Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[NH2:10])[CH:6]=1.[CH2:18]([O:20][C:21]1[C:26](=[O:27])[NH:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[C:30]([F:38])[CH:29]=2)[CH:22]=1)[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:51].CCN(CC)CC>CN(C=O)C>[ClH:51].[CH2:18]([O:20][C:21]1[C:26](=[O:27])[NH:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:10][C:9]3[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=[C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)[CH:8]=3)=[O:36])=[C:30]([F:38])[CH:29]=2)[CH:22]=1)[CH3:19]
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(-n4cnc(C)c4)cc(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Product: Cl
Temperature: 50 °C
Reaction time: 12 h
Yield: 10.7 %

Procedure:
A suspension of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (6.63 mg, 0.027 mmol) in DMF (5 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (8 mg, 0.027 mmol) in DMF (5 mL). HOBt (6.31 mg, 0.041 mmol), EDC (7.90 mg, 0.041 mmol) and Et3N (0.011 mL, 0.082 mmol) were added and the mixture was stirred at 50° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield an off white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide, hydrochloride (1.60 mg, 2.90 μmol, 10.6% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 9.41 (d, J=1.54 Hz, 1H), 8.37-8.45 (m, 1H), 7.96 (s, 1H), 7.73-7.88 (m, 2H), 7.18-7.52 (m, 5H), 4.14 (q, J=7.06 Hz, 2H), 3.87 (s, 2H), 2.43 (s, 3H), 1.46 (t, J=6.95 Hz, 3H); ES-LCMS m/z 515.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:7][N:6]1[C:2]([NH:1][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:3]([NH:8][CH:9]=[O:10])[CH:4]=[N:5]1
Reactant: Cn1ncc(NC=O)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1ncc(NC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 52.7 %

Procedure:
The crude product of N-(5-amino-1-methyl-1H-pyrazol-4-yl)formamide (13.33 g) was dissolved in N,N-dimethylformamide (130 ml). To the solution were added trityl chloride (29.2 g), triethylamine (66.3 ml) and 4-dimethylaminopyridine (465 mg), and the mixture was stirred at 60° C. for 5 hours. To the reaction mixture was added water, and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a white solid. The solid was triturated with ethyl acetate/diisopropyl ether (1:1) to give N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]formamide (19.18 g). The NMR spectrum of this compound indicates the existence of its rotamer.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:1][O:2][N:3]=[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[N:29]([C@H:37]3[CH2:38][CH2:39][C@@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:41][CH2:42]3)[N:28]=2)=[CH:9][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON=C(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CON=C(c1ccccc1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A mixture of phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone O-methyloxime (intermediate AQ) (0.701 g, 0.0021 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.80 g, 0.0018 mol), tetrakis-(triphenylphosphine)palladium (0.125 g, 0.00011 mol) and sodium carbonate (0.48 g, 0.0045 mol) was heated in a mixture of ethylene glycol dimethyl ether (40 mL) and water (20 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (70 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime as a white solid (0.700 g, 0.00133 mol). Cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime (0.201 g, 0.00039 mol) was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.178 g, 0.0015 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate as a white solid (0.212 g, 0.00028 mol): 1H NMR (DMSO-d6, 400 MHz) 8.26 (s, 1H), 7.74 (d, 1H), 7.66 (d, 1H), 7.51 (m, 6H), 7.33 (d, 1H), 6.14 (s, 4H), 4.85 (m, 1H), 3.91 (s, 3H) 3.1 (br, 9H), 2.71 (s, 3H), 2.33 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H);
