Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].OC1[CH2:38][C:37](C)([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]1.C([Sn](=O)CCCC)CCC.C(O)C>C1(C)C(C)=CC=CC=1>[C:28]([C:23]1[CH:22]=[C:21]([C:12]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)([CH3:20])[CH2:13][CH2:14][C:15]([O:17][CH:18]2[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:39])([CH3:38])[CH2:19]2)=[O:16])[CH:26]=[CH:25][C:24]=1[OH:27])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CC1(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 25 °C

Procedure:
8.5 g (0.02 mol) of ethyl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate and 3.1 g (0.02 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are dissolved in 200 ml of xylene. 0.1 g of dibutyltin oxide is added, and the mixture is heated at the boil under nitrogen for about 6 hours, during which the resulting ethanol is distilled off continuously. When no more ethanol distils off, the reaction solution is cooled down to room temperature, is admixed with 200 ml of water and is efficiently mixed. The organic phase is separated off, is dried over magnesium sulfate and is evaporated. The resulting oil is purified by column chromatography to give 2,2,6,6-tetramethylpiperidin-4-yl 4,4-bis-(3-tert.-butyl-4-hydroxyphenyl)-valerate in the form of a colourless solid having a melting point of 100°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:11]>CCO.O.O=[Pt]=O>[ClH:11].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccnc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CCCNC1C(=O)O
Temperature: 25 °C

Procedure:
3-Methylpicolinic acid (50 g, 365 mmol) was dissolved in 400 mL of EtOH:H2O (1:1) with 60 mL of aq. HCl (32%). PtO2 (5 g) was then added and the reaction stirred at rt under a hydrogen balloon until NMR indicated completion. The reaction was filtered through diatomaceous earth and concentrated to yield the title compound as a white solid which was used without further purification (60.5 g, 92%). 1H NMR (MeOD, 400 MHz) δ 4.13-4.11 (m, 1H), 3.40-3.33 (m, 1H), 3.05-2.99 (m, 1H), 2.61-2.58 (m, 1H), 1.92-1.72 (m, 4H), 1.09 (d, J=7.0 Hz, 3H). MS (ESI) 452.16 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1cccc(Oc2ccncc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccncc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-pyridyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(4-pyridyloxy)-phenyl]-1,8(2H,5H)-acridinedione. Purification by column chromatography on silica gel using dichloromethane/methanol (95:5) as the eluent gave a beige solid of melting point 186-188° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:5]1.Br[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1>CN(C)C=O>[CH:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:54]=[CH:55][C:46]=1[CH2:45][O:3][CH:4]1[CH:9]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:7][N:6]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:5]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
290 mg (6.05 mmol) of sodium hydride (50% dispersion in refined oil) were added to a solution of 2.08 g (3.78 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate and 1.0 g (4.54 mmol) of 2-bromomethylnaphthalene in 30 ml of dimethylformamide and the reaction mixture was stirred at room temperature for 2 hours. For the working-up, the reaction mixture was evaporated in an oil pump vacuum, the residue was partitioned between 100 ml of saturated ammonium chloride solution and 100 ml of ethyl acetate and thereafter the separated aqueous phase was extracted twice with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts were dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 2.27 g (87% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate as a colourless solid; MS: 707 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=O)[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl.[NH2:27][OH:28].C(=O)(O)[O-].[Na+]>C(O)C.C(O)C.ClCCl>[Cl:1][C:2]1[C:3]([C:17]([NH:19][C@@H:20]2[CH2:24][CH2:23][C:22](=[N:27][OH:28])[CH2:21]2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: NO
Reactant: O=C1CC[C@@H](NC(=O)c2noc(-c3ccc(C(F)(F)F)cc3)c2Cl)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=C(N[C@@H]1CCC(=NO)C1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl

Procedure:
A suspension of (R)-4-chloro-N-(3-oxocyclopentyl)-5-(4-(trifluoromethyl)phenyl) isoxazole-3-carboxamide (20 mg, 0.054 mmol), hydroxylamine hydrochloride (5 mg, 0.064 mmol), and sodium bicarbonate (7 mg, 0.083 mmol) in ethanol (2 mL) was heated to reflux overnight. The reaction mixture was diluted with ethanol/dichloromethane, filtered through a cotton plug and evaporated in vacuo. Purification by silica gel chromatography, eluting with 8% methanol in dichloromethane gave the title compound as a mixture of cis and trans isomers (10.5 mg, 0.027 mmol). MS (ESI) m/z (M+H+): 388.2/390.3
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:20][C:21]([NH2:26])([CH3:25])[CH2:22][O:23][CH3:24]>>[CH3:20][C:21]([NH:26][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)([CH3:25])[CH2:22][O:23][CH3:24]
Reactant: COCC(C)(C)N
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Product: COCC(C)(C)Nc1nc(Cl)nc2ccccc12
Yield: 13.2 %

Procedure:
A mixture of 2,4-dichloroquinazoline (995 mg, 5 mmol), triethylamine (0.7 ml, 5 mmol) and 1,1-dimethyl-2-methoxyethylamine (30 mL, 0.5M methanol sol., 15 mmol) was stood at room temperature for 1 week. The reaction mixture was concentrated and partitioned between ethyl acetate and water. Organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified on 50 g of silica gel column eluting with 50% ethyl acetate in hexane to obtain the title compound (176 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.CCN(CC)CC>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(O)c2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2c1
Yield: 74.2 %

