Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COP([O-])OC
Agent: Cl
Product: COc1ccc([C@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
The solution of ALB-CN in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 5 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 59 hours, 1N hydrochloric acid was added to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (R)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 25%. The chemical reaction in this Example is shown in chemical formula 46. ##STR40##
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][F:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[O:27]>C1COCC1>[F:11][CH2:10][CH2:9][O:8][C:7]1[C:2]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FCCOc1cccnc1Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ncccc2OCCF)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 28 (7.3 mmol) in THF was added 1.6 N butyllithium/hexane solution (7 ml) at −78° C. under N2 atmosphere. The solution was stirred at −78° C. for 1 hour and a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (1 g, 3.6 mmol) in THF was added. The solution was maintained at −78° C. for 4 hour, and then quenched with sat. aqueous NH4Cl and allowed to warm to rt with stirring. The organic layer was separated and then the aqueous layer was extracted with ethyl acetate. The combine extract was washed with water, dried over Na2SO4, filtered, concentrated, and the residue chromatographed on silica eluted with an ethyl acetate-hexane (1:4, v/v) and the aimed product was obtained. The yield was 40%. NMR (CDCl3): δ 1.47 (s, 9H), 1.62-1.70 (m, 4H), 2.83 (s, 2H), 3.64-3.73 (m, 1H), 4.17 (br, 2H), 4.25-4.36 (m, 2H), 4.68-4.87 (m, 2H), 7.23-7.26 (m, 1H), 7.38-7.40 (m, 1H), 8.25-8.30 (m, 1H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenyl-phosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassium fluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br)#[N:22]>>[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])#[N:22]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: N#Cc1ccccc1CBr
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2C#N)c1
Yield: 39.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (154 mg, yield: 39.5%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:23])CC)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH2:15][F:23])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCC(CO)(c2cccc(Br)n2)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cccc(Br)n2)N1
Reaction time: 4 h

Procedure:
To a solution of 5-(6-bromo-pyridin-2-yl)-5-hydroxymethyl-morpholin-3-one (2.8 g, 9.756 mmol) in dry THF (30 ml), diethylamino sulfur trifluoride (4.72 g, 29.268 mmol) was added at rt and stirring continued for 4 h. Na2CO3 was then added to the resultant reaction mixture and stirred for further 30 min. The reaction mixture was concentrated under reduced pressure and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to obtain crude compound as gummy residue. Purification of the crude product with 45% ethyl acetate in hexane solvent system furnished the title compound as off-white solid. Yield=1.15 g (40%). TLC (70% ethyl acetate in hexane) Rf=0.49; LCMS: RtH7=0.383, [M+1]+=289 and 289; HPLC RtH9=3.27 min (84%); 1H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H), 7.49 (dd, 1H), 7.32 (d, 1H), 7.09 (br. s, 1H), 4.92 (dd, 1H), 4.52 (dd, 1H), 4.32-4.17 (m, 3H), 3.98-3.93 (dd, 1H); 19F NMR (376.2 MHz): 6-255.65 (t, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
6-Bromo-3H-benzooxazol-2-one (0.165 g, 0.77 mmol) was added portionwise into a 0° C. suspension of NaH (44.8 mg, 1mmol, 55%) in dry DMF (4 ml). After 1 hour stirring at room temperature, a solution of triphenylmethylchloride (0.24 g, 0.85 mmol) in DMF (0.5 ml) was added. The reaction mixture was stirred 1 hour at room temperature then quenched with H2O (15 ml). The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with H2O and brine, dried over Na2SO4 and concentrated to provide 6-bromo -3-trityl-3H-benzooxazol-2-one (0.27 g, 77 %) as a beige solid, MS: m/e=457.1 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17].[CH2:19](O)[CH2:20][CH3:21].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17]
Reactant: CCCO
Reactant: O=C(O)c1ccc2sc3ccccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCOC(=O)c1ccc2sc3ccccc3c(=O)c2c1
Reaction time: 72 h

