Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].O[CH2:16][C@H:17]([NH:24]C(=O)OC(C)(C)C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[NH2:24][C@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C[C@H](N)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 1 g of N-methyl-2-nitrobenzenesulfonamide, 2.3 g of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate, 2.5 g of triphenylphosphine, 4.2 ml of diethyl azodicarboxylate, and 40 ml of toluene was stirred at 80° C. for 2 hours, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in chloroform was added silica gel, followed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in 3 ml of dichloromethane was added 3 ml of trifluoroacetic acid, followed by stirring for 1 hour. The solvent was evaporated under reduced pressure, and an aqueous sodium carbonate solution and chloroform were then added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 890 mg of N-[(2R)-2-amino-2-phenylethyl]-N-methyl-2-nitrobenzenesulfonamide.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].[C:88]([OH:105])(=[O:104])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH3:103]>CO>[CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[N:10]([C:11]([C@@H:13]([NH:21][C:22]([C@@H:24]([NH:29][C:30]([C@H:32]([NH:37][C:38]([C@@H:40]([NH:49][C:50]([C@@H:52]([NH:55][C:56]([C@@H:58]([NH:69][C:70]([C@@H:72]([NH:79][C:80]([C@H:82]2[NH:87][C:85](=[O:86])[CH2:84][CH2:83]2)=[O:81])[CH2:73][C:74]2[N:78]=[CH:77][NH:76][CH:75]=2)=[O:71])[CH2:59][C:60]2[C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=3[NH:62][CH:61]=2)=[O:57])[CH2:53][OH:54])=[O:51])[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)=[O:39])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5].[C:88]([O-:105])(=[O:104])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH3:103]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
A methanol solution containing 0. 1 mmol of leuprolide free base (prepared according to the method of Example 1) and 0.1 mmol of palmitic acid (SigmaChemical Co., P.O. Box 14508, St. Louis, Mo. 63178) was evaporated to dryness under s stream of dry nitrogen.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:27][C:28]1[C:29]([CH3:41])=[N:30][C:31]([CH3:40])=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)=O.O>CN(C=O)C>[CH2:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH2:27][C:28]3[C:29]([CH3:41])=[N:30][C:31]([CH3:40])=[CH:32][C:33]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:3]=2)[C:7]1=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Reactant: Cc1cc(-c2ccccc2)c(COS(C)(=O)=O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1Cc2cc(NCc3c(-c4ccccc4)cc(C)nc3C)ccc2C1=O
Reaction time: 8 h
Yield: 41.3 %

Procedure:
5-Amino-2-butylisoindolin-1-one (63.1 mg, 0.309 mmol), K2CO3 (85 mg, 0.618 mmol) and KI (51.3 mg, 0.309 mmol) were added to a solution of (2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (90 mg, 0.309 mmol) in DMF (6 mL). After stirring overnight, water was added, the mixture was extracted with EtOAc, the combined organic layers were washed with water and dried (MgSO4). Purification by flash chromatography (DCM/MeOH, gradient 2-8% MeOH) provided 2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one (51 mg, 40%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[OH-].[NH4+].[CH2:28](O)[CH3:29]>>[CH2:28]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH:14]=1)=[O:3])[CH3:29]
Reactant: CN1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 42 %

Procedure:
