Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1[N+:19]([O-])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=1[NH2:19])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: [H][H]
Reactant: CCOP(=O)(COc1ccc(C=O)cc1[N+](=O)[O-])OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(COc1ccc(CO)cc1N)OCC

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1 mmole) in methanol (5 mL) was treated with 10% palladium on carbon (0.05 mmole) under 1 atmosphere of hydrogen at room temperature for 12 h. Filtration followed by evaporation gave 2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was subjected to Step B of Example 29 followed by Step D of Example 27 to give 2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole (32.1). mp 181-184° C. Anal. calcd. for C10H10N3O5PS2+0.35H2O: C: 33.97; 11:3.05; N: 11.88. Found: C: 33.76; 11:2.66; N: 11.61.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:2].[H-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][Cl:22]>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[Br:18][CH2:19][CH2:20][CH2:21][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: ClCCCBr
Reactant: CCc1ccc2[nH]c3ccccc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)c1ccccc1n2CCCBr
Product: CCc1ccc2c(c1)c1ccccc1n2CCCCl
Yield: 76.7 %

Procedure:
The compound was synthesized in the same manner as in example 1. Treatment of 3-ethylcarbazole (2.0 g, 0.0102 mol) with NaH (0.27 g, 0.0112 mol) succeeded by the addition of 1-bromo-3-chloropropane (1.77 g, 0.0112 mol) in DMF gave the title compound 2.3 g (82%) as a yellow oil. 1H-NMR (δ, CDCl3): 1.35 (t, 3H); 2.4 (m, 2H); 2.8 (q, 2H); 3.35 (t, 1H); 3.45 (t, 1H); 4.35 (t, 2H); 7-7.4 (m, 4H); 7.9 (s, 2H); 8.1 (d, 2H). The product was isolated as an 1:1 mixture of the 3-bromo- and 3-chloro derivatives.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][C:7]3[C:18]([C:2]1=2)=[CH:17][C:10]1[CH2:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:9]=1[CH:8]=3.C[C:20]([CH3:23])([O-])[CH3:21].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CS(C)=O>[CH2:26]([C:11]1([CH2:17][CH2:18][CH2:2][CH2:3][CH2:4][CH2:21][CH2:20][CH3:23])[C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:9]2[C:10]1=[CH:17][C:18]1[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]=1[CH:8]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCBr
Reactant: c1cc2c(s1)-c1cc3c(cc1C2)-c1sccc1C3
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2cc3c(cc2-c2sccc21)C(CCCCCCCC)(CCCCCCCC)c1ccsc1-3
Temperature: 80 °C

Procedure:
To a 3-necked flask is added 4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene (3.0 g, 11.3 mmol) and anhydrous DMSO (60 cm3) and the mixture is degassed for 20 minutes. To this mixture is added sodium tert-butoxide (6.69 g, 68.9 mmol) portion wise and the mixture is heated to 80° C. 1-Bromooctane (12 cm3, 69.5 mmol) is added dropwise over 30 minutes ensuring the reaction mixture temperature did not rise above 90° C. The mixture is then heated at 85° C. for 3 hours. The mixture allowed to cool to 70° C. and poured into ice-water (100 cm3). The product is extracted with DCM (2×200 cm3) and the combined organics washed with water (3×200 cm3), dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The crude product is purified by column chromatography (eluent: petroleum ether 40-60) to yield the product as a yellow oil, which crystallised to a yellow solid (2.83 g, 28%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.27 (s, 2H, Ar—H), 7.25 (d, J=4.9 Hz, 2H, Ar—H), 6.96 (d, J=4.9 Hz, 2H, Ar—H), 1.79-2.02 (m, 8H, CH2), 1.02-1.34 (m, 40H, CH2), 0.71-0.93 (m, 20H, CH3 & CH2). 13C NMR (75 MHz; CDCl3): δ(ppm) 155.1, 153.2, 141.6, 135.6, 126.1, 121.7, 113.1, 53.7, 39.2, 31.8, 30.0, 29.33, 29.25, 24.2, 22.6, 14.1.
Reaction SMILES: Br[Si](C)(C)C.[C:6]([NH:9][C@@H:10]1[C@@H:15]([NH:16][C:17]([NH:26]C(OC(C)(C)C)=O)=[N:18]C(OC(C)(C)C)=O)[CH2:14][C:13]([P:34]([O:39]CC)(=[O:38])[O:35]CC)=[CH:12][C@H:11]1[O:42][CH:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=[O:8])[CH3:7]>C(Cl)(Cl)Cl>[C:6]([NH:9][C@@H:10]1[C@@H:15]([NH:16][C:17]([NH2:26])=[NH:18])[CH2:14][C:13]([P:34]([O-:39])(=[O:35])[O-:38])=[CH:12][C@H:11]1[O:42][CH:43]([CH2:44][CH3:45])[CH2:46][CH3:47])(=[O:8])[CH3:7].[NH4+:9].[NH4+:9]
Reactant: CCOP(=O)(OCC)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: CCC(CC)O[C@@H]1C=C(P(=O)([O-])[O-])C[C@H](NC(=N)N)[C@H]1NC(C)=O
Product: [NH4+]
Temperature: 25 °C
Reaction time: 24 h
Yield: 217.2 %

