Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH3:48])=[N:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[N:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCOc1ccc(CCl)cn1
Agent: Cl
Product: CCOc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 72.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-chloromethyl-2-ethoxypyridine (0.51 g) as starting materials, 5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH2:6]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCOCC
Reactant: CCCCC
Agent: [Li]C(C)(C)C
Product: CCCCc1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 min, cooling bath was removed. Reaction was continued for 2.5 h, and quenched with H2O (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried by Na2SO4, and filtered through a Celite pad. Removal of solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:24](=[O:35])[NH:25][CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:7]=1[C:8]([O:10]CCC#N)=[O:9].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:24](=[O:35])[NH:25][CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]([C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)NCC=Cc2ccccc2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
396 mg (0.814 mmol) of 2-cyanoethyl 2,6-dimethyl-4-(4-nitrophenyl)-5-[(3-phenyl-2-propene-1-yl)carbamoyl]-1,4-dihydropyridine-3-carboxylate was dissolved in 10 ml of methanol. 0.895 ml of 1 N aqueous sodium hydroxide solution was added to the solution, and they were stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture and then methanol was evaporated under reduced pressure. Water was added to the residue, and a precipitate thus obtained was taken by the filtration. The product was washed with water and then with hexane/ethyl acetate (3:1) and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and octanoyl chloride were treated in the same was as in Example 3 to give 3,5-di-t-butyl-4-hydroxybenzophenone O-octanoyloxime.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4o3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-benzoxazole.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]1([CH2:21][O:22][C@@H:23]([C@@H:27]([C@@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)O)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]([OH:26])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[CH2:9]([O:8][P:7]([O:11][CH2:12][CH3:13])([CH2:6][C:24]1([O:26][C@H:36]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:23]1[O:22][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:25])=[O:14])[CH3:10]
Reactant: O=C(O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 15.6 ml of 1.6M n-butyllithium in hexane and 20 ml of tetrahydrofuran at -78° C., was added a solution of 3.80 g of diethyl methylphosphonate in 10 ml of tetrahydrofuran during 10 minutes. After 15 minutes at -78° C., a solution of 4.18 g of 2,3,5-tris-O-(phenylmethyl)-D-arabinonic acid, qamma-lactone [Y. Rabinsohn & H. G. Fletcher, J. Org. Chem., 32, 3452-3457 (1967)] in 15 ml of tetrahydrofuran was added during 5 minutes. After 30 minutes at -78° C. the solution was warmed to 0° C. during 5 minutes, stirred at 0° C. for 2 minutes, recooled to -78° C. and quenched with 3.0 ml of glacial acetic acid. The mixture was partitioned with dichloromethane-water. The organic layer was washed successively with water, sodium bicarbonate solution, water and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (ethyl acetate-heptane) giving the desired compound as an oil, CMR δ 101.2 and 104.3 (doublets, corresponding to anomeric carbon of minor and major anomer, respectively).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([Cl:17])[CH:10]=2)=[O:5])C.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[C:28]([C@@H:20]([NH:19][C:7]1[C:6]([C:4]([OH:3])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:17])=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:30])=[O:29]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)c(Cl)cc2nc1N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 130 °C
Reaction time: 22 h
Yield: 38 %

Procedure:
A mixture of 2,6,7-trichloroquinoline-3-carboxylic acid ethyl ester (80 mg, 0.26 mmol), L-phenylalanine (80 mg, 0.52 mmol) and potassium carbonate (180 mg, 1.31 mmol) in DMF (1 mL) is stirred for 22 h at 130° C. in closed reaction vial. After cooling the reaction mixture is diluted with water, acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and air dried to give the title compound (40 mg, 38%) as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[N+:14]([CH3:17])([O-:16])=[O:15].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:17][N+:14]([O-:16])=[O:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)c(F)c1
Yield: 46 %

