Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:5]1[CH:10]([OH:11])[CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[C:25]([OH:27])=[O:26])(C)(C)C.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[CH2:23]([O:22][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:8][CH2:7][N:6]([C:25]([O:27][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:26])[CH2:5][CH:10]2[O:11][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:13][CH:14]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)CCc1ccc(C2CCN(C(=O)O)C(C(C)(C)C)C2O)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(=O)CCc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
Analogously to the procedure described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-hydroxy-piperidine-1-carboxylic acid with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate; MS: 518 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[C:12](=[O:13])[CH2:11][CH2:10][C@H:6]2[C:7]([OH:9])=O)[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:44][C:45]1[C:50]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:55][NH2:56].C(=O)([O-])O.[Na+]>ClCCl>[Cl:44][C:45]1[C:50]([C:51]([F:53])([F:54])[F:52])=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:55][NH:56][C:7](=[O:9])[C@@H:6]1[CH2:10][CH2:11][C:12](=[O:13])[N:5]1[CH:1]1[CH2:2][CH2:3][CH2:4]1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1C1CCC1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1C1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
1-Cyclobutyl-5-oxoproline (0.238 g, 0.82 mmol) was suspended in dichloromethane (3 ml) and to this was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.188 g, 0.98 mmol), 1-Hydroxybenzotriazole (0.132 g, 0.98 mmol), and N-ethyl morpholine (0.313 ml, 2.46 mmol). The mixture was stirred at room temperature for 30 minutes and then {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.205 g, 0.98 mmol) was added to the mixture and stirring continued for ˜20 hrs at room temperature. The mixture was then diluted with more dichloromethane and treated with saturated aqueous sodium hydrogen carbonate. The dichloromethane layer was separated and the aqueous layer was extracted with 3 further aliquots of dichloromethane. The combined organic extracts were washed with water and then with brine, dried over anhydrous magnesium sulphate and evaporated in vacuo to give the crude product. This was further purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-cyclobutyl-5-oxoprolinamide (0.105 g) as a white solid.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[CH3:24][N:25]([CH3:33])[CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[Br:16][C:17]1[C:18]([F:23])=[C:19]([C:29]2([OH:32])[CH2:30][CH2:31][CH:26]([N:25]([CH3:33])[CH3:24])[CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccccc1Br
Reactant: CN(C)C1CCC(=O)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Product: CN(C)C1CCC(O)(c2cccc(Br)c2F)CC1

Procedure:
Add n-BuLi (20.2 mL, 1.6M in hexanes, 32.3 mmol) into a solution of 2,2,6,6-tetramethyl-piperidine (4.56 g, 32.6 mmol) in hexanes (30 mL) at −78° C. Add 1-bromo-2-fluoro-benzene (4.71 g, 26.9 mmol) and stir for 1 hr. Slowly add 4-dimethylamino-cyclohexanone (3.80 mL) in hexanes (30 mL) and stir for 1 hr. Remove the cooling bath and stir for two more hours. Partition the reaction mixture between saturated aqueous NaCl and ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient) to give the title compound (2.04 g): MS (ES): m/z=318 (M+H)+ and 316 (M−H)−. 1HNMR (CDCl3): δ 7.43 (m, 2H), 6.98 (m, 1H), 2.45 (m, 2H), 2.21 (s, 6H), 2.13 (m, 1H), 1.92 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-methoxy-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M28) (293 mg, 0.61 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (180 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CO>O>[CH:23]([N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:5][N:2]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:3]5)[CH:27]=[CH:26][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: NC(=O)CBr
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(CC(N)=O)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 181 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.33 (s, 1 H); 8.21-8.14 (m, 2 H); 8.04 (s, 1 H); 7.21 (dd, J=8.42, 1.92 Hz, 2 H); 7.12-7.02 (m, 2 H); 5.44-5.36 (m, 1 H); 4.32 (t, J=5.05 Hz, 2 H); 3.80-3.61 (m, 3 H); 3.30 (t, J=7.44 Hz, 2 H); 3.16-3.09 (m, 4 H); 1.52 (d, J=6.59 Hz, 6 H). LCMS: RT=6.49 min, M+H+=408
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14](F)(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH3:18]>C1COCC1>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:18])(=[O:16])=[O:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(F)c1ccccc1S(=O)(=O)N1CCC1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1S(=O)(=O)N1CCC1