A solution of 0.513 gm (2 mMol) 5-carboxy-3-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)-1H-indole in 5.1 mL ethanol was cooled in an ice bath while 0.51 mL sulfuric acid was added dropwise. The resulting mixture was heated at reflux for 5 hours. The now homogeneous solution was poured into 50 mL cold water and was then made basic with saturated ammonium hydroxide. The light yellow precipitate was collected by filtration and then recrystallized from ethanol to provide 0.24 gm (42%) of the desired compound as light yellow crystals.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Clc1ccc(C(CNc2nc3ccccc3[nH]2)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2,2-bis(4-chlorophenyl)ethylamine (prepared by Procedure B from 2,2-bis(4-chloro-phenyl)acetaldehyde) by Procedure A (20 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 189-190° C.). MS(ES+) m/z 382 ([M+1]+, 100). 1NMR (DMSO-d6) δ 3.91 (m, 2H), 4.47 (t, 1H), 6.52 (m, 1H), 6.81-6.90 (m, 2H), 7.06-7.18 (m, 2H), 7.33-7.36 (m, 8H), 10.6 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH:38]([CH3:40])[CH3:39])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH:38]([O:37][C:33]1[C:30]2[C:31]([CH3:32])=[C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:41])=[O:2])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[CH:23][CH:22]=3)=[O:26])[O:28][C:29]=2[CH:36]=[CH:35][CH:34]=1)([CH3:40])[CH3:39]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(OC(C)C)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(OC(C)C)c12
Temperature: 25 °C
Reaction time: 144 h
Yield: 79.2 %

Procedure:
To 370 mg (S)-2-{4′-[(4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester dissolved in 2 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 6 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum to give 286 mg of (S)-2-{4′-[(4-isopropoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid, obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=13.5, 6.7 Hz, 6 H) 1.4 (d, J=6.1 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 3.5 (t, J=7.2 Hz, 1 H) 4.8 (m, 1 H) 6.9 (d, J=8.6 Hz, 1 H) 7.2 (d, J=8.6 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.8 (m, 4 H) 8.0 (m, 3 H) 10.5 (s, 1 H).
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[OH:12][C@@H:13]([CH2:18][O:19][C@H:20]([CH3:33])[CH2:21][O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:14](OC)=[O:15]>C1(C)C=CC=CC=1>[OH:12][C@@H:13]([CH2:18][O:19][C@H:20]([CH3:33])[CH2:21][O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[C:14]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:15]
Reactant: Nc1ccccn1
Reactant: COC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
Trimethylaluminium (2M in toluene) (2.99 ml, 5.98 mmol) was added to pyridin-2-amine (0.563 g, 5.98 mmol) in toluene (20.18 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (1 g, 2.99 mmol) (Intermediate AN1) in toluene (6.73 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 5 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 ml), then dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (0.657 g, 55.4%). 1H NMR (400 MHz, CDCl3) δ 1.03-1.17 (24H, m), 3.61-3.69 (3H, m), 3.82-3.86 (1H, m), 4.00-4.04 (1H, m), 4.13 (1H, d), 4.32 (1H, q), 7.02-7.06 (1H, m), 7.67-7.72 (1H, m), 8.23 (1H, d), 8.29-8.31 (1H, m), 9.20 (1H, s); m/z (ES+) (M+H)+=397.44; HPLC tR=3.36 min.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C(Cl)CCl>>[C:22]1([CH2:21][O:28][NH:29][C:7]([C:5]2[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=2)=[O:9])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc(C(=O)NOCc2ccccc2)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
To a solution of diethyl 1,3,5-benzenetricarboxylate (3.192 g, 20 mol) and O-benzylhydroxyamine hydrochloride (4.789 g, 19 mmol) in 40 mL were added N-methylmorpholine (2.2 mL, 20 mmol) and EDC (3.834 g, 20 mmol) at 0° C., and the mixture was stirred at room temperature for 20 hours. The solvent was removed by evaporator and the residue was dissolved in EtOAc (150 mL). The organic solution was washed with 1 N HCL (150 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4, and concentrated to give white solid. This material was recrystallized from EtOAc to give 4.154 g of white powder: 1H NMR (CDCl3) δ 1.41 (t, 6H), 4.40 (q, 4H), 5.05 (s, 2H), 7.3-7.5 (m, 5H), 8.52 (s, 2H), 8.76 (s, 1H), 9.1 (br, 1H). TLC: Rf 0.62 (EtOAc/Hexanes 1/1).
