Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][CH:35]3[CH2:37][CH2:36]3)[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]1)=O)(C)(C)C.O.[ClH:39].[OH-].[Na+]>O1CCOCC1>[ClH:39].[NH2:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:34][CH:35]3[CH2:37][CH2:36]3)[C:26]([CH3:33])=[N:27]4)=[CH:15][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:11]1
Reactant: CCOC(=O)c1cc(-c2c(F)ccc3nc(C)c(NC4CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NC1CC1
Temperature: 120 °C
Reaction time: 0.01 h
Yield: 95 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (283d) (0.38 g, 0.76 mmol) and LiOH monohydrate (Fluka/Aldrich) (191 mg, 4.56 mmol) in 1,4-Dioxane (7 mL)/Water (3.5 mL). The reaction mixture was stirred and heated in a Discover model microwave reactor (CEM, Matthews, N.C.) at 120° C. for 20 min (100 watts, Powermax feature off). This material was transferred to a 150-mL round-bottomed flask and added 4 M HCl in 1,4-dioxane (Aldrich) until pH 2-3. The mixture was stirred at RT for 2 h. The mixture was neutralized with 5 N NaOH (pH 7), then concentrated under reduced pressure to half of its volume. The residue was diluted with hexanes and placed into a sonicator for 30 sec. The precipitated solid was collected by filtration and washed with hexanes. This gave 2-(1-aminocyclopropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (283e) (0.30 g, 0.718 mmol, 95% yield) as a tan solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.86 (m, 1H), 7.44 (m, 1H), 7.34 (s, 1H), 2.68 (s, 3H), 1.56 (m, 4H), 1.14 (d, 2H), 0.91 (s, 2H). m/z (ESI, +ve) 383 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Product: C=CCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61D and benzyl bromide were processed as described in Example 6B to provide the title compound
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[Li+].[CH3:23]C([N-]C(C)C)C.CI.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:23])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cn(S(=O)(=O)c2ccc(Br)cc2)c2ncc(Br)cc12
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reaction time: 0.5 h

Procedure:
To a suspension of 5-bromo-1-(4-bromophenylsulfonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (B-6-2) (0.9 g, 2.56 mmol) in THF (20 mL) was added dropwise LDA (15 mL, 0.2 M in THF) at −40° C. The mixture was stirred at −10˜−20° C. for 0.5 hour. Methyl iodide (0.55 g 3.84 mmol) was added dropwise at −40˜−30° C. The reaction was stirred at room temperature overnight. LC-MS showed that the reaction was complete. Saturated aqueous NaCl (10 mL) and EtOAc (10 mL) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give 5-bromo-2,3-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-3) (0.9 g, 96.3%, containing some starting material (B-6-2) as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].Br[CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:41][CH2:42][CH3:43])[C:10]2[C:15]([C:16]=1[CH2:17][N:18]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(C(=O)OCC)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21
Reaction time: 0.25 h
Yield: 703.6 %

Procedure:
To a suspension of NaH (0.23 g, 1.9 mmol) in DMF (5 mL) was added 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid ethyl ester (0.03 g, 0.05 mmol), obtained in step (vi) of Example 124, at 0° C., and stirred for 15 min. Bromopropane (0.23 g, 1.9 mmol) was added to this at the same temperature and the reaction was stirred for another 1 h. The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford the crude residue which was purified by column chromatography over 100-200 mesh silica gel using 10% ethyl acetate and pet ether to afford 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-propyl-1H-indole-2-carboxylic acid ethyl ester (0.2 g, yield: 38%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
An amount of 1.36 mL (14.14 mmol) of pyridin-2-yl-methanol is dissolved in N,N-dimethylformamide (10 mL) and cooled to 0° C., addition of 678.72 mg (28.28 mmol) of sodium hydride followed. The reaction mixture is kept at 0° C. for 1.5 hours. 1-Fluoro-4-nitrobenzene 1.5 mL (14.14 mmol) is subsequent added and stirred at room temperature overnight. 100 mL of water is added to the mixture and stirred for 10 more mins. The precipitate is filtered and washed many times with water. The white solid is re-dissolved in methylene chloride extracted three times with brine, dried over darko and magnesium sulfate, and evaporated to give the desired product as a white solid 2.7 g (85% yield); mp: 116-117° C.
Reaction SMILES: [F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C:16](=[CH:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2.[H][H]>C(O)C.[Pd]>[F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@@H:16]([CH2:17][CH2:18]3)[CH2:15][C:14](=[O:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F

