cooled to 10° C., before the careful addition of NaBH4 (0.415 g, 10.96 mmol) (exothermic !!). The resulting mixture is allowed to reach RT and stirred for 1.5 h. The excess reducing agent is quenched with water, AcOEt is added and the reaction mixture is poured into an aqueous saturated solution of NaHCO3. The organic layer is separated and the aqueous layer extracted twice with AcOEt, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 95:5)=0.05. MS (LC-MS) [M+H]+=508.1. tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 4.53 min.
Reaction SMILES: C([Li])CCC.[B:6](OC(C)C)([O:11]C(C)C)[O:7]C(C)C.C(=O)=O.CC(C)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1.Cl>C1COCC1.FC1C=CC(C=C)=CN=1>[F:26][C:27]1[C:32]([B:6]([OH:11])[OH:7])=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1
Reactant: C=Cc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 639.6 %

Procedure:
2-Fluoro-5-vinylpyridine (64.8 mg, 0.526 mmol) was dissolved in THF (2.0 mL) and the reaction flask was cooled in a dry ice/acetone bath. Then, n-butyllithium (1.6 M solution in hexanes, 0.40 mL, 0.64 mmol) was added via syringe dropwise, turning the solution red. The reaction was stirred at −78° C. for 45 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 0.190 mL, 0.826 mmol) was added, and the reaction was allowed to slowly warm up to room temperature (the dry ice/acetone bath was removed after 80 minutes). The reaction was stirred at room temperature for 45 minutes, and then quenched with water. The layers were separated, and the organic phase was discarded. The aqueous phase was treated with 5N HCl to lower the pH from 9 to 4. Then, the aqueous phase was extracted with 10:1 DCM/MeOH, and the organic extracts were combined and set aside. In a separate flask, 2-fluoro-5-vinylpyridine (4.15 g, 33.7 mmol) was decanted from a solid precipitate, which was washed with THF. The 2-fluoro-5-vinylpyridine was dissolved in THF (120 mL), and the reaction flask was cooled in a dry ice/acetone bath under nitrogen. Then, n-butyllithium solution (1.6 M in hexanes, 25.5 mL, 40.8 mmol) was added via syringe, turning the yellow solution into a deep red color. The reaction was stirred at −78° C. for 50 minutes, and then triisopropyl borate (Aldrich, St. Louis, Mo. 98+%, 11.5 mL, 50.0 mmol) was added via syringe, and the reaction was allowed to warm to room temperature (after 90 minutes, the dry ice/acetone bath was removed). Almost 5 hours after the addition of triisopropyl borate, the reaction was quenched with water (125 ml), slowly at first. The biphasic solution was stirred for 15 minutes, and then the layers were separated. The organic phase extracted one time with saturated sodium bicarbonate. This sodium bicarbonate washing was discarded. The organic phase was extracted two times with 1 N NaOH (60 mL and then 50 mL). These aqueous extractions were combined, treated with concentrated HCl to lower the pH to 4, and extracted with 10:1 DCM/MeOH. These organic extracts did not contain product, so they were discarded, along with these second aqueous extractions. The original aqueous phase (from the initial phase separation after quenching the reaction with water) was treated with 5N HCl to lower the pH to around 3-4. This aqueous phase was extracted with 10:1 DCM/MeOH. These organic extracts were combined with the organic extracts from the first reaction, concentrated, and dried under high vacuum at room temperature to afford 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 61% purity, 11% yield over 2 steps). MS (ESI pos. ion) m/z 168 (M+H)+.