Procedure:
Finally, propyl thioxanthen-9-one-2-carboxylate (S-20) was prepared. Thioxanthen-9-one-2-carboxylic acid (35 g, 137 mmol) was suspended in a mixture of toluene (250 mL), n-propanol (250 mL), and concentrated sulfuric acid (2 mL) and heated at reflux with stirring for 3 d. The reaction mixture was concentrated, and the resulting solid residue was washed with water and dried. The product was purified by recrystallization from heptane to provide 26.6 g (65% of theory) of a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=[O:20])=[O:12])=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Product: CN1CCN(C(=O)c2cccc(CONC(=O)c3ccccc3NCc3ccncc3)c2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 403) and 1-methylpiperazine.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]([C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:24]1[CH:28]=[C:27]([C:29]([OH:34])([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:26][N:25]=1)CCC>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.O1CCOCC1>[OH:34][C:29]([C:27]1[NH:26][N:25]=[C:24]([C:2]2[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]3[C:10]([C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:8][C:7]=23)[CH:28]=1)([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(O)(CC)CC)[nH]n1
Reactant: COC(=O)C(=O)c1c[nH]c2c(Cl)ncc(OC)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)OC)c[nH]c23)n[nH]1
Temperature: 115 °C
Yield: 72.1 %

Procedure:
To a sealable flask containing methyl 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.070 g, 0.262 mmol) and 3-(3-(tributylstannyl)-1H-pyrazol-5-yl)pentan-3-ol (0.116 g, 0.262 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol). 1,4-Dioxane (5 ml) was added and the mixture was flushed with N2. The tube was sealed, and the mixture was heated to 115° C. After 16 h of heating, the mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with MeOH and was filtered through a pad of celite to remove any solids. The solution was concentrated again under reduced pressure and the residue was dissolved in DMF and was purified by prep HPLC to give the product, methyl 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.073 g, 0.189 mmol, 72.2% yield) as an off-white solid. LCMS: m/e 387.19 (M+H)+, ret time 1.075 min (method 3).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33].O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:38][N:37]=1)([O-:34])=[O:33]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (450 mg, 0.93 mmol) produced in Synthesis Example 31 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 148 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (373 mg, yield 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(O)c2o1
Product: Oc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 5.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (110 mg, 0.69 mol) and 2-(but-3-ynyl)benzo[d]oxazol-7-ol (130 mg, 0.69 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 10 mg (38 μmol, 5%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-7-ol.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:12][CH:13]=1)C.O>C1COCC1>[N:14]1([C:11]2[N:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(-n2cnnn2)nc1
Reaction time: 12 h

Procedure:
LiBH4 (0.48 mL, 0.96 mmol, 2 M in THF) was added to a stirred solution of ethyl[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (0.150 g, 0.64 mmol) in THF (20 ml) at 0° C. The resulting solution was stirred for 12 h. Water (5 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after flash chromatography (eluted with 10-50% ethyl acetate in hexanes) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 8.43 (br s, 1H), 8.01 (dd, J=2.7, J=2.7 Hz, 1H), 7.91 (dd, J=2.1, J=2.0 Hz, 1H), 3.99 (br s, 2H), 3.00 (t, J=6.1, J=6.2 Hz, 2H). LC-MS (IE, m/z): 164.1 [(M+1)+−28].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:15]#[N:16])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:25])[CH:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Reactant: Cc1ccccc1[Mg]Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Temperature: 85 °C
Yield: 107.2 %

Procedure:
A solution of (E)-ethyl 3-(4-bromophenyl)-2-cyanoacrylate (59.4 g, 212 mmol) in toluene (420 mL) was added over 80 min at 0-5° C. to o-tolylmagnesium chloride solution (1 M in tetrahydrofuran, 276 mL, 276 mmol). The reaction mixture was heated at 85° C. for 1½ h, then poured upon ice water and partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (84.6 g), which was directly used in the next step. Light yellow oil, MS: 370.0 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C@H:3]([NH:6][CH3:7])[CH2:4][OH:5].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:6]([C@@H:3]([CH:2]([CH3:8])[CH3:1])[CH2:4][OH:5])[CH3:7])=[O:15])=[CH:12][C:11]=1[CH3:19]
Reactant: CN[C@H](CO)C(C)C
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(=O)N(C)[C@H](CO)C(C)C)ccc1F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
TEA (1.774 mL, 12.80 mmol) was added to (S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (0.5 g, 4.3 mmol) in DCM (5 mL). The mixture was cooled on an ice-bath and 4-fluoro-3-methylbenzoyl chloride (1.27 mL, 8.96 mmol) in DCM (5 mL) was dropwise (over 5 min) added. The resultant mixture was stirred at rt over night. Additional TEA (0.414 mL, 2.99 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.368 g, 2.13 mmol) was added and the stirring was continued for 3 h. Water (12 mL) was added to the mixture. The organic layer was dried though a phase separator and concentrated. THF (15 mL) and NaOH was added to the residue and the resulting mixture was stirred over night. The mixture was neutralized by the addition of acetic acid. The solvent was removed and DCM (50 mL) was added. The organic phase was washed with Na2CO3 (saturated, 2×30 mL) and brine (30 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.91 g, 85%). The obtained crude product was used without further purification. Mixture of rotamers: (600 MHz, CD3OD) δ 0.77-0.82, 0.95, 1.02, 1.74-1.83, 1.89-1.97, 2.23-2.31, 2.83, 2.92, 3.37-3.44, 3.58-3.74, 3.79-3.86, 4.23-4.31, 7.01-7.11, 7.18-7.36. Ratio major:minor:1:0.6. Total no of protons: 19.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=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>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH:43]=2)=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 100 °C
Yield: 81.4 %