Procedure:
14α-Fluoro-3β-hydroxyandrost-5(6)-en-17-one (400mg) in ethanol (70 ml) was hydrogenated over palladium-charcoal (5%; 250 mg) until uptake of hydrogen ceased (72 hr). The solvent was evaporated in vacuo and the crude product was recrystallised from acetone: hexane to give prisms of
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:11]([CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Reactant: BrCc1ccccc1Br
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccccc3Br)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 2-bromobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[S:19][CH2:18][CH2:17][S:16]2)[C:6]([CH3:27])=[N:5][CH:4]=1.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl>[Cl:30][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[S:19][CH2:18][CH2:17][S:16]2)[C:6]([CH3:27])=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncc(CO)n1-c1ccc(Cl)cc1C1(c2ccccc2F)SCCS1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(CCl)n1-c1ccc(Cl)cc1C1(c2ccccc2F)SCCS1
Reaction time: 0.5 h

Procedure:
The hydroxy derivative of formula VIII (4 gm) was stirred in 20 ml of chloroform at 0° to 5° C. and to this was added thionyl chloride (2.5 gm) and stirred at 5°-10° C. for 30 minutes, and then for 1 hr. at 20°-25° C. Chloroform was recovered completely and to this was added 20 ml of THF. The precipitated solid was filtered under nitrogen atmosphere and washed well with THF (20 ml). The title compound was obtained as an off-white powder (4.6 gm) as its hydrochloride. Melting point 147°-150° C.; NMR (DMSO, 200 MHz): δ 2.19 (S, 3H, CH3), 3.2-3.5 (m, 4H, S--CH2 ×CH2 --S), 4.5-4.9 (dd, 2H, CH2,Cl) 7.19-8.34 (m, 3H, aromatic-H); IR (KBr): 3500, 1610, 1480, 1100, 780 cm-1.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([N+:18]([O-])=O)[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[CH2:30][CH:29]([NH:35][C@@H:36]([CH2:40][CH2:41][CH3:42])[C:37](O)=[O:38])[CH2:28][CH2:27]2>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([NH:18][C:37](=[O:38])[C@@H:36]([NH:35][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:40][CH2:41][CH3:42])[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(C)CNC[C@H](c1ccccc1)n1cnc([N+](=O)[O-])c1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn([C@H](CNCC(C)(C)C)c2ccccc2)cn1

Procedure:
(S)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)propan-1-amine was reduced and coupled with (S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 538 m/z (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:83][C:84]1[CH:92]=[CH:91][CH:90]=[C:89]([F:93])[C:85]=1[C:86]([NH2:88])=[O:87]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:83][C:84]1[CH:92]=[CH:91][CH:90]=[C:89]([F:93])[C:85]=1[C:86]([NH:88][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:87]
Reactant: Fc1cccc(Nc2nccc(-c3c(-c4cccc(Br)c4)nn4cc(C(F)(F)F)ccc34)n2)c1
Reactant: NC(=O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1c(F)cccc1F
Yield: 29.6 %

Procedure:
To a solution of 4-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine (125 mg, 0.24 mmol) in dioxane (10 mL) was added Pd2 dba3 (7 mg, 0.007 mmol), Cs2CO3 (94 mg, 0.34 mmol), Xantphos (7 mg, 0.011 mmol), and 2,6-difluorobenzamide (44 mg, 0.28 mmol). The reaction mixture was then subjected to microwave irradiation (Personal Chemistry Optimizer, 170° C., 15 min). The reaction was then cooled and the mixture partitioned in EtOAc (100 mL) and water (25 mL). The organic layer was separated, dried (over MgSO4) and concentrated. The crude material was purified by silica gel column chromatography (20-50% EA/Hex) to provide the title compound (43 mg, 30%) as an beige solid. 1H NMR (400 MHz, d6-DMSO): δ 10.95 (s, 1H), 9.88 (s, 1H), 9.54 (s, 1H), 8.54 (d, J=9.3 Hz, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.07 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (m, 2H), 7.59 (m, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.43 (d, J=9.3 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.25 (m, 3H), 6.71 (dt, J=2.3, 8.4 Hz, 1H), 6.65 (d, J=5.1 Hz, 1H) ppm. ESIMS (M+H)+=605.
Reaction SMILES: [CH2:1]([NH2:14])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][NH2:13].[C:15]([OH:19])(=O)[CH2:16][OH:17]>O>[OH:19][CH2:15][C:16]([NH:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][CH2:1][NH:14][C:15](=[O:19])[CH2:16][OH:17])=[O:17]
Reactant: NCCCOCCCCOCCCN
Reactant: O=C(O)CO
Solvent: O
Product: O=C(CO)NCCCOCCCCOCCCNC(=O)CO
Reaction time: 2 h

Procedure:
4,9-Dioxadodecane-1,12-diamine (22.8 g, 0.112 mole) was placed in a 250 ml round bottom flask and glycolic acid (17.0 g, 0.224 mole) added portion-wise with stirring and cooling. The resultant liquid was heated in an oil bath to 185° C. whereupon distillation of water occurred. Heating was continued at 185° to 195° C. for 2 hours after which time distillation of water subsided and the liquid was poured into a crystallization dish. The resultant oil slowly crystallized in the form of large white clusters; yield 35.5 g (99.3%); m.p. 67°-71° C. The solid was recrystallized from cold absolute methanol to give a white, crystalline product; m.p. 74°-77° C.; infrared (Nujol), 1120 cm-1, 1625 cm-1, 3250 cm-1 ; proton nuclear magnetic resonance (CDCl3 /TMS, 100 MHz), δ1.55-1.95 (complex multiplet, 8 protons), δ3.30-3.65 (complex multiplet, 12 protons), δ4.03 (singlet, 4 protons), δ4.98 (broad singlet, 2 protons), δ7.51 (broad triplet, 2 protons).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(C2(CO)CCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn(C2(CO)CCC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 98.3 %

