Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:37][CH2:38][C:39]1[C:40]([OH:47])=[N:41][C:42]([CH3:46])=[CH:43][C:44]=1[CH3:45]>ClCCl.C(N(CC)CC)C>[OH:47][C:40]1[C:39]([CH2:38][NH:37][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])=[CH:14][CH:13]=2)=[C:44]([CH3:45])[CH:43]=[C:42]([CH3:46])[N:41]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCCC(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 4-(pentan-2-yl)benzoic acid (192 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol), 1-hydroxybenzotriazole t (202 mg, 1.5 mmol), triethylamine (0.5 mL) and dichloromethane (15.0 mL) was stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added to the above mixture. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (20 ml×2). The organic phase was dried by sodium sulphate. The mixture was filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methane=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(pentan-2-yl)benzamide as a white solid (100 mg, 40%). LRMS (M+H+) m/z: 326.2. found 326. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.26 (t, J=4.5 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.23 (m, J=8.1 Hz, 2H), 5.85 (s, 1H), 4.29 (d, J=4.5 Hz, 2H), 2.76-2.69 (m, 1H), 2.17 (s, 3H), 2.11 (s, 3H), 1.54-1.47 (m, 2H), 1.18-1.05 (m, 5H), 0.81 (t, J=14.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][CH2:20]O)[CH2:14]1>>[I:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:20][CH2:19][CH:15]2[O:16][CH2:17][CH2:18][N:13]([CH3:12])[CH2:14]2)[N:6]=1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CN1CCOC(CCO)C1
Product: CN1CCOC(CCn2nc(I)c3cc(F)ccc32)C1
Yield: 80 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 2-(4-methylmorpholin-2-yl)ethanol in 80% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=[C:13]2[F:16])=[CH:4][CH:3]=1.[CH2:26]([O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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:16][C:13]1[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:11]=3[CH:12]=1)=[CH:4][CH:3]=[C:2]([C:36]1[CH:37]=[N:38][C:33]([O:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=1)[CH:15]=2
Reactant: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(Br)ccc12
Reactant: CCCCCCOc1ccc(B(O)O)cn1
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
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc2c(c1)cc(F)c1cc(-c3ccc(OCCCCCC)nc3)ccc12

Procedure:
From 7-bromo-9-fluoro-2-octyloxyphenanthrene by reaction with 6-hexyloxypyridine-3-boronic acid, sodium carbonate and tetrakis(triphenylphosphine)palladium(0) in toluene/ethanol/H2O.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:24].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:32]=[C:33]1[CH2:38][S:37][C:36]2[CH:39]=[CH:40][C:41]([CH:43]=O)=[N:42][C:35]=2[NH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[OH:24][C@@H:3]1[CH2:4][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:6][C@@H:2]1[NH:1][CH2:43][C:41]1[CH:40]=[CH:39][C:36]2[S:37][CH2:38][C:33](=[O:32])[NH:34][C:35]=2[N:42]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (40 mg, 0.122 mmol) in DCM-EtOH (1.5 mL, 1:1) at 25° C. were added Na2SO4 (35 mg, 0.244 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (24 mg, 0.122 mmol). After 12 h, NaBH(OAc)3 was added and after stirring an additional 2 h the solution was partitioned between NaHCO3 (sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1% NH4OH)) yielding the title compound (29 mg, 47%) as a yellow foam: LCMS (ES) m/e 507 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=5.2 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.47 (s, 2H), 3.21-3.27 (m, 1H), 1.91-2.10 (m, 4H), 1.75-1.78 (m, 4H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58]([NH:65][CH2:66][CH:67]1[CH2:70][CH2:69][NH:68]1)([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>CN(C=O)C.CC(=O)OCC>[C:61]([O:60][C:58](=[O:59])[NH:65][CH2:66][CH:67]1[CH2:70][CH2:69][N:68]1[C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])([CH3:64])([CH3:62])[CH3:63]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN1C(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a mixture of 2-biphenylcarboxylic acid (107 mg), PyBOP (280 mg), DIEA (0.215 mL) in dry DMF (0.5 mL), was added a solution of 2-(N-Boc-aminomethyl)azetidine (100 mg) in dry DMF (0.5 mL). The resulting reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted once again with EA, the combined organic extracts were dried (MgSO4), filtered and concentrated to yield the crude product as light brown oil. FC (EA) gave 140 mg (71%) of the title compound as a light yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCO2
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
2,3-Dihydrobenzofuran (36 g, 0.3 mol) was added to glacial acetic acid (100 mL), heated to 65° C., then concentrated nitric acid (25 mL, 0.36 mol) was added dropwise into the reaction solution, the temperature of the reaction solution was controlled at 65-75° C. After the end of dropwise addition, the agitation was kept for 0.5 h. It was then cooled to room temperature, filtered, washed with water, and dried to obtain a product (22 g, 44.4%).
