Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](N)[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.C(O)(=[O:26])C>[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[C:4]([OH:26])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
A suspension of 1.0 g of 2,4-diamino-6[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 30 mL of 1N aqueous sodium hydroxide was heated under reflux under nitrogen for 3 hours. The resulting homogenous orange solution was cooled to room temperature, acidified with 6 mL of glacial acetic acid, and the resulting yellow precipitate collected by filtration. The filter cake was washed successively with water, methanol, acetone and ether and was then dried under reduced pressure to give 0.88 g (88%) of the title compound as a microcrystalline yellow powder, mp>250° C.; NMR (TFA-dl delta 6.8, 7.25 (AB q, 2H, J=12 Hz), 7.45, 8.2 (AB q, 4H, J=9 Hz), 8.55 (s, 1H), 8.85 (s, 1H); IR (Nujol) 3500-2500 (br), 1670, 1625, 1600 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH3:35])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][C@H:17]3[NH:22]C(=O)OC(C)(C)C)[N:9]=1)[CH3:2].[ClH:36]>O1CCOCC1>[ClH:36].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH3:35])[CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][C@H:17]3[NH2:22])[N:9]=1)[CH3:2]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@H]4N)no2)cc1OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To (R)-tert-butyl 4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-56 (150 mg, 0.312 mmol) in dioxane (1 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred at room temperature for 6 h, and product precipitated. The reaction mixture was diluted with Et2O and the solid collected by filtration to produce of (R)-4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride 65 (125 mg, 96%) as an off-white solid. LCMS-ESI (m/z): calcd for C22H25N3O3: 379.2; found 402.1 [M+Na]+, tR=2.38 min. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.90 (dt, J=8.2, 5.1 Hz, 2H), 4.81 (s, 1H), 4.35 (s, 2H), 4.01 (p, J=6.9 Hz, 4H), 3.36 (s, 2H), 3.22-3.04 (m, 1H), 2.55-2.43 (m, 2H), 2.05 (dd, J=14.0, 8.4 Hz, 1H), 1.32 (td, J=7.0, 4.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([C:24](OC)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
The crude ester 11 (0.85 g, 2.28 mmol) from the preceding procedure was dissolved in THF (25 mL) and added dropwise over 20 min to a stirred solution of DIBAL (9.1 mL of a 1M solution in toluene, 9.1 mmol) in THF (30 mL) under N2 at 0° C. The mixture was stirred for a further 30 min at 0° C., then poured into ice-cold 2 N HCl (40 mL) and extracted twice with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure below 30° C. and the residue was chromatographed on silica gel. Elution with CH2Cl2EtOAc (4:1) afforded a crude product which was crystallised from CH2Cl2 /iPr2O/petroleum ether to give 3-(tert-butyloxycarbonyl)-1-hydroxymethyl-5-nitro,1,2-dihydro-3H-benz[e]indole (12) (0.48 g, 61%). A sample recrystallised from iPr2O/petroleum ether had mp 176° C. 1H NMR (CDCl3) δ(br s, 1 H, H-9), 8.42 (br s, 1 H, H-7), 7.88 (d, J=7.9 Hz, 1 H, H-4), 7.62-7.51 (m, 2 H, H5,6), 4.30 (m, 1 H, H-2), 4.17 (dd, J=11.4, 9.5 Hz, 1 H, H-2), 4.04-3.93 (m, 2 H, H-3, CHHOH), 383-3.74 (m, 1 H, CHHOH), 1.61 (s, 9 H, C(CH3)3).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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:19]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
Reactant: OB(O)c1ccccc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3ccncc3c2)cc1
Temperature: 90 °C
Yield: 83 %

