Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[N:6](CC(OC(C)(C)C)=O)[CH:5]=1)#[N:2].[CH:24](C1NC2C(C=1)=C([N+]([O-])=O)C=CC=2)([CH3:26])[CH3:25]>>[CH:24]([C:5]1[NH:6][C:7]2[C:12]([C:4]=1[CH2:3][C:1]#[N:2])=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)([CH3:26])[CH3:25]
Reactant: CC(C)c1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c([N+](=O)[O-])cccc21
Product: CC(C)c1[nH]c2cccc([N+](=O)[O-])c2c1CC#N

Procedure:
Essentially following the procedures described for Intermediate 11, but using 2-isopropyl-4-nitro-1H-indole from Step B in place of 4-nitroindole, the title compound was prepared. MS: m/z=244 (M+1).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:20]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3cc(Cl)ccc3oc2c2ccccc12
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Product: Clc1ccc2oc3c4ccccc4c(Cl)nc3c2c1

Procedure:
The procedure was similar to step S19C, while the starting material was 24B in stead of 19B.
Reaction SMILES: Cl[C:2]1[C:7]2[Se:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[K+].[Br-]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:4]2[N:3]=[CH:2][C:7]3[Se:8][C:9]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[C:6]=3[N:5]=2)[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Clc1ncnc2c3c([se]c12)CCCC3
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: Fc1ccc(Nc2ncc3[se]c4c(c3n2)CCCC4)cc1Cl

Procedure:
To a solution of step c compound (700 mg, 2.57 mmol) in isopropanol (15 mL) was added 3-chloro-4-fluoroaniline (1.6 g, 11.56 mmol) at rt and the mixture was refluxed for 1.5 h. Work-up of the mixture as described in example 1, gave the product as an off-white color solid, mp 238-240° C. IR (KBr) νmax cm−1; 1H NMR (400 MHz, CDCl3): δ 8.71 (1H, s), 7.70 (1H, dd, J=6.4, 2.8 Hz), 7.37-7.41 (1H, m), 7.16 (1H, t, J=8.8 Hz), 6.53 (1H, br s, exchangeable with D2O), 2.92 (2H, t, J=6.0 Hz), 2.82 (2H, t, J=6.0 Hz), 1.86-1.99 (4H, m); 13C NMR (100 MHz, DMSO-d6): δ 162.5, 156.2, 153.8, 153.0 (d, J=241 Hz), 148.6, 136.9 (d, J=3.0 Hz), 133.1, 122.7, 121.6 (d, J=7.0 Hz), 118.8 (d, J=19 Hz), 116.5 (d, J=21.0 Hz), 115.6, 27.6, 24.4, 23.5, 21.3; LC-MS (negative ion mode): m/z 378, 380, 382 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][C:21](=[O:23])[CH3:22])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A mixture of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (900 mg, 3.37 mmol), acetic anhydride (1.7 mL, 18 mmol), triethylamine (1.4 mL, 10 mL) in N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. The mixture was acidified with 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (1:1 hexane/ethyl acetate) to give 5-(4-cyano-3-acetoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (818 mg, 79%).
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[Cl:40][NH:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: Cl
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Solvent: C1COCCO1
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NCl)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 42E (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1 H) 0.78 m, 10 H) 1.59 (s, 3 H) 2.08 m, 1 H) 2.23 (td, J=12.78, 4.60 Hz, 1 H) 7.07 m, 2 H) 7.53 m, 2 H) 7.77 (m, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 13.58 (s, 1 H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1C=C(O)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:26])[C:14]([C:24]#[N:25])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH3:11]>>[C:24]([C:14]1[C:13](=[O:26])[O:12][C:10]2[C:6]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:11]=2)#[N:25]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cccc(OC)c1
Product: COc1cccc(-c2c(C#N)c(=O)oc3cc(OC)ccc23)c1
Yield: 0.2 %

Procedure:
The title compound was prepared from 3-methoxyphenol and 3-(3-methoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.2% yield. 1H NMR (CDCl3): 7.50 (t, J=8.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.12 (dd, J=8.4, 2.4 Hz, 1H), 7.03-6.96 (m, 2H), 6.90-6.83 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]=[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1
Yield: 99 %