Procedure:
Bromotrimethylsilane (5 mL, 38 mmol) was added to a cold (0° C.) solution of 12b (287 mg, 0.46 mmol) in CHCl3 (20 mL). The mixture was stirred for 24 h at room temperature, and then concentrated under reduced pressure. The residue was taken up in water (15 mL), stirred for 2 h at room temperature, and subjected to lyophilization. The residue was purified on a C18 column (0.1 M aqueous NH4HCO3 solution) to afford ammonium phosphonate 13b (132 mg, 72% yield). White solid, mp 220-223° C.; [α]D20=−55.3 (c=1.5, H2O); IR (neat) 3512, 2901, 1716, 1101 cm−1; 1H NMR (600 MHz, D2O) δ 6.12 (1 H, d, JP-2=19.0 Hz), 4.12 (1 H, d, J=6.9 Hz), 3.80 (1 H, dd, J=10.0, 5.0 Hz), 3.71-3.62 (1 H, m), 3.41 (1 H, br s), 2.62-2.59 (1 H, m), 2.28-2.23 (1 H, m), 1.91 (3 H, s), 1.46-1.44 (3H, m), 1.34-1.28 (1 H, m), 0.77 (3 H, t, J=7.3 Hz), 0.72 (3 H, t, J=7.3 Hz); 13C NMR (150 MHz, D2O) δ 174.5, 156.6, 134.3 (C-1, d, JP-1=168 Hz), 132.7, 84.2, 76.3, 55.2, 51.0, 30.8, 25.5, 25.2, 21.8, 8.6, 8.2; 31P NMR (162 MHz, D2O) δ10.92; HRMS calcd for C14H26N4O5P [M+H−2 NH4]+: 361.1652, found: 361.1637. Anal. Calcd for C14H33N6O5P.(2H2O): C, 38.88; H, 8.62; N, 19.43. Found: C, 38.74; H, 8.71; N, 19.39.
Reaction SMILES: O=[C:2]([CH2:8]CC)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[CH3:7][C:6]1([CH:11]=[CH2:12])[O:5][C:3](=[O:4])[CH2:2][CH2:8]1
Reactant: CCCC(=O)C(=O)OCC
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC1(C)CCC(=O)O1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of ethyl 2-ketopentanoate (10 mL, 71 mmol) in 100 mL of THF at −78° C. was added dropwise a solution of 1.0 M vinyl magnesium bromide (80 mL, 80 mmol). After completion of the addition, the mixture was stirred for two more hours, the cooling bath was removed and the mixture was gradually warmed to ambient temperature. After the removal of the most of the solvent, the residue was poured to 2N HCl aqueous solution, extracted with ethyl acetate and dried over MgSO4. Purification by lash column chromatography on silica gel with DCM as elute afforded 4.80 grams of 5-methyl-5-vinyl-dihydro-furan-2-one. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.824-5.917 (dd, 1H); 5.29 (d, 1H); 5.13 (d, 1H); 2.50-2.56 m, (2H); 2.07-2.18 (m, 2H); 1.48 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: CCc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)Cn2c(=O)c3cc(CC)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-ethylphenyl)ethanone (0.88 g) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.87 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33](CN)[N:32]=1.C[CH2:40][N:41](C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:35]4[CH:36]=[CH:31][N:32]=[C:33]([NH:41][CH3:40])[N:34]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCc1nccc(Cl)n1
Solvent: C1COCCO1
Product: CNc1nccc(N2CCC(N(C)C(=O)c3ccc4c(c3)[C@H](NC(=O)c3ccccc3Cl)CC4)CC2)n1
Yield: 49 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (400 mg, 0.973 mmol, 1 eq), (4-chloropyrimidin-2-yl)methylamine (280 mg, 1.946 mmol, 2 eq) and DIPEA (0.33 ml, 1.946 mmol, 2 eq) in dioxane (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out and the residue was taken up in dichloromethane (100 ml) and washed with water (40 ml) and saturated sodium chloride solution (40 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane). The desired product was in the form of a white solid. Yield: 49% (250 mg, 0.482 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=[CH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][C:12](=[O:17])[CH2:11][C:9]([CH3:10])([CH3:8])[C:4]=2[CH:3]=1
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1(C)CC(=O)CC(C)(C)c2cc(Br)ccc21

