Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])C.O.Cl>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)c1
Yield: 79.4 %

Procedure:
To a solution of 1.61 g of (RS)-1-(2,2-diethoxyethyl)-3-(N′-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one in 40 ml of acetone were added 10 ml of water and 1 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into water, and the thus formed precipitate was collected by filtration and washed with ethyl ether to obtain 1.11 g (79%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:18]2[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=2)[N:3]=1.CCN(CC)CC.[CH3:35][C:36](OC(C)=O)=[O:37]>C(Cl)Cl>[C:36]([N:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:37])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Yield: 47.9 %

Procedure:
Prepared according to Example 50, using (R)-2-(2-methyl-3-(pyrrolidin-3-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 61, 135 mg, 0.372 mmol), Et3N (57.0 μl, 0.410 mmol), and Ac2O (70.3 μl, 0.745 mmol) in DCM (3.7 mL). Purification by trituration with Et2O provided 2-(3-(((3R)-1-acetyl-3-pyrrolidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (72 mg, 47.8%). 1H NMR (DMSO-d6) δ: 7.84-7.91 (m, 1H), 7.57-7.62 (m, 1H), 7.32-7.40 (m, 1H), 7.12-7.21 (m, 2H), 6.91-6.98 (m, 1H), 4.61-4.75 (m, 1H), 3.45-3.98 (m, 3H), 3.38-3.45 (m, 2H), 2.82-2.90 (m, 2H), 2.57 (s, 3H), 2.04-2.44 (m, 2H), 1.98 (s, 3H), 1.12-1.21 (m, 2H). m/z (ESI, +ve) 405.1 (M−H)+.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]O)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:1]1[CH2:3][CH2:2]1
Reactant: CC(C)NC(=O)NC(CCO)C1CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)NC(=O)NC(CCBr)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
The 1-(1-cyclopropyl-3-hydroxy-propyl)-3-isopropyl-urea (0.189 g, 0.950 mmol) was then dissolved in CH2Cl2 (10 mL) and CBr4 (0.477 g, 1.40 mmol) was added and the mixture was cooled to 0° C. To the mixture was added PPh3-polymer-bound resin (0.889 g, 1.40 mmol; 1.6 mmol/g) in portionwise. After stirring for at rt for 3 h, the mixture was diluted with CH2Cl2 (50 mL), filtered, and washed with CH2Cl2/MeOH/Acetone. The combined filtrates were concentrated in vacuo to give 1-(3-Bromo-1-cyclopropyl-propyl)-3-isopropyl-urea (0.212 g). GC-MS m/z 262.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:2].P(Cl)(Cl)(Cl)=O.[Cl:23][C:24]([Cl:29])(Cl)[C:25](Cl)=[O:26]>C(OCC)C.[Cu].[Zn]>[CH2:11]([O:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[CH:1]1[CH2:2][C:25](=[O:26])[C:24]1([Cl:29])[Cl:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=Cc1cc(F)ccc1OCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Zinc-copper couple (1.71 g, 13.1 mmol) was added to a solution of benzyl 2-ethenyl-4-fluorophenyl ether (C17) (1.0 g, 4.38 mmol) in diethyl ether (15 mL). To this mixture was added drop-wise a mixture of phosphorus oxychloride (446 μL, 4.82 mmol) and trichloroacetyl chloride (978 μL, 8.76 mmol) in diethyl ether (5 mL). The mixture was stirred at 40° C. for 2 hours, cooled to room temperature and stirred for an additional 18 hours. The solution was filtered through Celite, and the filtrate was washed with water (2×100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colorless oil. Yield: 1.4 g, 4.13 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 3.57 (dd, half of ABX pattern, J=18.0, 10.5 Hz, 1H), 3.65 (dd, half of ABX pattern, J=18.0, 9.4 Hz, 1H), 4.49 (dd, J=10.1, 9.8 Hz, 1H), 5.14 (AB quartet, JAB=12.0 Hz, ΔνAB=12.2 Hz, 2H), 6.91-6.95 (m, 2H), 7.01 (ddd, J=9.0, 7.8, 2.9 Hz, 1H), 7.32-7.44 (m, 3H), 7.45-7.49 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[C:16]1([CH:15]=[CH:14][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH:9]([CH3:10])[CH3:11])=[C:7]([OH:12])[CH:6]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)c1c(O)cc(C=Cc2ccccc2)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To the crude 1-(3,5-dimethoxy-4-i-propylphenyl)-2-phenylethene (18.07 g) in dry CH2Cl2 (100 mL) at −78° C. under N2 was added BBr3 (5.2 mL, 55 mmol) dropwise. After the reaction was stirred at −78° C. for 1 h, the temperature was allowed to rise to room temperature and the reaction mixture was stirred at room temperature for 2 days. Water was added to quench the reaction, followed by 20% NaOH to adjust pH>12. The organic layer was removed and the aqueous layer was washed with hexane (2×100 mL). The aqueous layer was acidified with 6N HCl to pH 1 and extracted with ether (3×200 mL). The organic layer was separated and washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of ether gave a red syrup. Recrystallization with chloroform yielded pure stilbene product 20B (6.92 g) as a white crystal. The mother liquid was concentrated and the residue was recrystallized once more to afford an additional 2.5 g of 20B (total 9.42 g, 67.7% over two steps). 1HNMR (CDCl3, ppm): δ 1.38 (d, J=7.3 Hz, 6H), 3.46 (hept., J=7.3 Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J=17.2 Hz, 1H), 6.97 (d, J=17.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([C:9]1[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:4]([O:6][C:7]([C:9]1[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(C)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
An acetonitrile (8.0 mL) mixture of ethyl-3-methyl-1H-pyrazole-5-carboxylate (15) (0.50 g. 3.2 mmol), benzyl bromide (0.48 mL, 4.0 mmol), and K2CO3 (0.90 g, 6.5 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of solvent under reduced pressure, the residue was purified by flash column chromatography [silica gel, eluting with mixtures of ethyl acetate and hexanes (0% ramped to 15% EtOAc/hexanes)] to yield 0.30 g of ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16). 1H NMR (CDCl3): δ 7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71(s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LCMS: purity: 99%; MS (m/z): 345(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1.[Li][CH3:29]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])([CH3:29])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C@H:11]([CH3:27])[CH2:10]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3F)C[C@H]2C)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(F)cc2F)CCN1S(=O)(=O)c1ccc(C(C)(C)O)cc1
Yield: 73 %

