Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCCC5CCN(C6CC6)CC5)N=4)SC=3C=CC=2)=O)[CH2:5][CH2:4]1.[CH3:38][NH:39][C:40]([C:42]1[C:50]2[CH:49]=[C:48]([C:51]3[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)[N:52]=3)[S:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]>>[ClH:24].[ClH:1].[CH3:38][NH:39][C:40]([C:42]1[C:50]2[CH:49]=[C:48]([C:51]3[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH:61]4[CH2:62][CH2:63][N:64]([CH:3]5[CH2:5][CH2:4]5)[CH2:65][CH2:66]4)[N:52]=3)[S:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Br)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCN(C5CC5)CC4)ncc3Cl)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCN(C5CC5)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(1-cyclopropylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-bromo-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 514 (79Br) and 516 (81Br) [M(free base)+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[F:36][CH:37]([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([S:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:18][C:17]=2[Cl:26])(=[O:13])=[O:14])[CH2:38][CH:37]([F:47])[F:36])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)c1nccnc1NS(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nccnc1N(CC(F)F)S(=O)(=O)Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 44 h
Yield: 75 %

Procedure:
To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (1.2 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 44 hours. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenylmethanesulfonyl)-(2,2-difluoro-ethyl)-amino]-pyrazine-2-carboxylic acid methyl ester as a light yellow solid (1.300 g). 1H-NMR (400 MHz, CDCl3): 8.63 (s, 1H), 8.53 (s, 1H), 7.76 (m, 1H), 7.53-7.59 (m, 2H), 6.15 (tt, 1H), 4.69 (s, 2H), 4.23-4.31 (m, 2H), 4.02 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)[C:11](Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1ncsc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1scnc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-methylthiazole-5-carboxylic acid was dissolved in DCM, cooled to 0° C., added oxalyl chloride (7.6 ml, 88 mmol) and DMF (2 drops). Reaction mixture was stirred for 30 mins and DCM was removed on rotavapour. Residue was dissolved in MeOH at 0° C. and stirred for 30 mins at rt. MeOH was removed on rotavapour and crude was worked up (AcOEt/H2O) to obtain the title compound (4.1 g) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.83 (s, 1H), 4.35 (q, J 7.2, 2H), 2.78 (s, 3H), 1.37 (t, J 7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14](C(OC(C)(C)C)=O)[N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[C:9]=2[C:44]#[N:45])=[C:4]([F:46])[CH:3]=1.[CH3:47][O-].[Na+].C=O.[BH4-].[Na+]>CO.O>[C:44]([C:9]1[C:10]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)=[C:11]2[C:16]([CH3:17])=[N:15][NH:14][C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH3:47])=[CH:3][C:4]=1[F:46])#[N:45]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2nc(-c3ccc(N)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Reactant: C[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1ccc(-c2nc3[nH]nc(C)c3c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2C#N)c(F)c1
Yield: 20.8 %

Procedure:
To a solution of 0.20 g (0.32 mmol) of tert-butyl 6-(4-amino-2-fluorophenyl)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate in 40 ml of MeOH are added 0.16 mg (2.9 mmol) of sodium methoxide and 0.10 g (3.2 mmol) of paraformaldehyde. The reaction mixture is refluxed for 2 h. The mixture is then cooled, 0.24 g (6.34 mmol) of sodium borohydride is added, and the mixture is refluxed for 1 h. The mixture is then cooled, diluted with iced water, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The solid obtained is then purified by chromatography on silica (methanol gradient in dichloromethane: 1 to 2%) to give 0.036 g (18%) of tert-butyl 4-(4-(5-cyano-6-(2-fluoro-4-(methylamino)phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)piperazine-1-carboxylate in the form of yellow crystals. Deprotection of the piperazine following general procedure E2 gives 0.02 g (68%) of 6-(2-fluoro-4-(methylamino)phenyl)-3-methyl-4-(4-(piperazine-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile hydrochloride in the form of orange crystals.
Reaction SMILES: [CH:1]1([CH:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[C:21](F)[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Cl:27][Sn]Cl>>[Cl:27][C:21]1[C:20]([O:24][CH3:25])=[CH:19][C:18]([CH3:26])=[C:17]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[C:13]=2[NH2:14])[CH:22]=1
Reactant: Cl[Sn]Cl
Reactant: CCC(Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-])C1CC1
Product: CCC(Nc1nccc(-c2cc(Cl)c(OC)cc2C)c1N)C1CC1
Yield: 102 %