Procedure:
To a slurry of 7-(trifluoromethanesulfonyloxy)isoquinoline (prepared by the method of D. F. Ortwine et al., J. Med. Chem., 1992, 35, 1345) (2.1 g, 7.5 mmol) in toluene (20 ml) was added phenyl boronic acid (1.21 g, 10 mmol) and a 2M solution of sodium carbonate (15 ml). The reaction vessel was filled with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sodium carbonate solution (50 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using hexane/ethyl acetate (1:1) as eluant to give the title compound (1.27 g, 83%); δH (DMSO-d6) 7.41-7.88 (6H, m, ArH and isoquinolinyl H), 7.95 (1H, d, J 6.2 Hz, isoquinolinyl H), 8.14 (1H, dd, J 8.5, 1.75 Hz, isoquinolinyl H), 8.44 (1H, t, J 0.85 Hz, isoquinolinyl H), 8.52 (1H, d, 5.75 Hz, 3-H), and 9.31 (1H, s, 1-H); m/z (CI+, NH3) 206 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: C1COCCO1
Product: COC(=O)c1ccc(Cc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of 4-bromomethyl-benzoic acid methyl ester 17h (1 g, 4.37 mmol), 3-trifluoromethylphenylboronic acid 15b (1 g, 5.25 mmol) and Pd(PPh3)4 (50 mg, 0.044 mmol) in dioxane (15 mL) was stirred at room temperature for 1 min. An aqueous solution of Na2CO3 (2M, 4 mL) was added. The resulting solution was heated at 90° C. for 5 h and was then cooled to room temperature. The reaction was partitioned between EtOAc and water. The organic phase was concentrated and purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to give compound 17i.
Reaction SMILES: [C:1]([CH2:4][S:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:20][C:7]1=2)([OH:3])=O.[C:33]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([S:39]([NH:42][C:1]([CH2:4][S:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]3[CH:17]=[CH:18][C:19]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:20][C:7]2=3)=[O:3])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: NS(=O)(=O)c1ccccc1
Product: O=C(CSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21)NS(=O)(=O)c1ccccc1

Procedure:
11-Carboxymethylthio-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and benzensulfonamide were used and reacted in the same manner as in Example 39 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[O:10][CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[O:16][CH:15]([N:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]3=[O:24])[CH:14]([O:25][C:26](=[O:28])[CH3:27])[CH:13]2[OH:29])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:49](Cl)([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[O:16][CH:15]([N:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]3=[O:24])[CH:14]([O:25][C:26](=[O:28])[CH3:27])[CH:13]2[O:29][Si:49]([C:62]([CH3:65])([CH3:64])[CH3:63])([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(OC(C)=O)C2O)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(OC(C)=O)C2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The preparation of tert-butyldiphenylsilyl ethers is a common, routine procedure (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 141-144 and references therein, Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York). In general, a solution of one eq. of 7 and imidazole (3.5 eq.) in anhydrous N,N-dimethylformamide (DMF) is treated with tert-butyldiphenylsilyl chloride (1.2 eq.). After stirring at room temperature for several hours, the reaction mixture is poured into ethyl acetate and washed extensively with water and saturated brine solution. The resulting organic solution is dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography to give Compound 8.
Reaction SMILES: Cl[CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH:4]1([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH:2]=[CH:3]1
Reactant: ClC1CC(COCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C1=CC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
[[(3-Chlorocyclobutyl)methoxy]methyl]benzene (82 g, 0.39 mole) in 390 ml of dry dimethylsulfoxide was slowly added to a solution of potassium t-butoxide (132 g, 1.17 mole) in 390 ml of dry dimethylsulfoxide in a water-bath at 18° C. under a dry argon atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into 1600 ml of water and extracted with ether (3×1000 ml). The ether extracts were back-extracted with water (4×2000 ml) and the ether extract was then dried over sodium sulfate. The ether was removed in vacuo and the crude product was purified on a Merck silica column, eluting the column with 5% ethyl acetate-hexane. Appropriate fractions were combined and the solvents removed in vacuo yielding 60.0 g of the title compound as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](O)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([NH2:34])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:19])[NH:34][C:31]3[NH:30][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[C:33]=4[N:32]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)nc12
Yield: 9 %