Procedure:
Tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (2.4633 g, 4.752 mmol) was dissolved in DMF (19.24 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.204 g, 7.128 mmol) and Pd(PPh3)2Cl2 (196.6 mg, 0.4752 mmol) were added followed by Na2CO3 (7.130 mL of 2 M, 14.26 mmol) and the reaction heated at 100° C. under nitrogen for 15 minutes. The reaction mixture was allowed to cool to RT and the solvent removed in vacuo. The mixture was diluted with EtOAc/water and the organic layer washed with water (×4) followed by brine (×3). After drying over MgSO4, the reaction was filtered and evaporated to dryness to give a dark brown oil which was purified on silica gel by flash column chromatography (0-40% EtOAc/Petrol) to afford the title compound (2.40 g, 81% Yield).
Reaction SMILES: [CH:1](Br)=[CH2:2].N(CC)CC.[CH2:9]([S:16]/[C:17](=[CH:20]\[CH:21]=[C:22](/[S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)\[C:23]#[C:24][C:25]#[C:26][CH3:27])/[C:18]#[CH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.[Cu]I.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>[CH2:9]([S:16]/[C:17](=[CH:20]\[CH:21]=[C:22](/[S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[C:23]#[C:24][C:25]#[C:26][CH3:27])/[C:18]#[C:19][CH:1]=[CH2:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#C/C(=C/C=C(/C#CC#CC)SCc1ccccc1)SCc1ccccc1
Reactant: C=CBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: c1ccccc1
Solvent: CCNCC
Product: C=CC#C/C(=C/C=C(/C#CC#CC)SCc1ccccc1)SCc1ccccc1
Reaction time: 16 h
Yield: 70 %

Procedure:
Vinyl bromide (0.5 mL, excess) was condensed into a flask under argon, followed by addition of CuI (7.2 mg, 0.015 mmol), (Ph3P)2PdCl2 (26 mg, 0.0376 mmol) and Et2NH (3 mL). Compound 10 (145 mg, 0.376 mmol) in benzene (10 mL) was added at 5° C. and the mixture was stirred in the dark for 16 h. Benzene was removed in vacuo, the residue was dissolved in CH2Cl2 (10 mL), washed with NH4Cl solution (2×15 ml) and water (15 mL), dried (MgSO4), concentrated in vacuo, and the residue purified by flash column chromatography (1:5 CH2Cl2 :hexanes) giving 11 as a yellow-green oil (109 mg, yield 70%): EI-MS, m/z 410 (M+), NH3CI-MS, m/z 428 (MNH4 +); UV (CH2Cl2) λ max 403; IR (CH2Cl2) 2226 (m), 2193 (w), 2142 (w) (all C=C), 1602 (m, C=C) cm-1 ; 1H NMR δ 7.1-7.3 (m, 10H), 6.95 (d, J=17.7, 2.1 Hz, 1 H), 5.49 (dd, J=11.1, 2.1 Hz, 1 H), 4.03 (s, 2 H), 4.02 (s, 2 H), 1.96 (s, 3 H); 13C NMR δ 116-138 (several), 94.90, 88.69, 84.46, 80.94, 72.69, 64.46, 37.52, 4.99.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:18][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCC1CCCO1
Product: Cc1cc([N+](=O)[O-])ccc1NCC1CCCO1
Temperature: 0 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (11 g, 70.9 mmoles) is refluxed for 5 hours with 41.5 g (0.41 moles) of tetrahydrofurfurylamine. After that, the reaction product is poured onto 400 g of ice/water and the solid obtained is filtered off. Recrystallization from ethanol/water results in a yellow, grainy dye with a melting point of 56°-58° C.