Reaction SMILES: [O:1]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:53])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][CH:44]=2)[CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:32][O:33][C:34](=[O:53])[C:35]1[CH:40]=[C:39]([O:12][C@@H:10]([CH3:11])[CH2:9][O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:38]=[C:37]([O:42][C:43]2[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[CH:45][CH:44]=2)[CH:36]=1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After then adding 11.8 g (62.1 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 16.3 g (62.1 mmol) of triphenylphosphine to a solution of 10.0 g (31.0 mmol) of the obtained 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methyl ester in tetrahydrofuran (200 ml), 33.8 ml (77.6 mmol) of a solution of diethyl azodicarboxylate in 40% toluene was added while cooling on ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=8:2) to obtain 5-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1([CH2:12]O)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:20])CC)C.C(=O)(O)[O-].[Na+].Cl>CCOC(C)=O.C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1([CH2:12][F:20])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)C1(CO)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)C1(CF)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a round-bottom flask equipped with a stir bar was added N-(tert-butyl)-1-(hydroxymethyl)cyclopropane-1-sulfonamide (8.66 g, 41.8 mmol) and CH2Cl2 (110 mL). The stirred solution was cooled to 0° C. and to the solution was added (diethylamino)sulfur trifluoride (11 mL, 84 mmol). The solution was allowed to warm to room temperature with stirring for 4 h. The solution was then slowly added to a stirred sat. aq. sodium bicarbonate (100 mL) and following the addition stirring was maintained for 18 h. The pH of the aqueous phase was adjusted to pH=4 using aq. HCl. The mixture was transferred to a separatory funnel and was twice extracted with CH2Cl2. The combined organics were washed with brine; dried over MgSO4; filtered; and then concentrated in vacuo to afford a brown solid residue. This material was subjected to SiO2 chromatography (hexanes:EtOAc, 90:10 to 40:60) to afford N-(tert-butyl)-1-(fluoromethyl)cyclopropane-1-sulfonamide as a colorless, crystalline solid (5.66 g, 65%). 1H NMR (400 MHz, CDCl3) δ 4.73 (s, 1H), 4.60 (s, 1H), 4.22 (br. s., 1H), 1.59-1.53 (m, 2H), 1.37 (s, 9H), 1.12-1.07 (m, 2H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCN3CCCC3)C(=O)C3CC3)cc(Cl)c1O2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.44 mL, 4.8 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) and the reaction mixture was stirred at 55° C. for 2 h. It was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.280 g, (81.63%); 1H NMR (DMSO-d6): δ 0.71 (bs, 2H, CH2), 0.88 (bs, 2H, CH2), 1.87 (bs, 2H, CH2), 2.01 (bs, 2H, CH2), 2.70 (s, 3H, CH3), 3.00 (bs, 2H, CH2), 3.18 (bs, 2H, CH2), 3.57 (bs, 2H, CH2), 3.70 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.04 (bs, 2H, CH2), 5.38 (s, 2H, CH2), 7.78 (s, 1H, Ar), 7.98 (s, 1H, Ar), 8.19 (s, 1H, Ar), 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:44]([O:46]C)=[O:45])[CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[C:31]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:30]([CH3:43])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C@@H:26]([C:44]([OH:46])=[O:45])[CH2:27][C:28]3[CH:33]=[C:32]([CH3:34])[C:31]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:30]([CH3:43])[CH:29]=3)=[O:24])[CH2:21][CH2:22]2)[C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OCc2ccccc2)c(C)c1)OC(=O)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 250 mg (10.42 mmol) LiOH in 10 mL water was added to a solution of 2.50 g (4.11 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the reaction mixture was stirred for 2 h at RT. The organic solvent was removed i.vac., the aqueous residue was acidified with 2 M HCL and combined with EtOAc/DCM (2:1). The precipitate formed was filtered off and dried.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=O>C1(C)C=CC=CC=1.O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)nn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Trimethylaluminium (0.72 mL of a 2 M solution in toluene, 1.44 mmol) was added dropwise to a stirred solution of isopropylamine (85 mg, 1.44 mmol) in dioxane (3 mL) at room temperature under argon. After 1 h, a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. After 2 h the reaction mixture was cooled in an ice/water bath and quenched with Seignette salt solution (1 mL). The resultant mixture was filtered, the filter cake washed with dichloromethane, then the combined filtrates were concentrated then purified by chromatography (silica, 0 to 80% ethyl acetate in heptane) to give the title compound (45 mg, 38%) as a colourless oil. MS: m/e=333.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8])([O-])=O.Cl.[OH-].[Na+]>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:8]