Procedure:
6-(4-Methoxycarbonyl-1H-benzoimidazol-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (114 mg, 90%) was synthesized according to General Procedure A using 798 mg (2.82 mmol) of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester, 540 mg (2.82 mmol) of intermediate A (2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester), 1.28 g (3.38 mmol) of HBTU, 0.992 mL (5.64 mmol) of DIEA and 15 mL of DMF stirring at room temperature overnight. LCMS: 451 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[I:17]I>O>[C:1]([C:5]1[CH:11]=[C:10]([I:17])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(I)ccc1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 500 mL round-bottomed flask was combined 2-tert-butylaniline (7.46 g, 50 mmol) and sodium bicarbonate (7.56 g, 90 mmol) in water (50 mL). The mixture was cooled to 0° C. and iodine (12.69 g, 50.0 mmol) was added portion-wise over 20 minutes. The mixture was stirred for 16 hours at room temperature, partitioned between ethyl acetate and 10% aqueous sodium thiosulfate and stirred vigorously for 20 minutes. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil that was purified on an Isco 120 g silica cartridge eluting with ethyl acetate/hexane (0% to 10%) to give the title compound.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]3[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=3)[CH2:3][CH2:2]2)=[N:10][CH:11]=1
Reactant: C1CNCCNC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Yield: 65.5 %

Procedure:
To a solution of hexahydro-1,4-diazepine (2.84 g, 28.4 mmol) in dimethylformamide (14 mL) were added 2,5-dibromopyridine (16.23 g, 68.5 mmol) and potassium carbonate powdered in a mortar (8.00 g, 57.9 mmol), and the resultant mixture was stirred at 120° for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals of the title compound (7.67 g, yield: 66%). The crude crystals were recrystallized from chloroform-hexane to give colorless fine needles (melting point: 178.0-181.0° C.).
Reaction SMILES: C[NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:13]C1C=CC(C(Cl)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:13][C:7]1[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=1[S:3]([NH2:2])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(N)(=O)=O)c(C)c1

Procedure:
N-Methyl-4-methylbenzene sulfonamide (3.70 g, 0.02 mol) and 4-methylbenzoyl chloride (3.08 g, 0.02 mol) were dissolved in xylene and refluxed for 72 hrs. After evaporation of the xylene, the residue was dissolved in ethyl acetate and washed with dilute sodium carbonate solution. After separation, drying over anhydrous magnesium sulfate and evaporation of the solvent in vacuo, the residue was recrystallized from hexane-ethyl acetate to give N-4-methylbenzoyl-N*-methyl-4-methylbenzene sulfonamide mp 90–92° C. MS m/z 303. (M+ calcd for C16H17NO3S=303). H NMR (300 Mhz, CDCl3) d 2.30 (s, 3, CH3), 2.46 (s, 3, CH3), 7.21 (m, 2, aromatic), 7.35 (m, 2, aromatic), 7.49 (m, 2, aromatic), 7.84 (m, 2, aromatic).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:9]Cl>>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][N:5]=1
Reactant: N#Cc1cccnc1
Reactant: ClCl
Product: N#Cc1ccc(Cl)nc1

