Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>>[CH2:14]([O:17][N:18]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10])[CH:15]=[CH2:16]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: C=CCON
Agent: Cl
Product: C=CCON=C(C(=O)O)c1cccc(O)c1
Yield: 101.4 %

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Preparation (5-2) (a) to give oil of 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=2[OH:20])=[CH:4][CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:22][CH2:23][CH2:24][OH:25])=[CH:3][CH:4]=2)=[O:21])=[C:10]([OH:20])[CH:11]=1)[CH2:17][CH2:18][CH3:19]
Reactant: OCCS
Reactant: CCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1ccc(C(=O)c2ccc(SCCO)cc2)c(O)c1

Procedure:
Following the procedure of Example 2, the title compound is prepared by reacting equimolar amounts of 4′-chloro-2-hydroxy-4-butoxybenzophenone and 2-mercaptoethanol in the presence of potassium carbonate.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
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: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(OC(F)(F)F)cc4)nc3C)c(C)nc12
Temperature: 160 °C
Yield: 70.5 %

Procedure:
To a microwave pressure tube is added 0.100 g (0.254 mmol) of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.157 g (0.762 mmol) of 4-(trifluoromethoxy)benzene boronic acid, 0.147 g (0.127 mmol) of Pd(PPh3)4, 0.381 mL (0.762 mmol) of 2 M aqueous sodium carbonate, and 2 mL Ethanol. The reaction mixture is heated in the microwave at 160° C. for up to 1 hour. The reaction mixture is partitioned between 50 mL of ethyl acetate and 50 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using 2% methanol in dichloromethane as a solvent system. The product containing fractions are combined to obtain 0.085 g of the product, 70% yield. MS, ES+=475.2 (M+1); 1H-NMR (DMSO-d6)=8.134-8.112 (d, 2H); 7.553-7.532 (d, 2H); 7.059 (s, 1H); 3.142-3.113 (m, 1H); 2.500 (s, 3H); 2.399 (s, 3H); 2.330 (s, 3H); 1.907-1.782 (m, 4H); 0.827-0.791 (m, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([CH2:20][C:21]#[N:22])=[C:15]([Cl:23])[CH:14]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:12][C:13]1[CH:14]=[C:15]([Cl:23])[C:16]([CH:20]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=2)[C:21]#[N:22])=[C:17]([Cl:19])[CH:18]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: N#CCc1c(Cl)cc(N)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(C#N)c2c(Cl)cc(N)cc2Cl)nnc1Cl
Temperature: 60 °C
Yield: 76.6 %

