Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.N[C@H](C(O)=O)C[SeH].[Li]CCCC.[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]=[O:59])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[N:44](C(OC(C)(C)C)=O)[C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1>CC1OCCC1>[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]([OH:59])[CH:12]3[CH2:11][CH2:10][CH2:9][N:8]3[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[NH:44][C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: CN(C)CCN(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: CCOc1nc2c(C(O)C3CCCN3C(=O)OC(C)(C)C)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
N-Boc-pyrrolidine (150 mg, 0.39 mmol) and TMEDA (0.2 mL, 158 mg, 1.36 mmol) was dissolved in dry MeTHF (2.6 mL) under Ar and cooled to −78° C. Sec-BuLi (1.4M, 0.97 mL, 1.36 mmol) was added dropwise and the reaction was allowed to stir at −78° C. for 40 mins. tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (150 mg, 0.39 mmol) was dissolved in MeTHF (0.5 mL) and added dropwise via syringe to the reaction and allowed to stir at −78° C. for 10 minutes. The reaction was quenched with water and extracted three times with EtOAc, combined organic layers were washed once with brine, concentrated, and purified by reverse-phase HPLC to give tert-butyl 2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (53 mg, 30%) as a white powder. The solid (50 mg, 0.11 mmol) was dissolved in EtOH (5 mL) and HCl (1 mL) and heated for 12 hours at 65° C. The reaction was cooled and concentrated to afford the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:21]([CH2:11][CH2:10][C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirred solution of 366 (810 mg, 1.88 mmol) in DMSO (4 mL) at RT was added NaCN (102 mg, 2.07 mmol) and the resulting mixture was stirred at 80° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The product was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 534 mgs (86%) of (R)-tert-butyl 3-cyano-1-(3,4-dichlorophenyl)propylcarbamate (368).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])[C:15](=O)[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([O-])=O.[Na+].Cl.[NH2:31][OH:32]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])/[C:15](=[N:31]/[OH:32])/[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H]1c2cn[nH]c2C(=O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@@H]1c2cn[nH]c2/C(=N\O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 62 (67 mg, 0.17 mmol) in a mixture of MeOH/H2O (5:1, 9 mL) was added NaOAc (141 mg, 1.7 mmol) followed by hydroxylamine hydrochloride (131.6 mg, 1.9 mmol). The resulting solution was stirred at room temperature for a weekend. The solvent was removed by rotary evaporation and the residue was taken up in EtOAc. The organic phase was washed with water, brine and dried (MgSO4). After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography to give a white solid as the product 63 1H NMR (CDCl3) δ 10.28 (bs, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 7.20 (d, J=9.0 Hz, 2H), 5.48 (dd, J=4.5, 10.5 Hz, 1H), 4.97 (t, J=7.5 Hz, 1H), 2.06-1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.57 (m, 1H), 1.22 (t, J=6.9 Hz, 3H), 114 (t, J=7.2 Hz, 3H); MS (m/z) 383.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:29][C:26]3[N:25]=[CH:24][C:23]([C:22]([F:31])([F:21])[F:30])=[CH:28][N:27]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: Nc1ncc(C(F)(F)F)cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3ncc(C(F)(F)F)cn3)cc2)C1
Temperature: 120 °C
Yield: 108.3 %

Procedure:
To a 10 ml glass vial was added (S)-2-(4-bromo-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (70 mg, CAS 1131220-37-5) and 5-trifluoromethyl-pyrimidin-2-ylamine (66.7 mg, CAS 69034-08-8) in dioxane (2 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.3 mg), tris(dibenzylideneacetone)dipalladium(0) (7.49 mg) and sodium tert-butoxide (21.6 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexanes) to afford (S)-2-[4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (94 mg, quant.) as an off-white solid. MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: [NH:1]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:7][N:6]=1)[C:2]([NH2:4])=[S:3].O=[C:16]([CH3:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.N>>[CH3:28][C:16]1[N:4]=[C:2]([NH:1][C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:7][N:6]=2)[S:3][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:22][CH:23]=1
Reactant: NC(=S)Nc1nnc(CCC(=O)O)s1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Agent: N
Product: Cc1nc(Nc2nnc(CCC(=O)O)s2)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
The titled compound is prepared from 3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid (56b) and from 4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) following procedures described for Example 1 using ammonia to prepare the sulfonamide.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:19]=1)(=O)C.N.C(Cl)Cl>CO>[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:5][OH:4])[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(F)Cn1c(CO)nc2c(N)nc3cccnc3c21
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A solution of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.13 g, 3.41 mmol) dissolved in 10 mL of methanol was treated with 10 mL of a 7% solution of ammonia in methanol. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting solid was treated with H2O and the mixture was heated to reflux for 15 minutes. The mixture was cooled and the resulting light-yellow solid was isolated by filtration. The light-yellow solid was then treated with 20 mL of CH2Cl2 and the mixture was stirred rapidly for several minutes. The mixture was filtered and the resulting white solid was washed with several portions of cold CH2Cl2 and dried with suction. Crystallization from ethanol/H2O gave 477 mg of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol as fluffy cream colored crystals, mp 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (dd, J=1.5, 4.3 Hz, 1H), 7.93 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (dd, J=4.3, 8.4 Hz, 1H), 6.92 (s, 2H), 5.62 (t, J=5.8 Hz, 1H), 5.33 (br s, 2H), 4.83 (d, J=4.7 Hz, 2H), 1.33 (d, J=20.3 Hz, 6H); 13C NMR (125 MHz, DMSO-d6) δ 154.3, 152.7, 143.1, 140.8, 134.2, 133.4, 133.2, 128.7, 122.5, 96.8 (d, J=170 Hz), 56.7 (d, J=9.5 Hz), 52.7 (d, J=21.4 Hz), 24.5; MS (ESI) m/z 290 (M+H)+; Anal. calcd for C14H16FN5O: C, 58.12; H, 5.57; N, 24.21. Found: C, 58.19; H, 5.54; N, 24.16.
Reaction SMILES: ClC(Cl)C.[CH3:5][N:6]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][C:14](=[O:17])[C:13]3=[O:18])=[C:8]2[CH2:7]1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:17]=[C:14]1[CH:13]2[O:18][CH2:27][CH2:28][O:29][C:11]3=[C:12]2[C:16](=[C:8]2[CH2:7][N:6]([CH3:5])[CH2:20][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]2=[CH:10]3)[NH:15]1
Reactant: OCCO
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)Cl
Product: CN1Cc2c(cc3c4c2NC(=O)C4OCCO3)C(c2ccccc2)C1