Procedure:
In a 1-1 flask was placed 9.8 g of 2-(azetidin-1-ylsulfonyl)benzenesulfonyl fluoride and 500 ml of THF. Then 9 ml of ammonia was added and the mixture was refluxed for two days. Four 25 ml portions of liquid ammonia were then added to the refluxing solution over a 48 hour period. The reaction mixture was concentrated and the residue chromatographed on silica gel (dichloroethane). The desired product was collected to give 4.9 g of a solid m.p. 121°-123° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][NH:2][C:36]([C:33]1([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:35][CH2:34]1)=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)NCCc3c(-c4ccccc4)c4cc(OC)ccc4c(=O)n3C)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (70 mg, 0.20 mmol) in 3 mL of dimethylformamide was added 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (0.39 mg, 0.20 mmol), triethylamine (0.085 mL, 0.61 mmol), 1-hydroxybenzotriazole hydrate (37 mg, 0.24 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (47 mg, 0.24 mmol). After three hours, the mixture was partitioned between EtOAc and water, and the organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was triturated with ether-hexane solution to provide the titled product. HRMS (ES) exact mass calculated for C30H30N2O4 (M+H+): 483.2258. Found 483.2279.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:27])[C:8]2[N:9]=[CH:10][N:11]([CH2:14][O:15][CH:16]([CH2:22][O:23]C(=O)C)[CH2:17][O:18]C(=O)C)[C:12]=2[N:13]=1)(=O)C>CN>[OH:18][CH2:17][CH:16]([O:15][CH2:14][N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:27])[NH:6][C:5]([NH2:4])=[N:13][C:12]1=2)[CH2:22][OH:23]
Reactant: CC(=O)Nc1nc2c(ncn2COC(COC(C)=O)COC(C)=O)c(=O)[nH]1
Agent: CN
Product: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1

Procedure:
A solution of 838 mg (2.2 mmole) of 2-acetamido-9-(1,3-diacetoxy-2-propoxymethyl)hypoxanthine in 8.5 ml of 40% methylamine (aqueous) was stirred at gentle reflux under N2 for 1 hour. The solution was then cooled and concentrated to dryness. The residual white solid was recrystallized from a minimum volume of H2O containing 2 drops of acetic acid. After standing in the refrigerator, the product was collected on a filter and washed with a small amount of H2O, then acetone. The material was dried under high vacuum at 75° for 3 hours to giive 529 mg (90% based on hydration with 0.75H2O) of white crystals, mp 249°-250° dec. The material was homogeneous by TLC (80:20:2 CHCl3 --MeOH--H2O), and the structure was confirmed by NMR.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[C:5]([CH:15]=[O:16])=[CH:4][CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(O)c2oc3ccccc3c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c2oc3ccccc3c12
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
Intermediate 19 (1 gm, 5.10 mmol) was dissolved in dry DMF (10 ml). Anhydrous potassium carbonate (1.05 gm, 7.65 mmol) was added to the above solution and was stirred for 10 min. at 80° C. To this was added benzyl bromide (0.87 gm, 5.10 mmol) and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to room temperature and diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (50 ml) and brine solution (25 ml) and dried over anhydrous sodium sulfate. Removal of solvent gave the product as a brown solid (1.4 gm).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[NH:5]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@@H:6]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:5]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@@H:6]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:11]
Reactant: O=C(O)CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 72 h