Procedure:
47.1 g of bromobenzene and 37.8 g of phorone are stirred at room temperature for 48 hours in the presence of 40 g of aluminum trichloride in 600 ml of carbon disulfide. The reaction mixture is then poured on to ice, extracted with diethyl ether. The extract is washed with water, dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling) and ethyl acetate (9:1) and recrystallization from hexane, there is obtained 2-bromo-5,6,8,9-tetrahydro-5,5,9,9-tetramethyl-7H-benzocyclohepten-7-one of m.p. 104°-105°.
Reaction SMILES: C[CH:2]([B:7]([O:12][CH:13]([CH3:15])[CH3:14])OC(C)C)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][Li].Cl.[B].[CH2:25]=C(C)C>C(OCC)C>[CH2:2]([B:7]([C:19]#[C:18][C:17]([CH3:22])([CH3:21])[CH3:16])[O:12][CH:13]([CH3:14])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:25]
Reactant: C=C(C)C
Reactant: CCCCC(C)B(OC(C)C)OC(C)C
Reactant: [Li]CCC(C)(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCB(C#CC(C)(C)C)OC(C)C

Procedure:
n-Hexyl(3,3-dimethyl-1-butynyl)isopropoxyborane was prepared by adding 2-n-hexyl-diisopropoxyborane (8.35 g, 39 mmol) in ethyl ether (18 mL) to an ethyl ether solution of 3,3-dimethyl-1-butyllithium (44 mmol in 44 mL of ethyl ether), following the method of Example 14, and quenched with HCl in ethyl ether (12.87 mL, 44 mmol). Yield: 7.2 g (79%), bp 80°-82° C. (0.1 mm Hg); n20D 1.4265, boron NMR (ethyl ether)δ+40.6 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 237 (M+H, 7%); IR (thin film) 2186, 1327 cm-1. Anal. Calcd. for C15H29BO: C, 76.23; H, 12.38; B, 4.58. Found: C, 76.35; H, 12.02; B, 4.61.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[Sb](F)(F)(F)(F)F>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][CH:5]2[CH:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C:9]3([CH2:11][OH:12])[O:4][CH:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: F[Sb](F)(F)(F)F
Solvent: CC(C)=O
Product: CC1(C)OCC2OC3(CO)OC(C)(C)OC3C2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 164.6 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 65.0 mg of antimony pentafluoride, and the mixture was refluxed with stirring in a water bath of 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. The quantitative analysis of the reaction solution according to the same procedure as described in Example 14 showed that there was obtained 11.89 g (82.3%) of 2,3:4,6-di-O-isopropylidene-α-L-sorbofuranose.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:52]=[CH:51][C:42]2[C:43](=[O:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:47])(=[O:46])[C:41]=2[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:52]=[CH:51][C:42]2[C:43](=[O:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:46])(=[O:47])[C:41]=2[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)c2ccc(Br)cc2S1(=O)=O
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C(C)(C)C2=O
Yield: 91 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-bromo-2,2-dimethyl-1-benzothiophen-3(2H)-one 1,1-dioxide (Intermediate 241), the title compound was obtained in 91% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:13][C:12]([CH:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8][NH:7]1)=[O:14]
Reactant: CO
Reactant: O=C(O)C1Cc2cc(F)ccc2CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1Cc2cc(F)ccc2CN1

Procedure:
To a suspension of 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in methanol (500 mL) was added SOCl2 (50 mL). The reaction mixture was then refluxed for 1 h until LC-MS indicated the completion of the reaction. The mixture was concentrated, and the resulting residue was dissolved in a mixture of EtOAc (1 L) and sat. sodium bicarbonate solution (500 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give 6-fluoro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester as an oil (92 g). LRMS (M+H+) m/z 210.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:12]1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90348.4 %

Procedure:
Ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (1.6 g., 0.0064 mmol) is dissolved in tetrahydrofuran (40 mL). N-bromosuccinimide (1.14 g., 0.0064 mmol) is added in small portions at 25°-28° C. After the addition is complete, the solution is stirred overnight at room temperature. The solution is concentrated in vacuo and the solid residue partioned between water and ether. The ether layer is separated and dried over magnesium sulfate. Work-up of the ether extract leaves 1.9 g (90%) of a white solid which is purified by stirring with a mixture of 80/20 hexane/ethyl acetate. The insoluble solid (1.3 g, 62%) is collected and has m.p. 161°-164° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.CC(C)=O>O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 94 %