Procedure:
100 ml of dichloroethane are added to 20.6 g (0.0624 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione, 21 ml (0.374 mol) of ethylene glycol and 0.336 g (0.00176 mol) of toluene-4-sulphonic acid monohydrate, with stirring, and the mixture is heated under reflux for 3.5 hours, using a water separator. Ice is added to the reaction mixture and the mixture is brought to pH 6.8 with aqueous KHCO3 solution. The mixture is extracted with CH2Cl2, the CH2Cl2 phase is washed with H2O and dried over Na2SO4 and the solvent is stripped off in a rotary evaporator. The residue is chromatographed on Al2O3 (aluminum oxide from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate and MeOH (20:0.2). After trituration with ethyl acetate/petroleum ether, the substance becomes crystalline. It is dried over P2O5 at 80° C. in vacuo.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccnc2)cc1
Yield: 63.5 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.61 g) and 3-pyridinebutanamine (0.61 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual workup, the crude product was crystallized form ethyl acetate to provide 1.05 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 121°-123° C.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][NH2:13].C(O)(=O)C>CO.N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][N:13]=[C:3]([CH3:4])[CH2:2][OH:1]
Reactant: CC(=O)CO
Reactant: NOC1CCCCO1
Solvent: CO
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(CO)=NOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A mixture of 1-hydroxypropan-2-one (1 g, 13.5 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.9 g, 16.2 mmol) in methanol (20 mL) and pyridine (7 mL) was treated with acetic acid (0.23 mL, 4 mmol) and stirred at room temperature for 12 hours. The mixture was then concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extract was concentrated and purified by chromatography (SiO2, eluted with EtOAc-hexane-2:1) to afford 1.8 g of the title compound. MS (DCI/NH3) m/z 174 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH:11]([CH3:12])[CH3:13])[C:8](=[O:14])[CH2:7]2
Reactant: CC(C)N1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)N1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.854 g, 15.3 mmol) is added portionwise to a mixture of 7-fluoro-1-isopropyl-5-nitro-1,3-dihydro-indol-2-one (17, 0.91 g, 3.82 mmol) and ammonium chloride (2.04 g, 38.2 mmol) in ethanol (50 ml) and water (25 ml) at 90° C. The reaction is stirred vigorously and heated for 30 min, cooled to room temperature and diluted with dichloromethane (150 mL). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a solid. HPLC r.t. 2.97 min; MS for C11H13FN2O m/z 209.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([CH2:15][O:16][CH2:17]C)=[CH:8][C:5]=1[CH:6]=O)([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]([CH2:15][O:16][CH3:17])=[CH:8][C:5]=1[CH:6]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])[CH3:3]
Reactant: CCOCc1cc(C=O)c(C(C)C)cc1C(C)C
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(C=Nc2ccccc2)c(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A solution of 10.36 g (44.3 mmol) of the compound from Example 5, 4.06 g (44.6 mmol) of freshly distilled aniline and 0.3 g of p-toluenesulphonic acid in 370 ml of toluene is heated under reflux for 1.5 h in a water separator (molecular sieve 4 Å), diluted with ethyl acetate after cooling to room temperature, washed with saturated sodium hydrogencarbonate solution and water, dried using sodium sulphate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[CH3:30][NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:31][CH3:30])=[O:27])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (40 mg, 0.1 mmol) was reacted with methylamine (2M, 0.2 mL) in THF to provide 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-N-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide 139. LC/MS (ESI+): m/z 422 (M+H). 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.5, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.72 (t, J=10.9, 1H), 7.68-7.51 (m, 4H), 7.47-7.28 (m, 2H), 4.50 (t, J=15.6, 4H), 2.76 (d, J=4.5, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23](Cl)(=[O:25])=[O:24])([O-:15])=[O:14]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:23]([C:17]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:24])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)c2cccnc12
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Yield: 53.6 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloro-8-aminoquinoline (Intermediate 27) (150 mg, 0.84 mmol), 2-nitro-4-methylbenzenesulfonyl chloride (Intermediate 20) (228 mg, 1.26 mmol) gave the title compound (170 mg, 54%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=[C:1]([Br:5])[Br:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrC(Br)(Br)Br
Reactant: O=CCCOC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCCOC1CCCCC1
Yield: 73.4 %