Procedure:
To a solution of (R)-1-(4-(4-(2,4-difluorophenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)ethanone (220 mg, 0.558 mmol, prepared according to procedures similar to those described in Example 29A in THF (3 mL) was added MeLi (0.42 mL, 1.6 M in THF, 0.67 mmol) at −78° C. The resultant mixture was stirred for 6 h then quenched with aq. NH4Cl and aq. layer. It was extracted with DCM. The organic layer was dried over Na2SO4. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the desired product as a white solid (167 mg, 73%). HRMS: calcd for C20H24F2N2O3S+H+, 411.15484. found (ESI-FTMS, [M+H]1+), 411.15477.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)=[N:7][C:8]=2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH3:2].O.NN>CO.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[N:5]=[C:4]3[C:9]=2[N:10]=[CH:11][N:3]3[CH2:1][CH3:2])=[CH:14][CH:15]=1
Reactant: CCn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCn1cnc2c(Nc3ccc(N)cc3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
A flask is charged with 12.15 g (30.57 mmol) of trans-4-[9-ethyl-6-(4-nitro-phenylamino)-9H-purin-2-yl-amino]-cyclohexanol in 1.15 l of methanol and kept under argon. At 40° C. Raney-Nickel is added slowly, followed by dropwise addition of 15.04 ml (50.06 mmol) of hydrazine monohydrate. After completion the reaction mixture is filtered, the filtrate concentrated and the crude product is purified by chromatography to obtain trans-4-[6-(4-amino-phenyl-amino)-9-ethyl-9H-purin-2-yl-amino]-cyclohexanol (74% yield); ESI-MS: 368 (M+H)+; tRet (HPLC) 7.48 min (method: same system as in method d, gradient 5®40% acetonitrile in 7,5 min.+12 min. 40% acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH:29]([CH2:32]OS(C)(=O)=O)[CH2:28]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][CH:29]2[CH2:30][CH2:31][NH:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCNC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid pyrrolidin-3-ylmethyl ester (described in WO 9742189) gave the title compound. ES-MS m/e (%): 450.2(M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[N+:5]([O-])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C(Cl)(=[O:17])C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]([CH2:7][OH:17])=[N:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)[n+]([O-])c1C
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ccccc2)nc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
7.1 g of 4,5-dimethyl-2-phenyl-1,2,3-triazol-1-oxide was dissolved in 25 ml of toluene, and heated to 80° C. 4.8 g of acetyl chloride diluted with 13 ml of toluene and 9.1 ml of triethylamine diluted with 13 ml of toluene were simultaneouly added dropwise thereto, keeping the temperature below 85° C. After stirring for 1 hour at 80° C., 2.5 ml of acetyl chloride diluted with 5 ml of toluene and 4.5 ml of triethylamine diluted with 5 ml of toluene were simultaneously added. After stirring for 1 hour at 80° C., the solution was left overnight at room temperature. 7 ml of 30% aqueous solution of sodium hydroxide was added, then toluene and triethylamine were distilled off under reduced pressure. 5 ml of ethanol and 30% aqueous solution of sodium hydroxide were added, and refluxed with heating for 1 hour. After ethanol was distilled off under reduced pressure, 50 ml of 10% saline solution was added, and left for some time at room temperature. The deposited crystals was dissolved in ethyl acetate, washed with water and a saturated salt solution, then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (hexan/ethyl acetate=1/2), then washed with hexan/diisopropyl ether (=10/1) to obtain 5.7 g of the aimed compound.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:34]1([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[N:6]1[S:41]([CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:43])=[O:42])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1OC2C(C(=O)N2C(C(=O)OCc2ccccc2)=C(C)C)N1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 105.9 %