Procedure:
400 ml of isobutylene are added to a solution of 40 g (approx. 104 mmoles) of Z-D-Aad-OBzl in 400 ml of methylene chloride, followed, at -20°, by 4 ml of concentrated sulfuric acid. The mixture is allowed to stand in an autoclave for 3 days at room temperature. The batch is stirred with NaHCO3 solution in order to neutralize the sulfuric acid and the excess isobutylene is removed by means of a stream of nitrogen. The methylene chloride phase is extracted by shaking with water and is dried over Na2SO4 and concentrated. This leaves 46.3 g of an oil, which is chromatographed on 500 g of silica gel using a 9:1 mixture of methylene chloride and acetone. The eluate, which contains Z-Aad-(OBut)-OBzl, is concentrated. Yield: 42.35 g of a pale oil (92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:22][CH3:23])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([O:20][CH3:21])[CH:12]=3)[CH:5]=[CH:6][C:7]=1[OH:8].C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1>[CH2:22]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:20][CH3:21])[CH:12]=2)[C:17]([C:18]#[N:19])=[C:9]1[C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:29](=[O:30])[NH:1][C:2]=2[CH:3]=1)[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCn1c(-c2ccc(O)c(N)c2)c(C#N)c2ccc(OC)cc21
Solvent: C1CCOC1
Product: CCn1c(-c2ccc3oc(=O)[nH]c3c2)c(C#N)c2ccc(OC)cc21
Temperature: 65 °C
Yield: 80.9 %

Procedure:
2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This is heated at 65° C. for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (89 mg, 81%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(5-bromopentoxy)-3,4-dihydro-carbostyril (m.p.: 97°-98° C.) and 3,4-dichloro-thiophenol.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[OH:12][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc2c1CCC2
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc2c1CCC2
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
4-Aminoindan (3.0 g) was added to a solution of concentrated sulphuric acid (2.4 mL) in water (15 mL). More water (15 mL) was added and the mixture cooled to SOC. A solution of sodium nitrite (1.71 g) in water (4.5 ml) was added portionwise to the mixture while maintaining the temperature below 5C. After addition was complete the mixture was allowed to Mann to room temperature and urea (0.29 g) was added. The mixture was stirred for a further 5 minutes before being heated at 45° C. for 30 minutes. The mixture was then cooled to room temperature and extracted with ethyl acetate. The combined organic extracts were washed with 2M aqueous sodium hydroxide (2×100 mL) and these aqueous extracts were then acidified with hydrochloric acid and extracted with ethyl acetate (3×100 mL). The combined organic extracts were then washed with brine and dried (Na2SO4) before being concentrated in vacuo. The resulting crude product was chromatographed over silica gel. Elution with ethyl acetate/hexanes (1:7) gave 4-hydroxyindan as an orange oil (1.0 g).
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1)[CH3:21].C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:32]([C:29]3[N:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[CH:24][C:25]4=[N:31][CH:30]=3)=[O:33])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: CCOc1ccn2c(C(=O)O)cnc2c1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: CCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with 7-ethoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=412 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]([CH3:26])=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH2:9]1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:32](O)=[O:33].S(Cl)(Cl)=O.Cl>O1CCOCC1.C(N(CC)CC)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH:17]=[C:16]([CH3:26])[CH2:15][N:14]([CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:32](=[O:33])[C:31]1[CH:30]=[C:29]([O:28][CH3:27])[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[CH:35]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(=Cc1ccc(F)cc1F)CNC1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(CC(C)=Cc2ccc(F)cc2F)C2CCCNC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.1 %