Procedure:
3-Fluoro-4-trifluoromethyl-benzaldehyde (5 g, 25.9 mmol) was reacted with nitro methane (1.58 g, 25.9 mmol), 10N NaOH (1.08 g, 27.20 mmol) to afford 2.8 g of the product (46.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]([NH2:22])=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Reactant: N#Cc1ccc(F)cc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Yield: 23.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D-phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg).
Reaction SMILES: C([O:3][C:4](=[O:37])[C@H:5]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[C:22]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[S:20][N:19]=2)[C:7]1=[O:29])C.[Li+].[OH-]>O1CCOCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:5]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[S:20][N:19]=3)[C:7]2=[O:29])[C:4]([OH:37])=[O:3])=[CH:31][CH:32]=1
Reactant: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](C(=O)O)c4ccc(Cl)cc4)c(=O)c4ccccc43)nsc2c1
Reaction time: 4 h

Procedure:
To a solution of (S)-(4-Chloro-phenyl)-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid ethyl ester (50 mg, 0.094 mmol) in 1,4-dioxane (10 mL) and water (1 mL) is added LiOH (6.7 mg, 0.28 mmol) at room temperature. The solution is stirred at the same temperature for 4 hours. The solution is concentrated and water is added to the residue. The solution is acidified by 12N HCl in an ice-bath. The precipitated solid is collected by filtration to afford the title compound.: LCMS (ESMS): m/z 506.10 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[NH3:24]>CO>[NH2:24][C:6]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:2]([Cl:1])[N:3]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:5]=1
Reactant: N
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Solvent: CO
Product: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1Cl
Reaction time: 8 h

Procedure:
2.09 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine (EP-A- 0 526 708) were suspended in 75 ml of methanol and 150 ml of ammonia were condensed at 75° C. using a feedpipe. The reaction mixture was left to come to room temperature overnight, concentrated in a water-jet vacuum and the residue was partitioned between a small amount of water and methylene chloride (500 ml). The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was triturated with ether, the resulting solid was separated and dried in a high vacuum. The 4-amino-6-chloro-5-(2-methoxy-phenoxy )-2,2'-bipyrimidine was thus obtained as a fine, almost white powder. MS: 329 (M).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:21]CC2C=CC=CC=2)[CH2:19][F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:29]([CH3:31])[CH3:30])[S:14]2)[C@H:10]1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[CH3:30][N:29]([CH3:31])[C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:21])[CH2:19][F:20])[C@@H:9]([OH:8])[C@H:10]([OH:32])[C@H:11]2[N:12]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@H](CF)OCc3ccccc3)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)CF)O[C@@H]2S1
Yield: 23.6 %

Procedure:
A solution of 104 (400 mg, 0.7 mmol) in dichloromethane (15 mL) was treated with BCl3 (7 mL, 7 mmol, 1M in dichloromethane) for 30 min at −60° C., then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10% methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: (Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN; 5% CH3CN up to 100% in 8 min Detector, 220 nm to afford (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-2-fluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (46.3 mg, 23%), faster eluting isomer; (ES, m/z): [M+H]+ 281.0; III NMR (300 MHz, D2O) δ 6.17 (d, J=6.6 Hz, 1H), 4.29-4.69 (m, 2H), 3.95-4.15 (m, 3H), 3.68-3.72 (m, 1H), 3.54-3.58 (m, 1H), 2.88 (s, 3H), 2.87 (s, 3H); and (3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2-fluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (64 mg, 31%), slower eluting isomer; (ES, m/z): [M+H]+ 281.0; 1H NMR (300 MHz, D2O) δ 6.17 (d, 6.3 Hz, 1H), 4.44-4.57 (m, 1H), 4.28-4.39 (m, 1H), 3.92-4.12 (m, 3H), 3.67-3.72 (m, 1H), 3.27-3.49 (m, 1H), 2.89 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Br:42]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([Br:42])[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(Br)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (51 mg; 0.086 mmol) in methylene chloride (1.2 mL) was added N-bromosuccinimide (63 mg; 0.354 mmol) and triphenylphosphine (97 mg; 0.369 mmol). The reaction was stirred at room temperature for 16 hours. Reaction was directly purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane) to give 27 mg (48% yield) of the title compound as a colorless gum. MS (ES+): Calc: 657.1, Found: 658.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.71 (d, J=8.30 Hz, 1H), 7.65 (s, 2H), 7.59 (d, J=8.30 Hz, 1H), 7.28 (s, 1H), 4.99 (d, J=9.96 Hz, 1H), 4.91 (d, J=15.35 Hz, 1H), 4.68 (q, J=15.77 Hz, 2H), 4.68 (d, J=16.26 Hz, 1H), 4.24 (s, 3H), 2.34 (d, J=12.86, 1H), 2.00 (m, 1H), 1.80 (d, 13.28 Hz, 1H), 1.63 (t, J=10.35 Hz, 2H), 1.39-1.22 (m, 2H), 1.14 (m, 2H), 0.98 (m, 1H), 0.76 (m, 1H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[C:7]([I:22])=[C:8]([C:19](Cl)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1>CC(N(C)C)=O>[C:1]([CH2:4][NH:5][C:6]1[C:7]([I:22])=[C:8]([C:19]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=2)=[O:20])[C:9]([I:18])=[C:10]([NH:13][CH2:14][C:15](=[O:17])[CH3:16])[C:11]=1[I:12])(=[O:3])[CH3:2]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)CNc1c(I)c(NCC(C)=O)c(I)c(C(=O)Nc2ccc(CC(=O)O)cc2)c1I
Temperature: 60 °C
Reaction time: 30 h
Yield: 57 %

