Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=4[CH3:28])=[N:17][NH:16][C:15](=O)[C:11]=3[NH:12][C:13]=2[CH:14]=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:15]1[C:11]2[NH:12][C:13]3[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[CH:8][C:9]=3[C:10]=2[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=2[CH3:28])=[N:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Product: COCCOc1ccc2c(c1)[nH]c1c(Cl)nnc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A yellow, homogeneous solution of 7-(2-methoxyethoxy)-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one (0.2510 g, 0.636 mmol) in phosphoryl trichloride (20 mL, 0.636 mmol) under nitrogen was heated at 100° C. After 1 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in cold EtOAc (250 mL) and was with ice-cold water (40 mL), ice-cold saturated aqueous NaHCO3 (40 mL), ice-cold water (40 mL) and ice-cold brine (40 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give the desired product (0.2115 g, 0.512 mmol, 80% yield) as a light orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[CH:18][CH:19]=3)[CH2:14][C:13]([CH3:32])([CH3:31])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33].[Cu][C:35]#[N:36].Cl>CN(C)C=O>[CH3:32][C:13]1([CH3:31])[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:16]=2)[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]#[N:36])=[C:3]([F:33])[CH:4]=2)(=[O:10])=[O:9])[CH2:12]1
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(Br)c(F)c2)C1
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(F)c2)C1
Temperature: 200 °C
Yield: 75.2 %

Procedure:
710 mg 1-(4-Bromo-3-fluoro-benzenesulfonyl)-3,3-dimethyl-6-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinoline and 123 mg copper(I)cyanide were dissolved in 1.5 ml dimethylformamide and heated to 200° C. under microwave irradiation for thirty minutes. The cooled reaction mixture was poured into 50 ml 2M hydrochloric acid and extracted five times with portions of 20 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel to obtain 481 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:7][CH2:2][CH2:3][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C(=O)OC)c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 177.5 %

Procedure:
To a solution of methyl 2,4-dichlorophenylacetate (2 g) in anh. THF (27 mL), at −78° C., under N2, a 1M solution of LHMDS in THF (10.04 mL) was added dropwise and the mixture was stirred at −78° C. for 30 min. Neat intermediate 20 (2.87 g, 1.3 eq) was then added dropwise at −78° C. and the dropping funnel was washed with anh. THF (2 mL). The cooling bath was then removed and the mixture was stirred at r.t. for 3.5 hr. The solvents were evaporated under reduced pressure. The residue was dissolved in ether, washed with water (3×30 mL) and brine (1×30 mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1) to give the title compound as a pale yellow oil (2.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].Cl.CN(C)[CH:21]=[O:22]>C(OC)=O>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9](=[CH:21][OH:22])[C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1csc2ccc(C)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC=O
Product: COC(=O)C(=CO)c1csc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 79.7 g of methyl 5-methyl-3-benzo[b]thienylacetate in 200 ml of dimethylformamide and 200 ml of methyl formate is slowly added dropwise to a suspension of 10.4 g of sodium hydride in 100 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at room temperature and then acidified with dilute hydrochloric acid, and this is then extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this manner, methyl α-(5-methyl-3-benzo[b]thienyl)-β-hydroxyacrylate is obtained as the crude product which is used unpurified as the starting material in the next process step.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:28][C@:20]2([CH2:19][N:18]=1)[CH:25]1[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]1)[CH2:21]2
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: CSC(=Nc1nc2cccnc2s1)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2c1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (90 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (97 mg, 0.42 mmol) and cesium carbonate (230 mg, 0.71 mmol) in DMF (1 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (84 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (br. s., 1 H) 8.37 (dd, J=4.77, 1.51 Hz, 1 H) 7.82 (dd, J=8.03, 1.51 Hz, 1 H) 7.28 (dd, J=8.03, 4.77 Hz, 1 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.75-3.07 (m, 5 H) 2.14-2.26 (m, 2 H) 1.71-1.84 (m, J=13.99, 9.79, 4.17, 4.17 Hz, 1 H) 1.48-1.68 (m, 2 H). MS (LC/MS) R.T.=0.64; [M+H]+=316.15.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH:13]([Si:15](Cl)([CH3:17])[CH3:16])=[CH2:14]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[C:10]([Si:15]([CH:13]=[CH2:14])([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2]
Reactant: CCNC(=O)c1ccccc1Cl
Reactant: C=C[Si](C)(C)Cl
Product: C=C[Si](C)(C)c1cccc(Cl)c1C(=O)NCC