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([S:6][C:7]2[CH:24]=[CH:23][C:10]([CH2:11][NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=3[Cl:22])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:27]([N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[S:32]Cl)[CH2:28][CH2:29][CH3:30]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:27]([N:31]([CH2:34][CH2:35][CH2:36][CH3:37])[S:32][N:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([S:6][C:5]2[CH:25]=[CH:26][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:24][CH:23]=1)[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=1[Cl:22])=[O:14])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN(CCCC)SCl
Reactant: Cc1ccc(Sc2ccc(CNC(=O)c3c(Cl)c(C)nn3C)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCN(CCCC)SN(Cc1ccc(Sc2ccc(C)cc2)cc1)C(=O)c1c(Cl)c(C)nn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a stirred mixture of N-[4-(4-methylthiophenoxy)benzyl]-4-chloro-1,3-dimethylpyrazole-5-carboxamide (300 mg, 0.746 mM), 4-(N,N-dimethylamino)pyridine (119 mg, 0.970 mM) and dry pyridine (5 ml) was added dropwise N,N-di-n-butylaminosulfenyl chloride (190 mg, 0.970 mM) at 0°-10° C., and the mixture was stirred for 4 h at the room temperature. The mixture was poured into ice water, and the mixture was extracted with dichloromethane. The extract was washed with saturated ammonium chloride solution(x2) and brine, dried with sodium sulfate, and concentrated in vacuo. The residue was chromatographed over silica gel to give N-(N,N-di-n-butylaminosulfenyl)-N-[4-(4-methylthiophenoxy)benzyl]4-chloro-1,3-dimethylpyrazole-5-carboxamide (217 mg, 52%) as a colorless oil, nD23.3 1.5748.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([N:46]1[CH2:51][CH2:50][CH:49]([CH2:52][C:53](O)=[O:54])[CH2:48][CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:53]([CH2:52][CH:49]2[CH2:48][CH2:47][N:46]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:51][CH2:50]2)=[O:54])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)CC1
Yield: 66.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), N-Boc-4-piperidineacetic acid (AstaTech, Inc.) (365 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (441 mg). MS (ESI, pos. ion) m/z: 661 (M+1); (ESI, neg. ion) m/z: 590 (M−1). Calc'd for C33H45ClN4O6S: 661.25.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.CCCCCC.[K+].[Br-]>O>[C:22]([C:19]1[CH:20]=[CH:21][C:13]2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:14]=2[CH:18]=1)([O:24][CH3:25])=[O:23]
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-6-carbomethoxy-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 70% overall yield as a white solid, after trituration with hexane, IR (KBr) 3468, 2952, 1688, 1452, 1285, 1260, 765 cm-1 ; 1H NMR (CDCl3) δ 1.61 (br s, 1H plus HDO), 2.17-2.39 (m, 2H), 3.86 (s, 3H), 3.93 (t, J=5.7 Hz, 2H), 4.94 (dd, J=7.6, 5.5 Hz, 1H), 5.16 (s, 2H), 7.04 (d, J=8.4, 1H), 7.15-7.33 (m, 4H), 7.59 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.4, 1.8 Hz, 1H); MH+ at m/z=376; Anal. Calc'd for C19 H18ClNO5.0.1 H2O: C, 60.44; H, 4.86; N, 3.71. Found: C, 60.26; H, 4.60; N, 3.58.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1.CCCCCC>[Cl:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: O=C=O
Reactant: Clc1cc(Br)c2[nH]ncc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc2cn[nH]c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
463 mg (2 mmol) of 7-bromo-5-chloro-1H-indazol were dissolved in 12 ml THF. The so-lution was cooled to −78° C. under argon. 3.75 ml (6 mmol) of a 1.6 M butyl lithium solution in hexane were added slowly within 10 min. The reaction mixture was warmed to 5° C. and stirred for 30 min at this temperature. A suspension was obtained, which was cooled to −78° C. Solid carbon dioxide was added and the reaction mixture was warmed to rt. At 10° C. the suspension became a clear solution. The solvent was evaporated and the residue was treated with water and diethyl ether. The aqueous layer was extracted once with diethyl ether, acidified with 1N aqueous HCl solution. A white solid precipitated, which was filtered off and washed with water. The solid was suspended in diethyl ether/heptane in order to remove pentanoic acid. 130 mg (33%) of 5-chloro-1H-indazole-7-carboxylic acid were obtained as a white solid after filtration and drying. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:10])[CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:16](=O)([O-:37])[O:17][C:18]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:39]1([C:45]2[CH:50]=[CH:49][C:48](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.C1COCC1>[OH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[C@H:2]([N:1]([C:48]1[CH:47]=[CH:46][C:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:50][CH:49]=1)[C:16]([O:17][CH3:18])=[O:37])[C:3]([OH:5])=[O:4]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Reactant: CC(C)[C@@H](O)[C@H](N)C(=O)O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@H](C(=O)O)[C@H](O)C(C)C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a stirred diastereomeric mixture containing (2S*,3R*)-2-amino-3-hydroxy-4-methyl-pentanoic acid (0.156 g, 1.06 mmol) and NaHCO3 (0.09 g, 1.06 mmol) in H2O (5.0 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (1.4 g, 4.6 mmol) [prepared as for example 17, step 1] in THF (5.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.196 g, 52% over two steps), as a yellowish solid, which was used in the next step without further purification. MS (ESI) m/z: 375 [M−NH4]+; (ESI) m/z: 356 [M−H]−. 1H NMR (DMSO-d6) δ 0.82 (d, J=6.66 Hz, 3H), 0.92 (d, J=6.39 Hz, 3H), 1.54-1.70 (m, 1H), 3.51 (t, J=8.38 Hz, 1H), 4.20 (dd, J=2.88, 9.42 Hz, 1H), 4.63 (d, J=8.86 Hz, 1H), 5.11 (s, 2H), 6.94 (d, J=9.44 Hz, 1H), 7.37 (t, J=6.55 Hz, 1H), 7.44-7.52 (m, 4H), 7.63-7.75 (m, 4H), 12.57 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH:3]1([N:2]([CH3:1])[C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To an ice cold stirred solution of N-methylcylohexylamine (20 ml, 0.15 mol) and triethylamine (22 ml) in dry THF (100 ml) under argon was slowly added p-toluoyl chloride (20 ml, 0.15 mol). A white precipitate formed. The ice bath-was removed and. the mixture stirred at ambient temperature for 24 h. Ice cold 2M hydrochloric acid (100 ml) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (3×100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give the crude amide, which was crystallised from hexane to give N-cyclohexyl-N-methyl-4-methylbenzamide (30.9 g, 87%) as a white crystalline solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16]S(C1C=CC(C)=CC=1)(=O)=O.C(O)(=O)C>C(O)C.O>[CH3:31][O:30][C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[CH:29]=1)[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: COc1cc(COc2ccccc2OS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(COc2ccccc2O)cc(OC)c1
Yield: 75 %

Procedure:
A solution of potassium hydroxide (1.75 g, 31.26 mmol) in ethanol (30 cm3, absolute) and water (30 cm3) was added in portions 15 minutes apart to 1-[3,5-dimethoxy-benzyloxy]-2-[toluene-4-sulfonyloxy]benzene (0.68 g, 1.64 mmol). After heating to reflux for 1 hour, the cooled solution was neutralized with glacial acetic acid and evaporated under reduced pressure. The residue was extracted with diethyl ether (3×20 cm3), and the extracts were washed with sodium bicarbonate (40 cm3) and sodium hydroxide (3×20 cm3, 3% aqueous solution). The sodium hydroxide portion was saturated with solid carbon dioxide pellets, and the precipitate was removed by filtration to give the phenol (0.32 g, 74%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1.C1C(=O)N([I:30])C(=O)C1>CC(C)=O>[I:30][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:22])[NH:12][N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Solvent: CC(C)=O
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1[nH]c2ccccc2c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
577 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one is suspended in 30 mL acetone and 550 mg NIS is added. The reaction mixture is stirred for 3 hours at room temperature, the precipitated product isolated by filtration and washed with acetone. The material product is used without further purification
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:8][C@@:9]12[O:19][C@H:18]1[C@@H:17]1[O:20][C@@H:16]1[C:15]1[C:21]([O:23][C@H:13]([CH:14]=1)[C@@H:12]1[C:24]([C:26]([O:28][C@H:11]1[CH2:10]2)=[O:27])=[CH2:25])=[O:22]>CC(C)=O>[CH:1]([N:4]([CH2:25][CH:24]1[CH:12]2[CH:11]([CH2:10][C:9]3([CH3:8])[CH:18]([CH:17]4[CH:16]([C:15]5[C:21](=[O:22])[O:23][CH:13]2[CH:14]=5)[O:20]4)[O:19]3)[O:28][C:26]1=[O:27])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@H]12