Procedure:
To a solution of (1-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)methanol (480 mg) obtained in Step B of Example 127 in ethanol (30 mL) was added 10% palladium-carbon (100 mg), and the mixture was stirred at room temperature for 10 hr under hydrogen atmosphere (at normal pressures). The palladium-carbon was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (400 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([F:13])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.CO>ClCCCl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([F:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Fc1cccc(C2(F)CCN(Cc3ccccc3)C2)c1F
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: Fc1cccc(C2(F)CCNC2)c1F
Yield: 19.3 %

Procedure:
To a solution of 1-benzyl-3-(2,3-difluorophenyl)-3-fluoropyrrolidine (1.6 g, 5.5 mmol) in dry 1,2-dichloroethane (10 mL) under nitrogen was added 1-chloroethylchloroformate (600 μl, 5.5 mmol). The mixture was stirred at ambient temperature for 7 h after which methanol was added and the mixture was evaporated. Methanol (10 mL) was added and the mixture was heated at reflux for 4 h. The mixture was evaporated and purified by column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) to give the title compound (214 mg). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 136° C.; MS m/z (relative intensity, 70 eV) 201 (M+, 35), 151 (bp), 158 (69), 138 (45), 133 (42).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCCCC12OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(COCC2CCCCC23OCCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-6-ylmethanol (2.3 g, 13.3 mmol) in THF (20 mL) and cooled in an ice bath, was treated with a NaH (0.48 g, 20.0 mmol). The reaction mixture was stirred for 1 hour and then benzyl bromide (2.4 mL, 20 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at rt for 5 hours and then diluted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulfate and concentarted. Purification by silica chromatography using hexane-Et2O 20% linear gradient afforded the title compound as pale yellow solid. MS m/z 263.2 (M+1).
Reaction SMILES: C([NH:8][C@:9]([CH3:30])([CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH:15]=1)[CH2:10][OH:11])(OC(C)(C)C)=O>Cl>[NH2:8][C@:9]([CH3:30])([CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH:15]=1)[CH2:10][OH:11]
Reactant: CCCCCOc1ccc2cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc2c1
Agent: Cl
Product: CCCCCOc1ccc2cc(CC[C@@](C)(N)CO)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Boc-(R)-2-amino-2-methyl-4-(6-pentyloxynaphthalen-2-yl)butan-1-ol (21 mg, 0.05 mmol) is dissolved in methanolic hydrochloric acid solution and stirred for 2 hours at RT. The solvent is distilled off in vacuo, and the residue is dried to obtain the title compound as its hydrochloride salt. NMR (CDCl3/d6DMSO=2/1) δ 7.65 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.07-7.17 (m, 2H), 4.06 (t, J=6.7 Hz, 2H), 3.71 (s, 2H), 2.78-2.88 (m, 2H), 2.0-2.1 (m, 2H), 1.8-1.9 (m, 2H), 1.38-1.53 (m, 4H), 1.41 (s, 3H), 0.95 (t, J=7 Hz, 3H). ESI+ MS: m/z=316.5 (MH)+.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.Cl.[CH2:35]([O:38][NH2:39])[CH:36]=[CH2:37]>>[CH2:35]([O:38][NH:39][C:3](=[O:5])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:36]=[CH2:37]
Reactant: C=CCON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: C=CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with O-allylhydroxylamine hydrochloride. ESI-MS [M+H]+: 498.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:34])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:33])=O)=[CH:27][CH:26]=2)[C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)(=[O:38])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=[O:34])[NH:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:33])[NH:52][C:49]3[CH:50]=[CH:51][C:46]([CH2:45][N:42]4[CH2:41][CH2:40][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:44][CH2:43]4)=[CH:47][CH:48]=3)=[CH:29][CH:30]=2)[C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-(4′-Carboxy-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (50 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (29 mg), HBTU (61 mg) and N-methyl morpholine (0.033 ml) in dry DMF (3 ml) was stirred at room temp for 18 h. Water (10 ml) was then added and the cream solid collected by filtration and used without purification or characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:6]1[C:7]2[O:11][C:10]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1cccc2oc(C3(C)OCCO3)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c2oc(C3(C)OCCO3)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole (129 m), N-bromosuccinimide (107 mg) and acetonitrile (5 ml) were combined and stirred at room temperature under nitrogen for 4 h. The mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (2×50 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as a white solid (95 mg).