Procedure:
The title compound was prepared from the compound of Example f and 1.5 eq vinyldimethylsilyl chloride according to General Method C. Purification by HPLC with 1:4 ethyl acetate/hexanes gave 630 mg of the desired product as a white solid, a 9% yield. m.p. 86°-89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH2:26]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH3:18])[C:6]1[CH2:11][C@H:12]3[NH:17][C@@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C=Cc1ccccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccc2C)C[C@@H]2CCC[C@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1-methyl-2-vinylbenzene (115 mg, 0.972 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.10-1.34 (m, 3H), 1.59-1.96 (m, 4H), 2.00 (s, 3H), 2.40 (s, 3H), 2.79 (dd, J=17, 7 Hz, 1H), 2.97-3.09 (m, 1H), 3.11-3.22 (m, 1H), 3.37-3.43 (m, 1H), 4.20 (ddd, J=14, 9, 5 Hz, 1H), 4.31-4.42 (m, 2H), 6.90-6.97 (m, 2H), 6.99-7.11 (m, 3H), 7.14 (s, 1H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:25])[CH2:23][CH3:24]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: CCC(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and propionic acid (18.5 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)propionamide. NMR; δH [2H6]—DMSO 9.84,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.47,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.29,(2H, q), 2.15,(3H, s), 1.08-1.02,(4H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.00 min, MH+337.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]2)=[O:10])=[CH:14][CH:13]=1
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid monomethylester (2 g, 13.88 mmol) was dissolved in DMF (28 mL) and 4-fluoroaniline (1.999 mL, 20.82 mmol) was added, followed by diisopropylethylamine (12.12 mL, 69.4 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (8.91 g, 27.8 mmol). The mixture stirred at room temperature for 15 hours and was then diluted with ethyl acetate (200 mL) and washed with 10% aqueous lithium chloride (3×100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and evaporated to yield the crude product as a brown solid. It was purified by silica gel chromatography (0 to 20% ethyl acetate/hexane) to give methyl 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylate (3.28 g, 99% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H)), 3.66 (s, 3H), 1.38 (m, 4H); MS (ESI) m/z: 238.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][C:26](=[O:37])[CH2:25]1)=O)C=C>>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C:26](=[O:37])[CH2:25]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 85.9 %