Procedure:
Trifluoromethanesulfonic anhydride (9.35 g, 32.8 mmol) was added dropwise to a solution of 3-methoxy-1-naphthol (5.77 g, 32.8 mmol) and Et3N (10 ml) in dichloromethane (100 ml) at 0° C. with stirring. After 1 h the resulting solution was washed with HCl (50 ml, 1 M) and saturated Na2CO3 (50 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using EtOAc (7% in hexanes) to give the title compound (7.45 g, 74%) as a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH2:40][CH2:41][CH3:42]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using butyraldehyde. The final product was obtained in 13% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:4][C@H:5]2[C@:18]([CH3:20])([CH:19]=1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]2([O:22][CH2:23][CH2:24][O:25]2)[CH2:4][C@H:5]2[C@:18]([CH3:20])([CH:19]=1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2
Reactant: C[C@]12C=C(Cl)C3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12)OCCO3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: C[C@]12C=C(Cl)C3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)OCCO3
Yield: 100.6 %

Procedure:
5.0 g of 2-chloro-3,3-ethylenedioxy-5α-androst-1-en-17β-ol is stirred in 50 ml of dimethylformamide with 10 g of pyridinium dichromate for 17 hours at room temperature and then worked up as described in Example 10B. After evaporation, 5 g of 2-chloro-3,3-ethylenedioxy-5α-androst-1-en-17-one is obtained.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Reactant: CCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.36 ml (5.0 mmol) of 1-propanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The, residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1). After the solvent was distilled off, the residue was recrystallized from ether to yield 1.14 g (41.7%, white crystal) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:56](N2C=CN=C2)=[O:57])[CH2:51][CH2:50]1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:56]([NH:55][CH:52]3[CH2:51][CH2:50][N:49]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=4)[CH2:54][CH2:53]3)=[O:57])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (Preparation 30) by a similar method to Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([NH:23][N+]([O-])=O)=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1.NN>[Pd].C(O)C>[Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(N[N+](=O)[O-])cc1)N1Cc2ccc(Cl)n2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1

Procedure:
A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-nitroaminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2.5 mmol of anhydrous hydrazine, 50 mg of palladium on carbon and 10 ml of ethyl alcohol is refluxed for 1.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness to give the desired product as a solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[C:27]([OH:37])[CH:26]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:38])[C:25]1[CH:26]=[C:27]([O:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:30]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(O)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(Oc2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 40 %

Procedure:
A mixture of N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzamide (E2) (52 mg, 0.1 mmol), benzeneboronic acid (25 mg, 0.2 mmol), cupric acetate (18 mg, 0.1 mmol) and powdered 4 A molecular sieves in dichloromethane (1 ml) were treated with triethylamine (0.070 ml, 0.5 mmol). After stirring for 40 hrs at room temperature, the mixture was partitioned between ethyl acetate and 2N HCl and the product was extracted into ethyl acetate. The extracts were washed with sodium bicarbonate solution and brine and then dried (Na2SO4) and concentrated. Chromatography on silica gel (elution with ethyl acetate) gave E11 as a white solid (24 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[F:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>C1COCC1>[F:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[OH:23]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(C=O)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc3cc(OC)ccc3c2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 1953 %

Procedure:
n-Butyllithium (2.5 M, 16.9 mL) was added dropwise into a cold (−78° C.) solution of 2-bromo-6-methoxynaphthalene (10.0 g, 42.2 mmol), and THF (200 mL). The reaction mixture was stirred at −78° C. for 2 h, and then 2-fluoro-4-methoxybenzaldehyde (6.5 g, 42 2 mmol) in THF (10 mL) was added. The mixture was allowed to warm up to 0° C. stirred for 10 min, and then quenched with aqueous ammonium cholride. The mixture was poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave a brown solid (12.2 g, 93% yield, m.p. 68-69° C.); MS m/e 312 (M+).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1ccccc1I
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-2-trifluoromethyl-benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[C:37](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1CCNCC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Yield: 18.4 %

Procedure:
To 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.174 mmol) was added N,N-Dimethylformamide (DMF) (2 mL) and cesium carbonate (170 mg, 0.522 mmol). The mixture was then added iodomethane (0.014 mL, 0.226 mmol) and the reaction was let stir at room temp overnight. The reaction was then filtered using the syringe filter and the filtrate was then diluted with water (20 ml) then extracted with EtOAc (3×15 ml). The organics were combined, washed with brine, dried over MgSO4, filtered, concentrated and then loaded on to a 10 g Biotage SNAP column. Elution with 0 to 10% MeOH in DCM over 30 min gradient afforded 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methyl-4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (16 mg, 0.032 mmol, 18.30% yield) as a white solid. LC/MS (ES) m/z=503.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.08 (d, J=8.08 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.15-7.30 (m, 4H), 4.56 (d, J=3.54 Hz, 1H), 4.29 (t, J=8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 2.93 (br. s., 2H), 2.27 (s, 3H), 2.04-2.18 (m, 4H), 1.85-1.93 (m, 2H). NHs not observed.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])(=[O:18])=[O:17])=[O:14])[N:3]=1.C(O)C.[OH-].[K+]>O.Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:12][C:13]([NH:15][S:16]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])(=[O:17])=[O:18])=[O:14])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture containing 5 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate, 20 ml of ethanol, 2.5 ml of water and 2.5 g of potassium hydroxide is stirred at ambient temperature and pressure for 18 hours. The mixture is then diluted with water and 20 ml of concentrted hydrochloric acid added with stirring. The resulting precipitate is filtered, washed with water and dried.