Reactant: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1N
Yield: 0.1 %

Procedure:
5-(3-nitro-4-n-heptylbenzoyl)pentanoic acid (0.7 g; 2.1 mole) is stirred overnight at room temperature in a mixture of stannous chloride (1.35 g) and concentrated hydrochloric acid (1.8 ml). The reaction product is mixed with excess 1M sodium hydroxide and washed with ether. The aqueous phase is acidified to pH 5 with dilute hydrochloric acid. The precipitate is collected and recrystallized from aqueous ethanol to give 5-(3-amino-4-n-heptylbenzoyl)pentanoic acid (0.46 g) as a cream colored crystalline solid, m.p. 100°-102° C. The structure is confirmed by NMR and IR spectroscopy.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=O)C1C=CC=CC=1>C(O)C>[CH3:20][S:17]([CH2:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)C[C@@H]1CCCN1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of 0.86 g (2.9 mmol) (S)-2-methanesulfonylmethyl-pyrrolidine-1-carboxylic acid benzyl ester in 15 ml ethanol was deoxygenated by three cycles of evacuation and flushing with argon. After addition of 0.15 g palladium on charcoal (10%) the reaction vessel was evacuated and filled with hydrogen gas. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen over night. Filtration over decalite and evaporation of the solvent in vacuo gave 0.44 g (93%) of the crude title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), tert-butyl 4-aminobutanoate hydrochloride (20.88 mg, 0.107 mmol), and TEA (0.037 mL, 0.267 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=479.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[CH3:59][NH:60][O:61][CH3:62]>C(Cl)Cl>[CH3:62][O:61][N:60]([CH3:59])[C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:17]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a cold (0° C.) solution of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (5.00 g, 20.6 mmol) in CH2Cl2 (50 mL) including triethylamine (3.1 mL, 22.2 mmol) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (10.7 g, 20.6 mmol), N,O-dimethylhydroxyamine hydrochloride (2.21 g, 20.6 mmol) and Et3N (3.2 mL, 23.0 mmol) successively. The resulting mixture was allowed to warm to room temperature, and the stirring was continued for 18 hrs. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1:1) to give tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate as a colorless oil (5.39 g, yield; 92%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CS(C)=O.C1COCC1.O>[OH:3][N:2]=[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([OH:11])[CH:13]=1)[NH2:16]
Reactant: NO
Reactant: N#Cc1cccc(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NC(=NO)c1cccc(O)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 15.84 g (0.228 mol) of hydroxylamine hydrochloride in 75 ml of DMSO there are added 32 ml (0.228 mol) of triethylamine. The solution is stirred vigorously for 30 minutes and is then diluted with a small amount of THF. After stirring for 10 minutes, the triethylamine hydrochloride is filtered off and the residue is rinsed with THF. After the filtrate has been concentrated (evaporating off the THF), 10 g (83.9 mmol) of 3-hydroxybenzonitrile are added to the solution obtained. The solution is stirred at ambient temperature for 16 hours. After diluting with cold water, the mixture is extracted 3 times with ethyl acetate and the organic phase is washed with brine. The expected product is obtained after drying over MgSO4 and evaporation.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11]C)=O.C(OCC)(=O)C.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:5][C:6]1[CH:7]=[C:8]([C:9]2([OH:11])[CH2:2][CH2:1]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethylmagnesium bromide (3M solution in diethyl ether, 54.4 ml) was added at room temperature to a solution of methyl 3-bromo-4-methoxybenzoate (CAS No. 35450-37-4, 10 g) and titanium (IV) isopropoxide (23.9 ml) in THF (100 ml). The reaction mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture and the precipitate was removed through Celite. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (7.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]NC(=O)CCCCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: CCCCCC(=O)NCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-chloro-2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone is reacted with N-chlorohexanoamide to form 5-chloro-2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone.