Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([C:64]([F:67])([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:69]=[CH:68][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([C:64]([F:66])([F:67])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
To a solution of 98 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 161 mg of TBTU (0.5 mmol) in 6 ml DMF, were added 0.43 ml (2.51 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 200 mg (0.54 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; DCM/heptane 9:1) to give 206 mg white solid (69%). MS (EI) 546.2 (M)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH3:13])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[CH3:20][NH:21][C:22](SC)=[CH:23][N+:24]([O-:26])=[O:25]>O>[OH2:10].[CH3:20][NH:21][C:22]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH3:13])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)=[CH:23][N+:24]([O-:26])=[O:25].[CH3:20][NH:21][C:22]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][NH:12][CH3:13])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)=[CH:23][N+:24]([O-:26])=[O:25]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CNCc1oc(CSCCN)cc1-c1ccccc1
Solvent: O
Product: CNCc1oc(CSCCNC(=C[N+](=O)[O-])NC)cc1-c1ccccc1
Yield: 71.7 %

Procedure:
A mixture of 5-[[2-(amino)ethyl]thio]methyl-N-methyl-3-phenyl-2-furanmethanamine (0.45 g) and N-methyl-1-(methylthio)-2-nitroethenamine (0.24 g) was stirred in water (5 ml) for 24 hours. The solvent was removed in vacuo and the residue purified by column chromatography (Silica/methanol) affording the title compound (0.3 g) as an amber glass.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2(O)[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6]1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1
Temperature: 64 °C
Reaction time: 6.5 h
Yield: 39.7 %

Procedure:
To a solution of the product of Step C, 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester, (2354 g) in toluene (8 L) is added p-toluenesulfonic acid monohydrate (40.8 g.) The mixture is stirred at 64° C. for 6.5 hours and is subsequently filtered over Celite filter aid. The Celite cake is washed with toluene (2×1 L) and the filtrate is diluted with a mixture of isopropanol (6 L) and heptane (6 L) to form a precipitate. The precipitate is triturated to afford a solid. The solid is triturated in a mixture of isopropanol (6 L) and heptane (2 L) for 3.5 hours and is subsequently collected by filtration. The solid is dried to afford the synthetic intermediate 1-[3-(4-methoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (889 g.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:34][O:35][C:36](=[O:69])[NH:37][CH:38]([C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[C:49]1[NH:50][C:51]([C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)=[CH:52][N:53]=1)=[O:43])[CH:39]([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:57]3[CH:58]=[CH:59][C:54]([C:51]4[NH:50][C:49]([CH:45]5[CH2:46][CH2:47][CH2:48][N:44]5[C:42](=[O:43])[CH:38]([NH:37][C:36]([O:35][CH3:34])=[O:69])[CH:39]([CH3:41])[CH3:40])=[N:53][CH:52]=4)=[CH:55][CH:56]=3)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CC(COC(F)F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC(COC(F)F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 29.5 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (42 mg, 0.174 mmol), [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (95 mg, 0.191 mmol), Pd(PPh3)4 (20 mg, 0.0174 mmol) and K2CO3 (2M in H2O, 0.191 mL, 0.383 mmol) were combined in 1,2-dimethoxyethane (2 mL). The mixture was degassed with bubbling N2 for 12 min then heated to 85° C. for 4 h. After cooling to RT, the reaction mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC to provide the title compound (42 mg, 30%). MS (ESI) m/z 819 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Br[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1>N1C=CC=CC=1.[Cu]Br>[CH:3]1([N:7]2[CH2:8][CH2:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]5)=[N:22][CH:21]=4)=[CH:14][C:11]=3[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Brc1cnc(N2CCCCC2)nc1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1cc2c(cc1Oc1cnc(N3CCCCC3)nc1)CCN(C1CCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 44 mg, 1.1 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.92 mmol) and copper (I) bromide (184 mg, 1.3 mmol) in pyridine (10 ml) at 0° C. After stirring for 0.5 hour at room temperature, 5-bromo-2-(1-piperidinyl)pyrimidine (D32) (0.669 g, 2.8 mmol) was added and the reaction mixture heated at reflux for 2 hours. The reaction was allowed to cool, filtered and the filtrate was concentrated in vacuo. The crude residue was dissolved with ethyl acetate and washed with water and brine. The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Purification of the resulting residue by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.25:2.25:97.5 to 1:9:90) afforded the title compound (E140). MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[CH:11]=[CH:10][C:9]=1Br)[CH3:6])[CH3:2].[CH3:29][N:30](C)C=O>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[CH:11]=[CH:10][C:9]=1[C:29]#[N:30])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)Oc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1C#N

Procedure:
A 15 g of ethyl-α-[2-bromo-5-(2,6-dichloro-4-trifluoromethyl phenoxy) phenoxy]propionate produced in Example 7 was dissolved in 25 ml of dimethylformamide. A 3 g of cuprous cyanide was added to the solution and the reaction was conducted under reflux condition for 4 hours with stirring the mixture.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][C:17]([OH:19])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:34][CH2:35][CH:36](O)[CH2:37][CH3:38].C(N(CC)CC)C>CN(C)C=O.ClCCl.O1CCCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH2:16][C:17]3[O:19][C:36]([CH2:37][CH3:38])=[CH:35][N:34]=3)[C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: CCC(O)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(CC(C#Cc2ccccc2)c2ccc(OC)c(OC3CCCC3)c2)o1
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid (0.50 g, 1.37 mmol) and dimethyl formamide (3 drops) in dichloromethane (10 mL) at room temperature under an argon atmosphere was dropwise added oxalyl chloride (0.125 mL, 1.44 mmol). The reaction was stirred 0.5 h, was evaporated, was dissolved in tetrahydrofuran (5 mL) and was added to a solution of 1-amino-2-butanol (0.15 mL, 1.52 mmol) and triethylamine (0.23 mL, 1.64 mmol) in tetrahydrofuran (10 mL) and was stirred at room temperature under an argon atmosphere for 1 h. Water was added, the reaction was extracted with three times dichloromethane, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluted with 2:98 methanol:dichloromethane provided the title compound (0.54 g, 91%) as a white solid, mp.94-96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CO[CH:16](OC)[CH2:17]Br>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:16]=[CH:17][N:8]=2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Reactant: COC(CBr)OC
Solvent: CC(=O)O
Product: Cc1ccc(-c2nccs2)c([N+](=O)[O-])c1
Yield: 75 %

Procedure:
The procedure described in Example 15-1 was followed except that 4-methyl-2-nitro-thiobenzamide (56) was used instead of 4-trifluoromethyl-2-nitro-thiobenzamide, bromoacetaldehyde-dimethylacetal was used instead of 1-bromo-3-methyl-butan-2-one, and the reaction was acid catalyst with 5% acetic acid. This gave the title compound (66 mg, 75%). LC/MS: (Method I): tR=0.98 min, >90%, m/z (ESI+)=221 (MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(#N)C.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CCCNCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CC#N
Product: CCCN(CCC)c1ccc([N+](=O)[O-])cn1
Yield: 89.6 %

Procedure:
N,N-dipropylamine (3 ml, 22 mmol) was added to a solution of 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) in acetonitrile (7 ml) and heated to reflux overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was then washed with water, brine and dried. Evaporation to dryness gave (5-nitro-pyridin-2-yl)-dipropylamine (630 mg, 90%) as oil.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1)=[O:11])=[O:4].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([N:12]2[C:3](=[O:4])[CH:5]3[CH2:9][CH2:8][CH2:7][N:6]3[C:10]2=[O:11])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)Nc1ccc([N+](=O)[O-])c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1C2CCCN2C(=O)N1c1ccc([N+](=O)[O-])c2ccccc12
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A suspension of compound 2A (410 mg, 1.29 mmol) and DBU (0.2 mL, 1.33 mmol) in toluene (10 mL) was heated at 80° C. for 2 hours. HPLC check of the reaction showed little product formed. Additional DBU (0.1 mL) was added and the reaction heated at 90° C. overnight. After cooling to RT, the reaction mixture was filtered. The filtrate was diluted with EtOAc, washed with 1 N aqueous HCl, water, brine, dried over MgSO4 and concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with CH2Cl2, 0.2% to 0.4% MeOH in CH2Cl2 to give the title compound (racemate) (80 mg) as a brown solid. mp. 215-217° C. HPLC: 97.5% at 2.51 min (retention time) (YMC S5 ODS column 4.6×50 mm; 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nM), MS (ES): m/z 312 [M+1]+.
Reaction SMILES: O=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.Cl.[NH2:25][OH:26].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[OH:26][N:25]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)c3ccccc32)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=NO)c3ccccc32)CC1

Procedure:
A mixture of tert-butyl 4-oxo-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate A (1.24 g, 3.93 mmol), hydroxylamine hydrochloride (1.37 g, 19.7 mmol) and sodium acetate trihydrate (3.20 g, 23.5 mmol) in ethanol (50 ml) was heated under reflux for 20 h. The reaction was concentrated and the residue was suspended in water, extracted with dichloromethane (3×). The combined extracts were dried over Na2SO4 and concentrated to give tert-butyl 4-(hydroxyimino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate B (1.32 g). LC-MS: m/e=331.1 (M+H, 100%), 275.0 (M+H−C(CH3)3). Rt=3.35 min. 1H-NMR (500 MHz, CDCl3): 8.01 (d, 0.25H), 7.93 (d, 0.75H), 7.41-7.34 (m, 2H), 7.23-7.19 (m, 1H), 3.95-3.92 (m, 2H), 3.04-2.96 (m, 2H), 2.87 (t, 0.5H), 2.82 (t, 1.5H), 2.3 (br. s, 1H), 1.93-1.84 (m, 4H), 1.54-1.52 (d, 2H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[NH:34]1[CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:34]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:29][CH:28]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCC3)cc1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a stirred solution of the crude 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (930 mg, 2.42 mmol) in DCM (120 mL) was added acetic acid (0.3 mL) followed by azetidine (670 mg, 11.8 mmol), after the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. and NaBH(OAc)3 (764 mg, 3.62 mmol) was added. After the addition, the mixture was stirred at this temperature for 6 hr. DCM was removed under reduced pressure. The residue was added water followed by hydrochlorichttp://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure._structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D%3F+elsor+entry.catalogID%3D%3 acid (5 mL) at 25° C. The mixture was stirred at room temperature for 0.5 hr. The mixture was extracted with ethyl acetate (100 mL×3). The water layer was neutralized with potassium carbonate and filtered to obtain the title compound as a white solid (500 mg, yield 49%). LC-MS (ESI) m/z: 427 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.24-2.49 (m, 2H), 3.85-4.02 (m, 4H), 4.25 (d, 2H), 4.38 (d, 1H), 4.80 (d, 1H) 7.03 (t, 2H), 7.14-7.20 (m, 3H), 7.36-7.39 (m, 5H), 7.47 (s, 1H), 7.59 (t, 1H) 10.64 (s, 1H), 12.18 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1>>[O:28]1[CH2:29][CH2:30][CH:26]([NH:25][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: NC1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 69 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using rac-3-aminotetrahydrofuran instead of 2-amino-2-methyl-1-propanol, to the title compound (84 mg, 69%) which was obtained as a light brown solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=[CH:13]2)[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC[C@H](c1cccc(Br)c1)N1CCc2cccc(OCc3ccccc3)c21
Agent: C[Si](C)(C)Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
A stirred solution of (3R)-(-)-3-(3-bromophenyl)-3-(7-benzyloxyindolin-1-yl)propan-1-ol (1.0 g, 2.28 mmol) in dry dichloromethane (30.0 ml) under nitrogen at 5° C. was treated with triethylamine (0.52 ml, 3.77 mmol) followed by chlorotrimethylsilane (0.32 ml, 2.52 mmol) dropwise. The resulting suspension was stirred at room temperature for 20 min, treated with 2,3-dichloro-5, 6-dicyano-1,4-benzoquinone (0.57 g, 2.52 mmol) and stirred at room temperature until the reaction was judged to be complete from TLC inspection (~30 min). The solvent was removed by evaporation, the residue was taken up in ethyl acetate (200 ml), washed with 2M aqueous sodium hydroxide (3×100 ml), brine (100 ml) and 2M aqueous hydrochloric acid (2×100 ml). Evaporation of the dried organic extracts (Na2SO4) gave a yellow/brown oil. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:4) gave the title compound as a yellow oil (0.80 g, 80%). [α]D26 -157 (c=0.014 gml-1, CHCl3); νmax (thin film)/cm-1 3418.5 (br. OH), 3064.5, 3033.5, 2935.5, 2879.0, 1593.5, 1570.5; δH (270 MHz) 2.35 (2H, m, 2×2-H); 3.50 (2H, m, 2×1-H); 5.13 (2H, q, CH2Ph, 2J=11.1 Hz); 6.6 (m, 2H, 3-H, indole 3-H); 6.72 (1H, dd, indole 6-H, Jo =7.6 Hz, Jm =0.7 Hz); 6.90 (1H, dd, indole 4-H, Jo =8.3 Hz, Jm =0.8 Hz); 7.00 (2H, m, indole 5-H, 5'-H); 7.15 (1H, d, indole 2-H, 3J2,3 =3.0 Hz); 7.19-7.40 (8H, m, 8ArH). δC (67.8 MHz) 38.4 (2-C); 56.4 (3-C); 59.3 (1-C); 70.7 (PhCH2); 103.2 (indole 3-C); 104.3 (indole 6-C); 114.3 (indole 4-C); 120.1 (indole 5-C); 122.5 (3'-C); 125.0 (indole 2-C); 131.8 (1'-C); 136.4 (benzyl ipso-C); 144.9 (indole 7a-C); 146.5(indole 7-C). The remaining signals lie between 126.5-130.7 ppm and cannot be assigned with any certainty.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:16][CH:17]=2)=[CH:8][CH:7]=1)(=O)C>[Pd].C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:10][CH:11]=1
Reactant: CC(=O)OCc1ccc(C2=CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(CO)cc2)C1
Yield: 63.7 %

Procedure:
Palladium on charcoal was added to the solution of 3-(4-acetoxymethylphenyl)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine (0.71 g, 2.1 mmol) in ethyl acetate and stirred under hydrogen atmosphere. After filtration with celite and removal of the solvent under reduced pressure, methanol and 1N aqueous sodium hydroxide were added and stirred. Organic solvents were removed under reduced pressure after addition of water and extracted with ethyl acetate, washed with water and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane/ethyl acetate=3/1) to give 3-(4-hydroxymethylphenyl)-1-(tert-butoxycarbonyl)piperidine (0.39 g, 62%).
Reaction SMILES: C([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](COCC[Si](C)(C)C)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:18][C:19]#[N:20])[CH2:12][CH:11]1[F:43])(=O)C1C=CC=CC=1.[OH-].[Li+].[C:46](#[N:48])[CH3:47]>O.C(OCC)(=O)C>[C:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:15]2[CH:14]=[C:47]([CH:12]=[C:11]([F:43])[CH:10]=2)[C:46]#[N:48])[CH:11]([F:43])[CH2:12]1)#[N:20]
Reactant: CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(OC(=O)c5ccccc5)C(F)C4)c3)ncnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(CN1CCC(Oc2cc(F)cc(C#N)c2)C(F)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-fluoropiperidin-4-yl benzoate (0.389 g, 0.644 mmol) (diastereomer 2) in acetonitrile (2.0 mL) and water (1.0 mL) was added lithium hydroxide (30.8 mg, 1.29 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product (0.322 g, 100%). The product was synthesized from diastereomer 1 using same procedure in 100% yield. LCMS (M+H)+: 500.3.