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]([O:13][C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][OH:28])[CH:21]=1)[CH2:16][CH3:17])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:9]([O:13][C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH:27]=[O:28])[CH:21]=1)[CH2:16][CH3:17])([CH3:10])([CH3:11])[CH3:12]
Reactant: CCN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
NMO (133 mg, 0.956 mmol) was added to a sol. of [2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-ethyl-carbamic acid tert-butyl ester (110 mg, 0.319 mmol) in CH2Cl2 (7.0 mL). The mixture was stirred for 30 min, and tetrapropylammonium perruthenate (11.2 mg, 0.032 mmol) was added. The mixture was stirred for 1 h at rt, and was filtered over Celite. The filtrate was evaporated under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 49:1) yielded the title compound (80 mg, 80%). LC-MS: tR=1.07 min.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.Br[CH2:33][CH:34](O)[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:15]=[CH:16][C:17]3[O:27][CH2:33][CH:34]([CH2:35][OH:36])[N:20]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[C:18]=3[N:19]=2)=[N:6]1
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: OCC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1COc2cnc(-c3nn(Cc4ccccc4F)c4ccccc34)nc2N1c1ccncc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
25 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.061 mmol, 1. eq.), 28.2 mg of 3-bromopropane-1,2-diol (0.182 mmol, 3 eq.) and 41.9 mg of potassium carbonate (0.303 mmol, 5 eq.) were suspended in 470 μl of dry DMF under nitrogen atmosphere. The reaction mixture was stirred at 100° C. bath temperature for 18 hours. Then the mixture was partitioned between aqueous half saturated sodium chloride solution and ethyl acetate. The phases were separated and the aqueous layer was extracted once with ethyl acetate and once with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC in dichloromethane/methanol 9:1 to yield 6.26 mg (0.01 mmol, 19.8%) of the analytically pure target compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([OH:13])=[O:12])[CH2:8]2.CO.[CH3:16][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[C:11]([O:13][CH3:16])=[O:12])[CH2:4]2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of adamantane-2-carboxylic acid 1 (0.486 g, 2.70 mmol) in ethyl acetate (10 mL)/methanol (5 mL) was dropwise added (trimethylsilyl)diazomethane (1.348 ml, 2.70 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated and purified by flash chromotography (silica 40 g, 0%-30% ethyl acetate/hexanes).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[CH2:4][N:3]1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.O1CCC[CH2:30]1.C([N-]C(C)C)(C)C.[Li+].IC>CCCCCCC.O.C(OCC)(=O)C>[CH3:30][CH:4]1[C:5]2[CH:6]=[C:7]3[O:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[C:2](=[O:1])[N:3]1[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3cc4c(cc3C2=O)OCO4)CC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC1c2cc3c(cc2C(=O)N1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCO3
Temperature: -12.5 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a reaction vessel, 30 g (0.077 mol) compound XII and 300 ml tetrahydrofuran were added under nitrogen, the mixture was cooled to −10-−15° C., 78 ml (0.16 mol, 2 mol/L) solution of lithium diisopropylamide in n-heptane was added dropwise for about 30 min, after the addition was complete, the reaction was kept at this temperature for 30 min, 4.8 ml (0.077 mol) iodomethane was added dropwise, after the addition was complete, the mixture was warmed to room temperature and stirred for 2 h, 600 ml ethyl acetate and 300 ml water were added, extracted, the organic layer was collected, dried over sodium sulfate, filtered, the filtrate was concentrated to dry under reduced pressure, separated by column chromatography, and 14.5 g compound XIII was obtained, with yield of 46.7%. 1H NMR (CDCl3): δ 1.07-1.21 (m, 2H), 1.41 (d, 3H, J=6.7 Hz), 1.45 (s, 10H), 1.55 (q, 2H, J=7.4 Hz), 1.66-1.69 (m, 1H), 1.80-1.83 (m, 1H), 2.64-2.71 (m, 2H), 3.17-3.24 (m, 1H), 3.92-4.00 (m, 1H), 4.06-4.09 (m, 2H), 4.41 (q, 1H, J=6.7 Hz), 6.05 (s, 2H), 6.82 (s, 1H), 7.20 (s, 1H); MS (ESI): m/z 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([N:12]([CH2:14][CH2:15][CH3:16])O)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.Cl>[Cl-].[Cl-].[Cl-].[Ti+3].CO>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:12][CH2:14][CH2:15][CH3:16])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: CCCN(O)C1CCc2c(Cl)ccnc2C1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: CCCNC1CCc2c(Cl)ccnc2C1