Procedure:
To a solution of 500 mg of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 10 ml of tetrahydrofuran are added 0.27 ml of triethylamine and 343 mg of phenylmethanesulfonyl chloride under ice-cooling in nitrogen atmosphere, and the mixture stirred for 25 minutes. The reaction mixture is poured into ice water and extracted with ethyl acetate, and the extract washed with water, dried on sodium sulfate and concentrated under reduced pressure to yield 756 mg of benzyl α-(3ξ-carbomethoxy-2-phenylmethanesulfonyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate.
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[N:33]1([C:39]2[N:40]=[C:41]([CH2:46][C:47]([O-])=[O:48])[NH:42][C:43](=[O:45])[CH:44]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[Na+]>CN(C)C=O>[N:33]1([C:39]2[N:40]=[C:41]([CH2:46][C:47](=[O:48])[N:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:10]4([CH2:11][CH2:12][O:7][CH2:8][CH2:9]4)[CH2:13]3)[NH:42][C:43](=[O:45])[CH:44]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: c1ccc2c(c1)NCC21CCOCC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CC2(CCOCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 679 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 640 mg of 6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [OH:1]O.[F:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:15])C(=O)[NH:8]2.[OH-].[Na+].Cl>>[NH2:8][C:9]1[CH:10]=[C:11]([F:13])[CH:12]=[C:4]([F:3])[C:5]=1[C:6]([OH:15])=[O:1]
Reactant: O=C1Nc2cc(F)cc(F)c2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc(F)c1C(=O)O
Temperature: 70 °C

Procedure:
Hydrogen peroxide (35% solution in water, 23 ml) was added dropwise to a stirred solution of 4,6-difluoro-2,3-dioxoindoline (14 g) in a concentrated aqueous sodium hydroxide solution (33%, 115 ml) that was heated to 70° C. The mixture was heated to 70° C. for 15 minutes. The resultant mixture was cooled to 0° C. and the the mixture was acidified to pH4 by the addition of concentrated aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to give 2-amino-4,6-difluorobenzoic acid (12 g); NMR Spectrum: (DMSOd6) 6.25 (m, 1H), 6.38 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[S:12][C:13]1[C:18](=[O:19])[O:17][C:16]([C:28]2[CH:41]=[CH:40][C:31]([O:32][CH2:33][CH2:34]OS(C)(=O)=O)=[CH:30][CH:29]=2)([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C:14]=1[OH:42])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.Cl>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[S:12][C:13]1[C:18](=[O:19])[O:17][C:16]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:40][CH:41]=2)([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:15][C:14]=1[OH:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCOS(C)(=O)=O)cc3)OC2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCN4CCOCC4)cc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by combining methanesulfonic acid 2-{4-[5-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-oxo-2-phenethyl-3,6-dihydro-2H-pyran-2-yl]-phenoxy}-ethyl ester (0.07 g, 0.115 mmol) from the previous paragraph, K2CO3 (0.08 g, 0.57 mmol), and morpholine (0.15 mL, 1.72 mmol) in DMF (2 mL). The reaction was stirred overnight at room temperature then combined with H2O and acidified to pH 6.0 with 1N HCl. The product was extracted with EtOAc, dried (MgSO4) and concentrated. Purification by silica gel chromatography, eluting with MeOH:CH2Cl2 :hexane (3:50:50) gave the title compound, m.p. 140°-150° C. 1H NMR (CDCl3) δ 1.48 (s, 9 H), 1.80 (s, 3 H), 2.17-2.29 (m, 3 H), 2.38 (m, 1 H), 2.63 (m, 4 H), 2.84 (m, 2 H), 3.21 (dd, 2 H), 3.74 (m, 4 H), 4.00 (m, 2 H), 6.15 (s, 1 H), 6.78 (m, 2 H), 7.05 (d, 2 H), 7.10-7.22 (m, 5 H), 7.32 (d, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Compound A (4.5 g) was dissolved in pyridine (80 mL). Hydroxylamine hydrochloride (1.8 g, 26.4 mmol) was added, followed by sufficient water to dissolve the solids. The mixture was stirred at room temperature overnight. The solids were filtered, washed with water, and dried under vacuum to yield compound B (4.0 g).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Br[CH2:39][C:40]([N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]2([CH3:51])[CH3:50])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 30.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (26 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:47])[C@H:26]([CH2:45]O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:22][CH2:45][C@@H:26]([C:25]([OH:47])=[O:24])[NH2:27])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1ccc(C2(O)c3ccccc3Oc3ccccc32)cc1
Product: Cc1ccc(C2(OC[C@H](N)C(=O)O)c3ccccc3Oc3ccccc32)cc1

Procedure:
from 9-(4-methylphenyl)-9H-xanthen-9-ol (Example 1q) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: [CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[NH:12][CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1.[CH3:18][C:19]1[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=1[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[N:12]([C:28]([C:27]4[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]5[CH:33]=[CH:34][CH:35]=[CH:36][C:19]=5[CH3:18])=[CH:32][CH:31]=4)=[O:29])[CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1cn2c(n1)CNc1cc3c(cc1C2)OCO3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7,8-methylenedioxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.