Procedure:
A mixture of ethyl p-hydroxybenzoate (4.98 g), benzyl bromoacetate (4.75 ml) and K2CO3 (4.14 g) was stirred for 15 hr in 30 ml of DMF. The reaction mixture was diluted with water (200 ml) and extracted with a 1:1 ether:hexane mixture. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and evaporated leaving 9.3 g, (99%) of the title compound as a heavy oil; TLC, Rf =0.71, Et2O: hexane (1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2F)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
938 mg (3.07 mmol) of the compound from Example 87A were initially charged in 40 ml of dichloromethane and cooled to 0° C., and admixed with 1.28 ml (0.93 g, 9.22 mmol) of triethylamine and 0.62 g (3.07 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. It was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 1.21 g of crude product in 85% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]([CH3:17])[C:7]=1B1OC(C)(C)C(C)(C)O1.[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]([C:28]1[S:29][C:30]([S:43][CH3:44])=[C:31]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38](Br)[CH:37]=2)(=[O:35])=[O:34])[CH:32]=1)=[NH:27])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:19]([O:23][C:24](=[O:45])[NH:25][C:26]([C:28]1[S:29][C:30]([S:43][CH3:44])=[C:31]([S:33]([C:36]2[CH:37]=[C:38]([C:7]3[C:6]([CH3:17])=[CH:5][C:4]([OH:18])=[CH:3][C:2]=3[CH3:1])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH:32]=1)=[NH:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(O)cc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1

Procedure:
Following the same procedure as in Example 1, step c, reaction of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (355 mg, 0.8 mmol, assuming quantitative yield from Example 224, step a), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (58 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (0.8 mL, 2M), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 35 mg (13%) after purification (PTLC) of the title compound as a tan solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.8, 477.0, 433.1 (M−Boc).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH3:22].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
50% Sodium hydride 4 g (160 mmol) in mineral oil was suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, at room temperature, in a dropwise fashion and under stirring. The resulting mixture was stirred for 12 additional hours and then a solution of 18 ml (197 mmol) of 1-bromopropane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred for 18 hours further and thereafter poured into 1000 ml of ethyl acetate, washed with water (5×500 ml), dried and evaporated in vacuo. Purification of the residue by column chromatography on 500 g of silica gel, using hexane-ethyl acetate (90:10) as eluant provided 17.61 g (98%) of 1-propyl-2-(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CC#N>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:10][C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: CC(C)(C)c1nnc(N)o1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of 5-tert-butyl-[1,3,4]oxadiazol-2-ylamine (Atlantic, 141 mg, 1.00 mmol) and Et3N (279 μL, 2.00 mmol) in MeCN (2 mL), 2,2,2-trichloroethyl chloroformate (207 μL, 1.50 mmol) was added in 4 portions over 1 min at RT (CARE: exotherm to ˜40° C.). The resulting suspension was stirred for 1 h. The suspension was filtered, washing the solid with MeCN (3 mL), and concentrated to leave a yellow-brown paste. Purification by FCC, using 0-2.5% MeOH in DCM, gave a buff foam (232 mg, 73%). 1H NMR (400 MHz, CDCl3): 1.42 (9H, s), 4.86 (2H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18](O)=[O:19]>>[ClH:12].[NH2:13][CH2:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=1)=[O:19]
Reactant: NCC(=O)CCC(=O)O
Reactant: CC(C)c1ccc(CO)cc1
Agent: Cl
Product: CC(C)c1ccc(COC(=O)CCC(=O)CN)cc1
Reaction time: 48 h

Procedure:
From 4-isopropylbenzyl alcohol (5.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 2 days. The yield was 1.0 g (56%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([O:12][S:1](=[O:4])(=[O:3])[NH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)Oc1ccccc1
Yield: 30 %

Procedure:
The compound was prepared by procedures of Example 28 from sulfamoyl chloride and phenol in 30% yield as white solid, mp 81°-85° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: CCCc1ccc(B(O)O)cc1
Product: CCCc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 55 %

Procedure:
N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 33C, from 4-propylphenyl boronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as a white solid in 55% yield, m.p. 106-108° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].ClC[C:17]([N:19]=C=O)=[O:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([NH2:19])=[O:18])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Reactant: O=C=NC(=O)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1c(I)cc(NC(N)=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol) in dioxane (20 mL) at 0° C. was added chloroacetyl isocyanate (0.256 mL, 3.00 mmol) dropwise to give a solution that was stirred at room temperature for 3 hours. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.904 mL, 6.00 mmol) was added and the solution was stirred for 18 hours and partitioned between ethyl acetate and 1 M HCl. The ethyl acetate was washed with H2O, brine and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified on an Isco 40 g silica cartridge eluting with methanol/dichloromethane (0% to 5%) to give the title compound.
Reaction SMILES: O.[OH-].[Li+].C([O:11][C:12]([C:14]1([C:45](=[O:53])[NH:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[C:34]([F:44])[CH:33]=4)[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.O1CCCC1>[F:44][C:34]1[CH:33]=[C:32]([C:30]2[O:29][N:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][N:17]4[CH2:16][CH2:15][C:14]([C:45](=[O:53])[NH:46][N:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)([C:12]([OH:13])=[O:11])[CH2:19][CH2:18]4)=[CH:22][CH:23]=3)[N:31]=2)[CH:37]=[CH:36][C:35]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NN1CCCCC1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(C(=O)NN2CCCCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 70 °C