Procedure:
This compound was prepared from the product of Step 5 (5.8 g, 24 mmol) titanium trichloride, 20 wt. % solution in 20 wt. % hydrochloric acid (28 ml, 36 mmol), and methanol (50 ml) using the procedure described in Example 11. The crude amine (5.4 g) was converted directly into the product of Step 7.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:8]=2)[CH2:3]1.C1N=C[N:20](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([NH2:20])=[O:14])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
(R)-[4-(3-Oxo-cyclopentyl)-phenoxy]-acetic acid (preparation 31) (1.6 mmol, 375 mg) was dissolved in DMF (3 mL), then CDI (1.84 mmol, 299 mg) was added and the reaction mixture stirred at r.t. for 90 min. Ammonium hydroxide (25% aq, 7 mL) was added and a precipitate formed. Water (7 mL) was added and the precipitate filtered off and dried in vacuo to yield the title compound (302 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 7.25-7.14 (m, 2H), 6.97-6.83 (m, 2H), 6.78 (bs, 1H), 5.91 (bs, 1H), 4.49 (s, 2H), 3.52-3.28 (m, 1H), 2.77-2.57 (m, 1H), 2.57-2.11 (m, 5H), 2.09-1.79 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][C@H:28]3[CH3:47])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:29][C@H:28]3[CH3:47])[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H]1CN(C(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)CCN1c1ccc2ncn([C@H](C)c3ccc(Cl)cc3Cl)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(C(=O)[C@H]2CCCN2)CCN1c1ccc2ncn([C@H](C)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of the crude (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-3-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate in dichloromethane (2.0 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (5 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 20% 7 N ammonia/methanol in dichloromethane) to give the title compound as a white solid (0.011 g, 0.023 mmol, 21% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=2.8 Hz, 1 H), 7.69 (dd, J=4.0, 8.8 Hz, 1 H), 7.45 (dd, J=2.0, 2.0 Hz, 1 H), 7.14 (dd, J=2.0, 8.4 Hz, 1 H), 6.99-6.95 (m, 1 H), 6.83 (dd, J=4.8, 8.4 Hz, 1 H), 6.59 (dd, J=2.0, 18.4 Hz, 1 H), 5.90 (q, J=6.8 Hz, 1 H), 4.45-4.35 (m, 1 H), 3.82-3.43 (m, 4 H), 3.32-3.17 (m, 2 H), 3.11-2.94 (m, 2 H), 2.39-2.28 (m, 2 H), 1.98 (dd, J=2.4, 6.8 Hz, 3 H), 1.94-1.80 (m, 3 H), 0.90 and 0.81 (d, J=6.4 and 6.0 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+ 486.2. found 485.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH:32][CH3:33]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][N:32]([CH3:33])[CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: CN(C)CC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.069 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.3 mmol) and dimethylamine (0.14 g, 3.0 mmol). mp 199-201° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)[C:10]([CH3:33])([CH3:32])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:19]1[N:18]=[C:17]2[C:22]([N:23]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3([CH3:33])[CH3:32])[N:16]2[CH3:31])=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=1
Reactant: Cn1c(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(CN2CCNCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 1 h

Procedure:
To a solution of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (288 mg, 0.60 mmol) in DCM (30 mL) was added TFA (3 mL) and the mixture stirred at r.t for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (199 mg, 87%). 1H NMR (CDCl3, 400 MHz): δ 4.26 (4 H, brd s), 3.84-3.77 (9 H, m), 2.84 (2 H, t, J=4.87 Hz), 2.74 (2 H, s), 2.43 (2 H, t, J=4.89 Hz), 1.21 (6 H, s).