Procedure:
A mixture of sodium azide (9.5 g, 0.14 mol), 3-bromomethyl-3-hydroxymethyloxetane (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1H NMR 3.70 (s, 2H), 3.84 (d, J=4.9 Hz, 2H), 4.44 (s, 4H); NMR 44.283, 53,852, 64,073, 76.227.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[N+](C1C=CC=CC=1)([O-])=O.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[O:21]=[C:15]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cccs1
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 0.3 mole of thiophene in 100 ml. of nitrobenzene is added dropwise with stirring to a cooled mixture of 30 g. (0.3 mole) of succinic anhydride, 87.8 g. (0.66 mole) of aluminum chloride and 300 ml. of nitrobenzene. The mixture is cooled and stirred for 30 minutes and then allowed to stand at room temperature overnight. The mixture is poured onto ice and 50 ml. of concentrated hydrochloric acid. The nitrobenzene is removed by steam distillation. The aqueous layer is decanted and the residue is mixed with 650 ml. of water and 20 g. of sodium carbonate. The mixture is heated, mixed with diatomaceous earth and filtered. The filtrate is acidified with concentrated hydrochloric acid and the solid which separates is filtered and washed with water. Recrystallization from water gives 53% of 4-oxo-4-(2-thienyl)butyric acid, m.p. 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[N:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.CCN(C(C)C)C(C)C.[NH:27]1[C:31]([CH2:32][C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)=[N:30][N:29]=[N:28]1>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][C:31]4[NH:30][N:29]=[N:28][N:27]=4)[CH:34]=3)[N:12]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1cccc(Cc2nnn[nH]2)c1
Reactant: Clc1ncnc(-n2c(Cl)nc3ccccc32)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cc3nnn[nH]3)c2)n1
Temperature: 67.5 °C

Procedure:
To crude 2-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzimidazole was added DIEA (381 μl, 2.184 mmol) and then a solution of DMF (1 ml) and 3-(1H-tetrazol-5-ylmethyl)phenylamine (382.7 mg, 2.1845 mmol). The reaction was heated at 60-75° C. for 18 h. The reaction was cooled to RT and concentrated to a small volume. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 elution gradient, giving [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1H-tetrazol-5-ylmethyl)-phenyl]amine.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[S:29]1[CH2:33][CH:32]([C:34]([O:36]CC)=[O:35])[NH:31][CH2:30]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:31]2[CH:32]([C:34]([OH:36])=[O:35])[CH2:33][S:29][CH2:30]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CSCN1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)C1CSCN1C(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
One-tenth mole of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile to yield 3-[4-(16-bromohexadecylamino)benzoyl]-4-carboxythiazolidine. By means of the alkaline hydrolysis method of Example 10, the ethyl ester is converted to the subject carboxylic acid. This acid is also prepared using the procedure of this Example except that the acylation of the thiazolidine-4-carboxylic acid is carried out in aqueous acetone sodium bicarbonate solution.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:19][CH2:20][CH2:21]Br>CC#N>[Br:19][CH2:20][CH2:21][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1
Reactant: BrCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(OCCBr)cc1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenol (1 g, 5.61 mmole) in CH3CN (20 mL) was added Cs2CO3 (3.66 g, 11.23 mmole) then 1,2-dibromoethane (2.42 mL, 28.1 mmole). The mixture was heated to reflux. After 3 days the mixture was cooled to RT, filtered through a pad of Celite washing with CH2Cl2, and concentrated. Flash column (Biotage-SNAP-50 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (833 mg, 52%) as a clear liquid. 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J=8.7 Hz, 2 H); 6.95-6.88 (m, 2 H); 4.29 (m, 2 H); 3.64 (t, J=6.29 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.1 %

Procedure:
In a 10 ml flask, hydroxy-acetic acid methyl ester (0.4 ml, 0.53 mmol) was dissolved in tetrahydrofuran (1.5 ml), and then sodium hydride (23 mg, 0.57 mmol) was added thereto. After 40 minutes, 2-chloro-3-nitro-5-trifluoromethyl-pyridine (100 mg, 0.44 mmol) was added and then stirred for 2 hours at room temperature. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of n-hexane:ethyl acetate=9:1. The fractions containing the product were collected and evaporated to obtain white solid (84 mg, 68%).