Procedure:
passing a vaporized feed stream including 3-cyanopyridine, chlorine and an inert gas into a first reaction zone having a hot spot at a temperature of about 350° C. to about 420° C., and subsequently passing the stream through a second reaction zone having a temperature of about 200° C. to about 340° C., so as to produce 2-chloro-5-cyanopyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[P:34](Cl)([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][P:34]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C=O)c1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1C=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.03 g 3C in 20 mL anhydrous dichloromethane in an ice-water bath were added 0.60 ml triethylamine and 0.48 mL diethyl chlorophosphate. The mixture was kept in the ice-water bath for 1 hour and then kept at room temperature overnight. After wash with water, with brine and drying with anhydrous sodium sulfate, the mixture was concentrated to an oily liquid and then purified by flash column chromatography (0.1% Et3N/20% EtOAc/CH2Cl2). The desired orthoformylated phosphotyrosine (3D) was obtained as colorless oil (1.21 g, 85%). 1H NMR (CDCl3, 200 MHz): δ 10.37 (s, 1H), 7.64 (s, 1H), 7.43-7.31 (m, 7H), 5.28 (d, J=7.7 Hz, 1H), 5.11 (s, 2H), 4.66 (m, 1H), 4.33-4.18 (m, 4H), 3.75 (s, 3H), 3.21 (dd, J1=14.1 Hz, J2=5.6 Hz, 1H), 3.09 (dd, J1=14.1 Hz, J2=6.1 Hz, 1H), 1.37 (m, 6H). 13C NMR (CDCl3, 50 MHz): δ 188.3, 171.4, 155.5, 152.0 (d), 136.5, 136.1, 133.4, 129.3, 128.6, 128.3, 128.1, 127.2 (d), 121.3, 67.1, 65.2 (d), 54.7, 52.6, 37.4, 16.1 (d). 31P NMR (CDCl3, 81 MHz): δ −6.4.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)C.[OH-].[Na+]>CCO>[CH2:19]([CH:5]([CH2:6][C:7]1[C:8](=[O:18])[O:9][C:10]2[C:15]([C:16]=1[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([OH:26])=[O:3])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)Cc1c(O)c2ccccc2oc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester (160 mg) in EtOH (1 mL) was added 1N NaOH (1.36 mL). The resulting mixture was heated to 50° C. and stirred for 2 hours, cooled to room temperature, acidified with Conc. HCl/ice and extracted with ether. The organic layer was dried over MgSO4 and conc. in vacuo to give 2-Benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid as a pale yellow solid (120 mg). MS: 323[M−H].
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13](O)[C:12]=2[CH:18]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[CH:18]=1
Reactant: COc1ccc2c(c1)C(O)CCO2
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulfonyl chloride (14.9 ml) is added dropwise to a stirred solution of the product obtained in Step 1. (31.6 g) and triethylamine (29.3 ml) in methylene chloride (750 ml) cooled to 0° C. under nitrogen. The reaction mixture is stirred at RT for 21/2 hours and cooled to 0° C. Piperidine (175 ml) is added to the cooled reaction mixture and the solution stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the solution and the mixture is stirred for 30 minutes. The organic layer is separated, washed with sat'd NaCl and dried. The solution is filtered and the filtrate evaporated in vacuo yielding the desired product as its hydrochloride salt.
Reaction SMILES: [NH:1]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3][C:2]1=[O:14].[BH4-].[Na+]>C(O)C>[OH:13][CH:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCC(=O)c2ccccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCC(O)c2ccccc2N1

Procedure:
A solution of 4,5-dihydro-1-benzazocin-2,6-(1H,3H)dione (14.2 g), Tetrahedron Letters 4079-4082 (1976), and sodium borohydride (1.4 g) in ethanol (720 ml) is stirred at room temperature for 18 hours. The ethanol is removed under reduced pressure, and the residue dissolved in dichloromethane (350 ml). The solution is extracted with 2N hydrochloric acid (2×200 ml) and saturated brine (100 ml), and dried over sodium sulfate. The solvent is removed under reduced pressure to give 6-hydroxy-3,4,5,6-tetrahydro-1-benzazocin-2-(1H)-one.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)(=[O:26])[CH2:24][OH:25].N1C=CN=C1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([O:9][C:24](=[O:25])[CH2:23][OH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: O=C(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Acetylthio-2-methylpropanoic acid (6.48 g) is taken into 40 ml of dry tetrahydrofuran. To this 1,1'-carbonyldiimidazole (0.48 g) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g) and 11.2 ml of triethylamine in 60 ml of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo. The residue is taken up into ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo. This product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating by the addition of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120°-122°. This salt is then converted to the free acid, O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid by adding to ethyl acetate, adding 10% potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50°-51°.