Procedure:
A solution of 3,6-dichloro-4-isopropyl pyridazine (7) (5.54 g, 29.0 mmol) in tetrahydrofuran (116 mL) in a 500 mL round bottom flask (caution: use an extra large flask) was treated with (4-amino-2,6-dichloro-phenyl)-acetonitrile (44) (5.81 g, 28.9 mmol). The reaction mixture was equipped with a cold water condenser and heated to 60° C. The flask was then raised out of the oil bath and potassium tert-butoxide (6.85 g, 57.99 mmol) was added. The mixture was heated to 60° C. for 45 min. The reaction was cooled to room temperature, transferred to a separatory funnel, diluted with ethyl acetate (500 mL) and was washed with a saturated aqueous sodium chloride solution (2×250 mL). The organic layer was separated, dried with magnesium sulfate, and was filtered. Silica gel 60 (70-230 mesh) was added to the filtrate and the solvent was concentrated under vacuum. The resulting mixture was purified by flash chromatography (Biotage 75L) using silica gel eluted with 15%-30% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford (4-amino-2,6-dichloro-phenyl)-(6-chloro-5-isopropyl-pyridazin-3-yl)-acetonitrile (45) (7.87 g, 77%) as an orange foam; LRMS for C15H13Cl3N4 (M+H) m/z=355. This compound was used without further purification. Molecular Weight=355.6567; Exact Mass=354.0206
Reaction SMILES: [OH:1][C@H:2]1[C@@:6]2([O:9][CH2:8][CH2:7]2)[C@H:5]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:4][C@@H:3]1[CH2:18][OH:19].CN1C=CN=C1.Cl[C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31]>C1COCC1>[O:17]=[C:11]1[NH:12][C:13](=[O:16])[CH:14]=[CH:15][N:10]1[C@@H:5]1[O:4][C@H:3]([CH2:18][O:19][C:40]2[CH:41]=[CH:42][CH:43]=[CH:27][C:28]=2[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C@@H:2]([OH:1])[C@:6]21[O:9][CH2:8][CH2:7]2
Reactant: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1Cl
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@]23CCO3)c(=O)[nH]1
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]2(CCO2)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 10 (1.0 eq., 0.28 mmol, 75 mg) in dry THF (3 mL) was added 1-methylimidazole (NMI; 12.0 eq., 3.33 mmol, 0.27 mL) at room temperature. A solution of intermediate 11 (1.4 eq., 0.39 mmol, 0.43 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed three times with 0.5 M HCl. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% methanol in CH2Cl2) to give compound 12e (24 mg, yield=15%, purity=95%) as a mixture of diastereomers. HPLC Condition A; Rt: 1.49 min, m/z=526 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 3H), 1.37 (s, 3H), 2.42-2.43 (m, 2H), 3.56 (s, 3H), 3.70-3.79 (m, 1H), 3.80-3.88 (m, 0.4; H), 3.88-3.96 (m, 0.6; H), 4.09-4.20 (m, 1H), 4.26-4.48 (m, 3H), 5.50-5.56 (m, 1H), 5.61-5.69 (m, 1H), 5.88-5.97 (m, 1H), 5.97-6.04 (m, 1H), 7.12-7.24 (m, 3H), 7.31-7.41 (m, 2H), 7.44 (d, J=8.22 Hz, 0.4H), 7.52 (d, J=8.02 Hz, 0.6H), 11.49 (br. s., 1H).
Reaction SMILES: FC(F)(F)[C:3](=[O:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:7])[CH3:6].[OH-:19].[Na+]>O.C(O)C>[F:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:5]([CH3:6])([CH3:7])[CH2:4][C:3]([OH:16])=[O:19])[CH:13]=1
Reactant: [OH-]
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(F)cc1C(C)(C)CC(=O)O
Temperature: 80 °C

Procedure:
A solution of 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (4.88 g, 18.6 mmol) was treated with sodium hydroxide solution (4 M in a mixture of 30% water in ethanol, 40 mL) at room temperature. The mixture was heated to 80° C. for 1 hour. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with three 100 mL portions of diethyl ether. The aqueous layer was treated with 150 mL of ethyl acetate and the resulting mixture was treated with 6 M HCl dropwise until the solution had a pH of 2. The phases were separated and the aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 3.92 g of 3-(5-fluoro-2-methylphenyl)-3-methylbutyric acid as an oil, which solidified upon standing and was used without further purification (quantitative yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:20])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)=O)C.[NH3:21]>CO>[Cl:20][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:21])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:10]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C)n1
Reactant: N
Solvent: CO
Product: Cc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Reaction time: 4 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (137 mg, 0.468 mmol) was suspended in 7M ammonia in methanol (3 mL). After 4 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (123 mg, 100%) as an off-white solid which was used directly in the next step without purification. LCMS (EI/CI) m/z: 264 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[S:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[S:25][CH:26]=1)[CH3:2]
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1csc(-c2ccc(C(C)C)cc2)n1)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as light brown solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11](=[O:38])[CH2:12][CH2:13][C:14]([CH3:37])=[CH:15][CH2:16][C:17]1[C:18]([O:30]CC[Si](C)(C)C)=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:30][C:18]1[C:17]([CH2:16][CH:15]=[C:14]([CH3:37])[CH2:13][CH2:12][C:11]([NH:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:38])=[C:25]([O:26][CH3:27])[C:24]([CH3:28])=[C:23]2[C:19]=1[C:20](=[O:29])[O:21][CH2:22]2
Reactant: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 9 %