Procedure:
Subsequently, to a solution of carbon tetrabromide (36.5 g, 0.11 mol) in dichloromethane (120 ml) was added a solution of triphenylphosphine (57.7 g, 0.22 mol) in dichloromethane (120 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred for 5 minutes. After stirring, to the reaction mixture was added a solution of the crude 3-cyclohexyloxypropionaldehyde (8.60 g) obtained above in dichloromethane (90 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 25 minutes. After stirring, the reaction mixture was diluted with dichloromethane and washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (100:1-33:1) as the eluent to afford 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, overall yield in two steps: 55%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1)=[O:21]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl piperidin-4-ylmethylcarbamate 93-1 (1.07 g, 5.0 mmol), 2-fluoroisonicotinic acid 93-2 (706 mg, 5.0 mmol) and HATU (1.90 g, 5.0 mmol) in DMF (20 mL) was added DIEA (2.5 mL, 15.0 mmol) at room temperature. The mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol in dichloromethane to give tert-butyl (1-(2-fluoroisonicotinoyl)piperidin-4-yl)methylcarbamate 93-3 as a pale yellow solid. MS m/z 338.1 (M+1)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]1=[O:16])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1ccccn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
1 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane is refluxed for 40 hours with I g of 2-hydroxypyridine in 10 ml of dioxane, in the presence of 0.20 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The mixture is taken up with 30 ml of water and the precipitate obtained is-filtered off, washed with isopropyl ether and then recrystallized from 20 ml of absolute ethyl alcohol to give 0.9 g of the expected product.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[C:8]([OH:17])(=[O:16])[C@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[OH:10].O1CCCC1>O>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:13]([C@H:11]([C@@H:9]([C:8]([O-:17])=[O:16])[OH:10])[OH:12])([O-:15])=[O:14]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: O=C(O)C1CCN1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]

Procedure:
The method described in Example 1 above was followed using DL-AzeOH (2.9 g; 29 mmol), D-tartaric acid (4.3 g; 29 mmol), tetrahydrofuran (5.5 g) and water (4.5 g) to yield 3.9 g (109%, as calculated from the theoretical yield) of L-AzeOH-D-tartrate with a d.e. of 65%.
Reaction SMILES: N1C=CC(C=O)=CC=1.Cl.[CH:10]1[CH:14]=[C:13]([CH:15]([C:22]2[NH:26][CH:25]=[CH:24][CH:23]=2)C2C=CN=CC=2)[NH:12][CH:11]=1.B(F)(F)F.Cl.C1COCC1>CO.N1C=CC=C1>[CH:24]1[CH:23]=[C:22]([CH2:15][C:13]2[NH:12][CH:11]=[CH:10][CH:14]=2)[NH:26][CH:25]=1
Reactant: c1c[nH]c(C(c2ccncc2)c2ccc[nH]2)c1
Agent: Cl
Agent: FB(F)F
Agent: O=Cc1ccncc1
Solvent: CO
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Product: c1c[nH]c(Cc2ccc[nH]2)c1

Procedure:
The earliest one-flask synthesis entailed reaction of 4-pyridine carboxaldehyde with 2.1 molar equiv of pyrrole in methanol acidified with gaseous HCl, whereupon the corresponding 5-(4-pyridyl)dipyrromethane precipitated as the hydrochloride salt.2 In most applications such precipitation is not possible, in which case all excess of pyrrole is employed to suppress the continued reaction leading to linear and cyclic oligomers. A number of reports in the early-mid 1990s described methods where the aldehyde (0.04–0.5 M) was treated with excess pyrrole (2.1–40 molar equiv) in an acidified organic solvent: BF3-etherate/CH2Cl2,3 acetic acid/DMF4 or THF,5 SnCl4/CH2Cl2,6 p-toluenesulfonic acid/MeOH7,8 or toluene,9 or aq. HCl/THF.10 Workup typically entailed several steps including column chromatography, though Hammel et al. employed flash chromatography followed by Kugelrohr distillation.3 In 1994, we reported a method that employed the reaction of the aldehyde (0.34 M) dissolved in neat pyrrole (˜14 M) with no other solvent, relying on column chromatography for purification (“1994 procedure”).11 Catalysis was achieved at room temperature with TFA or BF3.O(Et)2, or in some cases12 upon heating without added acid. The reaction proceeded in a few minutes at room temperature and afforded the dipyrromethane in yields of ˜40–60%, but the use of chromatography for purification limited the scale.