Procedure:
A mixture of MDTA-Cl X (2.18 g, 3.3 mmole) and p-aminophenylacetic acid (1.2 g, 8.27 mmole) in DMA (8 mL) was stirred at 60° C. for 30 h. The solvent was removed and the residue was treated with hot EtOAc (600 mL) containing EtOH (25 mL). The solution was filtered and the filtrate was freed of the solvent. The solid was recrystallized from EtOAc-EtOH to afford the title compound as a white amorphous solid (1.54 g, 57%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([F:29])[C:11](=[O:28])[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)(C)(C)C>C(Cl)Cl.Cl.CCOCC>[ClH:36].[ClH:36].[NH2:7][CH2:8][CH2:9][C:10]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)([F:29])[C:11]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (226 mg, 0.43 mmol) in DCM (2 mL) and 2.0 M HCl in Et2O (1 mL) was stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 10% MeOH/DCM followed by 10% (7N NH3 in MeOH)/DCM as eluent. The purified material was dissolved in MeOH followed by the addition of 2.0N HCl in Et2O, and then concentrated in vacuo. The resulting glass was heated at reflux in isopropyl alcohol and concentrated in vacuo. The resulting solid was suspended in acetonitrile and concentrated in vacuo (repeated twice) to give 4-amino-2-(4-chlorophenyl)-2-fluoro-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one dihydrochloride as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 8.18 (m, 4H), 8.01 (m, 2H), 7.69 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 4.23 (m, 2H), 4.09 (m, 1H), 3.80 (m, 4H), 3.47 (m, 1H), 2.86 (m, 1H), 2.67 (m, 2H), 2.41 (m, 1H). LCMS (APCI+) m/z 428, 430 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([CH3:38])[CH:36]=O.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:34][CH:35]([CH3:38])[CH3:36])[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)C=O
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CC(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 409.2858, C26H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409.2, tr 5.97 min.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:19]#[N:20])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[C:19]([C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1)#[N:20]
Reactant: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1C#N)C(C)CNCC2
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A solution of N-trifluoroacetyl-8-cyano-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (10 mg, 0.032 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred 1 hour at 50 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 6.0 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.33 (s, 1 H), 6.93 (s, 1 H), 3.91 (s, 3 H), 3.18−2.97 (m, 5 H), 2.80 (m, 1 H), 2.60 (m, 1 H), 1.33 (d, J=8 Hz, 3 H). MS calculated for C13H16N2O+H: 217, observed: 217.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C@@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)[OH:8].C(N(CC)CC)C.[Cl:28][C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:8][C@@:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:29]([Cl:28])=[O:31])[CH2:10]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 159.1 %

Procedure:
A solution of (S)-5-methoxy-1-phenyl-1-((R)-piperidin-3-yl)pentan-1-ol (455.6 mg, 1.8 mmol) and triethylamine (1.50 mL, 10.7 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. A solution of triphosgene (278.6 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added with fast dropwise addition. The solution was stirred for 30 min at 0° C. and then for 2 h at rt. The reaction mixture was cooled to 0° C., washed with ice-cold satd aq NaHCO3 (3×10 mL) and ice-cold brine (3×10 mL), dried (Na2SO4), decanted, and stripped to afford (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride (540.8 mg, 99%) as a yellow oil. This material was carried on directly to the next step.