Procedure:
To a solution of ({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonic acid diethyl ester (40 mg, 0.07 mmol) in acetonitrile (1 mL) was added TMSBr (91 μL, 0.7 mmol) followed by 2,6-lutidine (81.5 μL, 0.7 mmol). The reaction was allowed to proceed overnight when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 2.6 mg (9%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.67 (s, 3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H), 3.82 (s, 3H), 5.26 (s, 3H) ppm; 31P (121.4 MHz, CD3OD) δ 10.27 ppm; MS (m/z) 412 [M−H]−, 414 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.CC1C=CC(S([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:28]1(=[O:37])=[O:36])([CH3:40])([CH3:39])[CH3:41]
Reactant: COc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: COc1ccccc1OCCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Yield: 72 %

Procedure:
The title compound was prepared as described for Example 12 from 2-methoxyphenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. Purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.077 mg, 72%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.43-7.40 (m, 3H), 6.97-6.94 (m, 1H), 6.92-6.88 (m, 2H), 6.81 (dd, 1H), 5.88 (t, 1H), 3.94 (t, 2H), 3.89 (s, 3H, 3.14-3.09 (m, 2H), 1.88-1.84 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 149.9, 148.1, 135.6, 131.8, 129.7, 128.8, 125.5, 121.9, 120.9, 113.8, 111.9, 106.9, 67.5, 61.6, 55.9, 42.6, 29.1, 27.9; Mass Spectrum M+H+ 445.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[C:7](OC)[CH:8]=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[C:1]([CH:3]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][CH2:20][CH:19]1[C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)#[N:2]
Reactant: COc1cccc2c1C(C#N)C2
Reactant: C=Cc1ccc(OC)cc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C2CCc3ccccc3C2C#N)cc1
Reaction time: 12 h

Procedure:
A solution of 1-cyano-4-methoxybenzocyclobutene (7.5 g.; described in the Journal of the American Chemical Society, 1976, 98, 8185) and p-methoxystyrene (11.1 g.) in o-dichlorobenzene (40 ml.) was heated under reflux for 30 minutes under an atmosphere of argon and then evaporated to dryness, and the residue was purified by chromatography on a silica gel column using a 20:1 v/v mixture of toluene and ethyl acetate as eluant. A mixture of a solution of the residue (12.0 g.) in toluene (200 ml.), a solution of sodium hydroxide (20 g.) in water (200 ml.) and 40% w/v aqueous tetrabutylammonium hydroxide solution (1 ml.) was stirred vigorously under an atmosphere of argon at laboratory temperature for 12 hours and the layers were then separated. The aqueous layer was extracted twice with diethyl ether (100 ml. each time) and the combined organic solutions were washed with water, dried and evaporated to dryness. There was thus obtained as residue (1RS,2SR)-1-cyano-1,2,3,4-tetrahydro-2-p-methoxyphenylnaphthalene, m.p. 126°-131° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([CH3:13])[C:11]#[N:12].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([CH3:13])([CH3:9])[C:11]#[N:12])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(Br)cn1
Temperature: 70 °C

Procedure:
2,5-Dibromopyridine (2 g, 8.44 mmol) was placed in a vial that was evacuated and backfilled with argon three times. Anhydrous dioxane (8.4 ml) was then added and the suspension was stirred. In a separate vial, 2-methylpropanenitrile (0.76 ml, 8.44 mmol) was added to a solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (28.1 ml of 0.6 M in toluene, 16.9 mmol). This was stirred for 10 minutes then added to the suspension. The reaction was heated to 70° C. for 1.5 hours. It was then cooled to room temperature, quenched with water, and extracted with ethyl acetate. Purification was performed via silica gel chromatography (0-75% ethyl acetate in hexane) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][S:26]([NH2:29])(=[O:28])=[O:27]>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=[N:29][S:26]([CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=O)C1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=NS(=O)(=O)CC[Si](C)(C)C)C1
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A mixture of tert-butyl 6′-bromo-1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (0.2863 g, 0.8 mmol), 2-(trimethylsilyl)ethanesulfonamide (0.2000 g, 1.1 mmol), and Ti(OEt)4 (0.6900 g, 3.0 mmol) in 1,2-dichloroethane (3 mL) was heated at 110° C. for 20 h. The reaction mixture was then quenched with ice, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.4031 g (96%) of tert-butyl 6′-bromo-1′-(((2-(trimethylsilyl)ethyl)sulfonyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate. LC-MS tR=2.31 min in 3 min chromatography, m/z 515, 517 (MH), 459, 461 (MH+-56).
Reaction SMILES: [CH3:1][C:2]([CH:4](O)[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])=[CH2:3].[C:12](OCC)([O:17]CC)([O:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)CC>N1C=CC=CC=1>[CH3:1]/[C:2](=[CH:4]\[CH2:5][CH2:6][C:7](=[CH2:10])[CH:8]=[CH2:9])/[CH2:3][CH2:13][C:12]([O:14][CH2:15][CH3:16])=[O:17]
Reactant: CCOC(C)(OCC)OCC
Reactant: C=CC(=C)CCC(O)C(=C)C
Solvent: CCC(=O)O
Solvent: c1ccncc1
Product: C=CC(=C)CC/C=C(\C)CCC(=O)OCC
Temperature: 135 °C
Yield: 70.5 %