Procedure:
Reaction of N-tert-butoxycarbonylpipecolic acid (460 mg, 2.0 mmol) and N-allyloxycarbonyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (530 mg, 1.82 mmol) was carried out by a method analogous to that reported by Chapman (Bioorg. & Med. Chem. Lett. 1992, 2, 613-618.) to give 654 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH:13](I)([CH3:15])[CH3:14]>>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][OH:8])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Reactant: CC(C)I
Product: CC(C)Oc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
10 g (60 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were reacted with 7.0 ml (70 mmol) of isopropyl iodide analogously to Example 4a); after purification over silica gel with n-heptane/ethyl acetate (3:2), 10.3 g of oily crude product.
Reaction SMILES: C1(C([NH:20][CH:21]2[C:40](=[O:41])[N:23]3[CH:24]([C:29]4[N:33]([CH2:34][C:35]5[O:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CC(C)=O>[NH2:20][CH:21]1[C:40](=[O:41])[N:23]2[CH:24]([C:29]3[N:33]([CH2:34][C:35]4[O:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]12.[CH3:53][C:43]1[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccco1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 0.422 g. (0.75 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam in 1 ml. of acetone at ambient temperature, is added 0.142 g. (0.75 mmole) of p-toluenesulfonic acid monohydrate. Stirring is continued for 30 minutes, and then the solvent is removed by evaporation in vacuo. This affords the title compound as its p-toluenesulfonate salt. IR (Nujol mull): 1780 cm-1 (β-lactam). NMR (DMSO-d6): 7.20 ppm (q, 4H), 6.40 ppm (m, 2H), 5.90 ppm (s, 2H), 5.60 ppm (m, 2H), 5.00 ppm (d, 1H), 2.20 ppm (s, 3H), 1.60 ppm (s, 3H), 0.80 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: C=Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Product: O=Cc1ccc(C=Cc2ccccc2)cc1
Yield: 72 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.63 g (25 mmols) of 4-bromobenzaldehyde and 3.16 ml (27.5 mmols) of styrene. After a reaction time of 4 hours at 130° C., 3.74 g (18.0 mmols) of 4-formylstilbene are obtained, corresponding to a yield of 72% of theory (conversion figure 7200; Pd content 0.01 mol %).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:19][N:18]=[C:17]2[CH2:25][NH:36][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: NCC1CC1
Reactant: CN(C)Cc1nnc(CO)n1-c1ccc(Br)cc1C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Product: CN(C)Cc1nnc(CNCC2CC2)n1-c1ccc(Br)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 47, 5-bromo-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by (cyclopropylmethyl)-amine to give 5-bromo-2-[3-[[(cyclopropylmethyl)amino]-methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]-benzophenone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C1CCCCC1)(C)C.[Li+].[CH2:25]([Sn:29](Cl)([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:34]([Sn:29]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:30][CH2:31][CH2:32][CH3:33])[C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmole, prepared as in Step C of Example 1) in THF was cooled at −78° C. and cannulated to a solution of lithium N-isopropyl-N-cyclohexylamide in THF at −78° C. over 15 min. The resulting mixture was stirred at −78° C. for 2 h and cannulated into a solution of tributyltin chloride (1 mmole) in THF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 1 h, and at 25° C. for 12 h. Extraction and chromatography gave compound (14) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5](N)=[C:4]([N+:15]([O-:17])=[O:16])[C:3]=1[F:18].[I:19]I>C(Cl)(Cl)Cl.S(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([F:18])=[C:4]([N+:15]([O-:17])=[O:16])[C:5]([I:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1
Reactant: Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(F)c(Br)cc(-c2ccccn2)c1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of 4-bromo-3-fluoro-2-nitro-6-(pyridin-2-yl)aniline (4.0 g, 12.81 mmol) in chloroform (50 mL) was added iodine (18.21 g, 71.77 mmol) and the resulting mixture was stirred at 0° C. for 10 min followed by addition of isoamyl nitrile (3.44 mL, 25.63 mmol). The mixture was then heated up to 65° C. for 5 h. After completion of reaction (by TLC), the reaction was diluted with 10% sodium bisulfite and extracted with DCM (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 20% EtOAc:hexane to obtain the desired product as an off white solid (2.0 g, 37%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:14][C:10]2[CH:11]=[C:12]([CH3:13])[C:6]3[N:5]=[C:4]([CH2:3][O:2][CH3:1])[NH:8][C:7]=3[CH:9]=2)[CH:21]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COCc1nc2c(C)cc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
0.77 g (4.00 mmol) 2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazol-6-ol and 0.68 g (4.40 mmol) 4,6-dichloropyrimidine in 5.0 mL DMF were combined with 1.66 g (12.0 mmol) potassium carbonate and stirred for 8 h at 70° C. Then ice water was added and the substance was extracted with ethyl acetate and concentrated by rotary evaporation i.vac. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12]C)=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COC(=O)c1ncc(OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(C(=O)O)c(Cl)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
In a 2-L round bottom flask, the methyl 3-chloro-5-methoxypicolinate (19.1 g, 95 mmol) was suspended in MeOH (104 ml). Aqueous 1N sodium hydroxide (104 ml, 104 mmol) was added. An air-cooled condenser was attached, and the reaction flask was heated in a 50° C. oil bath. After 1.5 h, the reaction was concentrated to remove the MeOH until a yellow sludge remained. The sludge was dissolved in 110 ml of water. The aqueous phase was extracted with diethyl ether (50 ml), which was discarded. The aqueous phase was acidified with aqueous hydrogen chloride (23 ml, 114 mmol), which caused extensive precipitation. The sludgy aqueous mixture was extracted with DCM in 6×250 ml. The organic layer were dried over MgSO4 and concentrated to yield 3-chloro-5-methoxypicolinic acid (17.88 g, 95 mmol, 100%) as a yellow solid. MS m/z=188 (M+H).
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][S:6]([NH2:5])(=[O:7])=[O:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OCCCCS(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.1 %

Procedure:
N-tert-Butyl-4-acetoxybutanesulfonamide (425 mg) was dissolved in trifluoroacetic acid (4.3 ml), and the mixture was stirred at room temperature for 4 hr and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=49:1) to give 4-acetoxybutanesulfonamide (347 mg) as a brown oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][SH:6].[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Cl)=[N:14][CH:13]=1>C1COCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][S:6][C:15]1[N:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=1
Reactant: FC(F)(F)CS
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(SCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in anhydrous THF (40 mL) at 0 C was added 2,2,2-trifluoro-ethanethiol (200 μL, 2.25 mmol) drop-wise under nitrogen. The resulting solution was stirred for 15 min and added to a solution of 6-chloro-nicotinic acid methyl ester (257 mg, 1.5 mmol) in anhydrous THF (40 mL) at 0 C drop-wise. The reaction mixture was allowed to warm to room temperature and stirring was continued for a further 3 h. The solution was quenched with water at 0 C and extracted into EtOAc (3×50 mL). Combined organics were washed with brine (20 mL), dried over magnesium sulfate, evaporated to dryness and purified by silica chromatography (25% EtOAc in heptane) to afford the title compound as a colourless oil (370 mg, 98%). Method C HPLC-MS: MH+ requires m/z=252. Found: m/z=252, Rt=1.41 min (94%).