Procedure:
A solution of lithium hydroxide monohydrate (0.031 g, 0.000735 mol) in demineralized water (2 mL) is added to a solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid benzyl ester (0.165 g, 0.000245 mol) in tetrahydrofuran (10 mL). The reaction mixture is heated at 70° C. for 2 hrs. Tetrahydrofuran is removed under reduced pressure and the residue is acidified with 2N HCl (pH ˜5). The solid mass thus formed is filtered and washed with acetone (5 mL) to furnish 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid [91, MS (ES+)=584.23].
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([N:3]2[C:2]([CH3:8])([CH3:1])[CH2:6][O:5][C:4]2=[O:7])[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: CC1(C)COC(=O)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 4,4-dimethyloxazolidin-2-one (0.103 g, 0.895 mmol) and 2,4,6-trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3 mL) was treated with NaH (60%, 0.0429 g, 1.07 mmol, 1.2 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided 3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (0.146 g, white solid) in 62.3% yield. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 4.16 (s, 2H), 1.74 (s, 9H); LCMS m/z 261.9 (M+H)+, Rt 0.91 min.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=O)[CH3:24])=[CH:18][CH:17]=1.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CO>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH3:24])=[CH:18][CH:17]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.05 g) and 4-methylphenylacetone (1.48 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4h. The solvent was removed under reduced pressure, replaced with methanol and sodium borohydride (3 g) added portionwise. The solvent was evaporated under reduced pressure, the residue partitioned between water and ether and the ether layer dried (MgSO4). Removal of the solvent under reduced pressure gave an oil which was dissolved in methanol and treated with an equivalent amount of methanolic fumaric acid. Evaporation of the solvent gave the title compound (fumarate salt) as a 58:42 mixture of diastereoisomers, mp 138°-144° (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
The N-Boc p-hydroxy phenyl glycine methyl ester from step (300a) (123.0 g, 440 mmol) was combined with benzyl bromide (90.3 g, 528 mmol), potassium carbonate (182 g, 1.3 mol) and acetone (800 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 h, allowed to cool to rt, diluted with ethyl acetate (800 mL) filtered to remove the solids and concentrated in vacuo to give a semisolid residue. The product was crystallized from ethyl ether to give the N-Boc p-benzyloxy phenyl glycine methyl ester (106.7 g, 65%) as a white powder. MS (M+H)+=372, (M+NH4)+=389.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14](CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H][H]>[Ni].[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCN(Cc4ccccc4)CC3)n[nH]c2c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Yield: 92 %

Procedure:
A mixture of 12 parts of 6-fluoro-3-[4-(phenylmethyl)-piperazinyl]-1H-indazole, 1 part of Raney nickel catalyst and 200 parts of methanol was hydrogenated in a Parr-apparatus at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 7.7 parts (92.0%) of 6-fluoro-3-(1-piperazinyl)-1H-indazole (int. 8).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCN1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(NC(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.0 Grams of N-acetylsulphanilyl chloride were added in portions to a stirred, ice cooled, mixture of 4.7 grams of 4-amino-1-n-butyl piperidine and 6.3 grams of sodium bicarbonate in 75 milliliters of water and 35 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, washed with water, and dried to give 4.2 grams of the title compound. Melting Point 174°-175°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH3:13])=[C:9](OC)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH3:18][NH:19][CH3:20]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([N:19]([CH3:20])[CH3:18])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CNC
Reactant: COc1c(C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: O
Product: Cc1c(N(C)C)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: -78 °C

Procedure:
8-Chloro-3-methoxy-4-methyl-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.4 g) was treated with 100 mL of liquid dimethylamine chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 26° C. for 72 hours. The excess dimethylamine was evaporated to give an oil which was dissolved in water and extracted with ethyl acetate. The organic extracts were combined and concentrated to a brown oil. The oil was crystallized using ether to give a yellow solid. The solid was purified by chromatography, with ethyl acetate: hexane (1:1) as the eluent, to give the title compound; NMR: 2.95 (s,6), 2.28 (s,3); MS: m/z=265(M+1).