Procedure:
A mixture of 2-methyl-6-methylene-1,7-octadien-3-ol (34 g, 0.224 M), triethyl orthoacetate (80 g, 0.5 M) and propionic acid (1 ml) is heated at 135° C. (bath temperature) under nitrogen for four hours. The resulting mixture is cooled to room temperature and treated with pyridine (1 ml). Most of the excess reagent is removed in vacuo (high vacuum pump) and the residue is purified by column chromatography on silica gel (300 g) with 5% ether in petroleum ether, to give ethyl 4-methyl-8-methylene-(E)-4,9-decadienoate (35 g, 70%) as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].C(O)(=O)C1C=CC=CC=1.N1CCCCC1.Cl>C1(C)C=CC=CC=1>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[C:32](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14](=[CH:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=3)=[CH:26][CH:27]=2)[S:28]1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=C4SC(=O)NC4=O)cc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 39 (4.0 g, 11.2 mmol), thiazolidine-2,4-dione (1.31 g, 11.2 mmol), and benzoic acid (1.64 g, 13.4 mmol) in 100 mL toluene was added piperidine (1.66 mL, 16.8 mmol). The mixture was vigorously refluxed with Dean Stark apparatus for 1.5 h under argon then cooled to room temperature. 5% HCl was added to pH 1. The solid was filtered, recrystallized out of toluene, filtered, and washed with hexane before drying under vacuum to a yellow solid (quantitative). 1H NMR (400 MHz, DMSO-d6) δ 12.70 (br s, 1H), 12.59 (br s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.22 (d, J=9.2 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H), 7.12 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 76 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone, was converted to the title compound (105 mg, 76%) which was obtained as a yellow solid. MS: m/e=492.9 [M+OAc]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:38][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:13])=[C:8]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]=2[CH:18]=1
Reactant: COc1ccc2oc(C(=O)O)c(OC(C)C)c2c1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2oc(C(=O)NCc3ccccc3)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid (250 mg, 1.00 mmol) [Connor, et al., J. Med. Chem. 35, 935(1992)] and 1,1'-carbonyldiimidazole (211 mg, 1.30 mmol) in 7 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and benzylamine (0.66 mL, 6.00 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:3 to 1:1) provides 5-methoxy-3-(1-methylethoxy)-N-(phenylmethyl)-2-benzofurancarboxamide in 79% yield; mp=68°-69° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Cl.Cl[CH2:27][C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1>CN(C=O)C>[CH3:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][N:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:29]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c3ccccc3c3c(OCC#N)cccc32)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.143 g, 0.64 mmol)) is added to a slurry of pentane-washed NaH (0.0825 g, 0.0021 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 4-Chloromethyl-2-methylthiazole hydrochloride (0163 g, 0.89 mmol) is added and after stirring for 2 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80 and 40/60) and solids are crystallized from dichloromethane/ether to give 0.162 g (76%) of the title compound; MS (ESI+) for C19H15N3OS m/z 334.2 (M+H)+; IR (drift) 1581, 1459, 1440, 1341, 1333, 1275, 1228, 1215, 1182, 1157, 1151, 1113, 782, 754, 718 cm−1; 1H NMR (CDCl3) δ2.74, 5.09, 5.62, 6.38, 6.78, 7.19, 7.31, 7.44, 8.32. Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.27; H, 4.53; N, 12.33.