Procedure:
Experimental condition analogous to Example 18 were used with 3-[3-(2,4-difluoro-phenyl)-2-methyl-allylamino]-piperidine-1-carboxylic acid tert-butyl ester 0.35 g (0.94 mmol), 3,4,5-trimethoxy benzoic acid 0.24 g (1.13 mmol), thionyl chloride 0.15 g (0.94 mmol) and triethylamine 0.1 ml. The reaction yielded 380 mg BOC protected intermediate. This intermediate 0.36 g (0.64 mmol) was dissolved in 5 ml dioxane, 6 N HCl was added, and the mixture was stirred at room temperature for 14 hr. A basic work up led to 319 mg of free amine. This was converted to the HCl salt, yielding 100 mg of a yellow solid. Yield: 33%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:33])([C:29]([F:32])([F:31])[F:30])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[Cl:28])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[CH2:35][CH3:36].O>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[C:16]([C:18]([OH:33])([C:29]([F:30])([F:31])[F:32])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH3:36])=[CH:23][C:22]=3[Cl:28])[CH3:20])[CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)ccn2)CC1
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OCC)cc3Cl)C(F)(F)F)ccn2)CC1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
4′-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (Step 1, 31 mg) and silver carbonate (18 mg) in DMF (1 mL), were reacted with iodoethane (0.006 mL) and stirred at 80° C. for 17 h. The reaction mixture was poured into water (10 mL), and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (4 g silica gel, heptane/ethyl acetate 2/1) to give the title compound as amorphous colorless solid (21 mg). MS (m/e)=515.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:18])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH2:2][C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:4]=2[F:18])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COc1ccc(CBr)c(F)c1-c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(Cc2ccc([N+](=O)[O-])cc2)c(F)c1-c1cccc(Cl)c1
Temperature: 60 °C
Yield: 76 %

Procedure:
In a 40 mL vial equipped with a stir bar was placed 3-bromomethyl-3′-chloro-2-fluoro-6-methoxy-biphenyl (I-33, 400 mg, 1.21 mmol), 4-nitrophenylboronic acid (420 mg, 1.45 mmol), potassium phosphate (tribasic) (514 mg, 2.42 mmol), dimethoxyethane (3.5 mL) and 50% aqueous ethanol (3.5 mL). After degassing with nitrogen for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.121 mmol) was added. The mixture was heated to 60° C. for 18 hours and then the palladium catalyst was removed by filtering through Celite. To the filtrate were added water (50 mL) and a saturated ammonium chloride solution (50 mL). After extracting with ethyl acetate (3×50 mL), the organic portions were combined, washed with brine (75 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel chromatography utilizing 20% ethyl acetate/hexanes as eluent to produce 342 mg (76%) of 3′-chloro-2-fluoro-6-methoxy-3-(4-nitro-benzyl)-biphenyl (I-34) as a yellow solid. MS (APCI−): 370.1 (M−1).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C:10]1([CH3:23])[CH3:22])C1C=CC=CC=1>CO.[Pd]>[NH2:8][C@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[O:11][C:10]1([CH3:23])[CH3:22]
Reactant: CC1(C)Oc2ccc(F)cc2NC(=O)[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(C)Oc2ccc(F)cc2NC(=O)[C@@H]1N

Procedure:
The title compound was prepared by hydrogenation of (+)-(R)-7-dibenzylamino-2-fluoro-6,6-dimethyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 225.3 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]4[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[N:15]([CH3:21])[CH:14]=4)=[CH:11][C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>[SiH](CC)(CC)CC.C(Cl)Cl>[CH:1]1([CH:4]2[CH2:8][C:7]3[CH:9]=[C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[N:15]([CH3:21])[CH:14]=4)[C:6]=3[O:5]2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Nc1cc(-c2cc(C)c(=O)n(C)c2)c2oc(C3CC3)cc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc2c(c(-c3cc(C)c(=O)n(C)c3)c1)OC(C1CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a mixture of the title compound from Example 495, Step 4, (30 mg, 0.08 mmol) in Et3SiH (1 mL) in a sealed tube was added TFA (0.2 mL) at 0° C. It was allowed to warm up to room temperature and stirred overnight. The resulting mixture was diluted with DCM (30 mL) and washed with 1 N NaOH, water and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give the title compound (3 mg, 10% yield) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.77 (s, 1H), 7.57 (s, 1H), 7.04 (d, J=3.0 Hz, 2H), 6.44 (s, 1H), 4.37-4.29 (m, 1H), 3.63 (s, 3H), 3.37-3.29 (m, 1H), 3.13-3.03 (m, 3H), 2.22 (s, 3H), 1.40 (t, J=7.5 Hz, 3H), 1.26-1.14 (m, 1H), 0.71-0.33 (m, 4H). LCMS: 389 (M+1)+.