Reactant: CC(C)NC(C)C
Solvent: CC(C)=O
Product: CC(C)N(CC1C(=O)OC2CC3(C)OC3C3OC3C3=CC(OC3=O)C21)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
Diisopropylamine (500 μmol; 70 μl) is added to a solution of mikanolide (100 μmol; 29 mg) in acetone (1 ml). The reaction mass is stirred for 30 minutes at ambient temperature then the solvent is eliminated by evaporation under reduced pressure. The residue is taken up in ether, filtered and dried under vacuum. 10 mg of product is obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][CH2:30]Br.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:21][CH2:28][O:29][CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCBr
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCOC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of ethyl 4-(benzyloxy)-2-hydroxy-6-methylbenzoate (15.0 g, 52.4 mmol) in DMF (100 mL) were added potassium carbonate (14.5 g, 105 mmol) and bromomethyl methyl ether (6.40 mL, 78.5 mmol), and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 4:1) to give the title compound (14.9 g, yield 86%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH3:10]N1CCOCC1.Cl[C:18]([O:20][CH2:21][CH:22]([CH3:24])C)=[O:19]>ClCCl>[CH3:10][CH:21]([O:20][C:18]([O:8][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:9])=[O:19])[CH2:22][CH3:24]
Reactant: CN1CCOCC1
Reactant: CC(=O)CCCC(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CCC(C)OC(=O)OCCCCC(C)=O

Procedure:
11.7 g (0.09 mole) of 5-ketohexanoic acid was dissolved in 100 ml of dichloromethane and cooled in an ice bath. 20.0 g (0.2 mole) of N-methylmorpholine was added to the reaction mixture which was stirred under nitrogen. 16.4 g (0.12 mole) of isobutyl chloroformate was dissolved in 25 ml of dichloromethane and slowly added to the reaction over 10 minutes. The reaction mixture continued to be stirred at 0° C., under nitrogen for one hour. The reaction mixture was evaporated in vacuo to an oily solid and used in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-])=O)=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3](=[O:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(N)ccc23)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of (E)-3-(4-{1-[2-(2-tert-butyl-6-nitro-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.70 g, 1.5 mmol) in ethanol (14 mL) and water (7 mL) was added iron powder (0.74 g, 13 mmol) and ammonium chloride (87 mg, 1.6 mmol) and the resulting mixture was stirred at 85° C. for 1 h. Additional iron powder (820 mg, 14.7 mmol), ethanol (6 mL) and water (3 mL) were added and the reaction was stirred at 85° C. for 50 h. The reaction mixture was filtered and concentrated in vacuo, and the residue was taken up in water. A brown solid precipitate was recovered via vacuum filtration to yield the title compound (0.40 g, 49% yield). LCMS (m/z): 446.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([NH:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21])=[O:16])[CH2:7][CH2:6]2.[OH-].[Na+]>CO.C1COCC1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH2:7][C:8]([C:15]([NH:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([OH:22])=[O:21])=[O:16])=[CH:9]2
Reactant: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CCC(C(=O)Nc1ccccc1C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred solution of methyl 2-(6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxamido)benzoate (440 mg, 1.2 mmol) in MeOH (6 mL) and THF (3 mL) was added 2N NaOH (3 mL) dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours, then quenched with 1N HCl and diluted with water. The resulting suspension was filtered and the solid was dried under vacuum to give 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoic acid (350 mg, 83%). 1H-NMR (400 MHz, DMSO-d6) δ 2.59 (t, J=8.4 Hz, 2H), 2.83 (t, J=8.4 Hz, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 6.90 (s, 1H), 6.97 (s, 1H), 7.15 (app t, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.62 (m, 1H), 8.03 (dd, J=8.0, 1.6 Hz, 1H), 8.69 (d, J=8.4 Hz, 1H), 11.89 (s, 1H); LC-MS (ES-API); rt 9.22 min; m/z calculated for C20H19NO5 [M+Na]+ 376.1, found 376.1.