Procedure:
(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.13 g, 0.34 mmol) and SnCl2 (0.19 g, 1.0 mmol) were treated substantially as described in Part D of Example 74a to yield 0.12 g (96%) of 4-(5-chloro-4-methoxy-2-methyl-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:23])[CH:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(O)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Oc2cc(F)c(C(F)(F)F)c(Cl)c2)ccc1Br
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-5-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]benzoic acid (15 g, 0.035 mol) in thionyl chloride (75 mL) is heated at 60° C. for 2 hours and concentrated in vacuo to give the title product.
Reaction SMILES: [CH2:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:28][C@H:29]([CH2:32][N:33](C)[C:34](OCC[Si](C)(C)C)=O)[CH2:30][OH:31])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([NH:28][C@H:29]([CH2:32][NH:33][CH3:34])[CH2:30][OH:31])=[O:27])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)N[C@@H](CO)CNC)C1
Temperature: 50 °C
Yield: 37.9 %

Procedure:
To a solution of (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (10.0 mg, 0.01 mmol) in acetonitrile (1.0 mL) was added excess tetraethylammonium fluoride. The resulting solution was heated at 50° C. for 2 h, and concentrated under vacuum. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(2-(2-ethylphenoxy)phenyl)-1-hydroxy-5-methoxypentyl)-N—((R)-1-hydroxy-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (2 mg) as its TFA salt. 1H NMR (400 MHz, CD3OD) 7.62 (d, 1H), 7.32 (d, 1H), 7.04-7.20 (m, 4H), 6.74 (d, 1H), 6.56 (d, 1H), 4.40 (d, 1H), 4.00 (m, 1H), 3.92 (d, 1H), 3.60 (m, 1H), 3.54 (m, 1H), 3.26 (t, 2H), 3.24 (s, 3H), 3.22 (m, 1H), 3.04 (m, 1H), 2.82 (m, 1H), 2.64 (s, 3H), 2.62 (q, 2H), 2.42 (m, 2H), 1.94 (m, 1H), 1.24-1.64 (m, 7H), 1.08 (t, 3H), 0.98 (m, 1H); MS m/z 528 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.[CH:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:20]([CH:17]2[CH2:19][CH2:18]2)[S:22][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C#N)cc1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C#N)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-cyano-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:18]=1[F:27]>CN(C=O)C>[F:27][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:17]=1[CH2:16][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(Cc2c(F)cccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Nitropyrazole (Aldrich; 4.974 g, 44.0 mmol) was dissolved in DMF (100 ml) and potassium carbonate (9.12 g, 66.0 mmol) was added. The reaction mixture was allowed to stir at ambient temperature under nitrogen for approximately 5 minutes. 2-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (Aldrich; 11.31 g, 44.0 mmol) in DMF (25 ml) was then added over a period of approximately 5 minutes and the reaction was left to stir overnight.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)=[O:4].[C:17]([O:21][C:22](=[O:38])[NH:23]/[C:24](/N1C=CC=N1)=[N:25]/[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:28]([O:27][C:26]([NH:25]/[C:24](/[NH:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[C:3]([NH:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)=[N:23]/[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:38])=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(N)cc1
Solvent: ClCCl
Product: CNC(=O)[C@H]1CCCN1c1ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To (R)-1-(4-amino-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 57; 1.0 g, 4.5 mmol) in DCM (60 ml) was added di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (1.7 g, 5.5 mmol) in one portion. The reaction was stirred overnight before removal of the solvent in vacuo. The residue was purified via column chromatography eluting with 20% EtOAc/isohexane, 50% EtOAc/iso-hexne and finally 100% EtOAc. The title compound was obtained as a white foam (1.9 g, 91%).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:29])[C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.[CH3:39][NH:40][CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH3:41])[C:25]([C:23]1[O:24][C:20]2[C:19]([CH3:29])=[CH:18][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:31])[C:2]([CH3:33])([CH3:32])[CH3:1])=[C:7]([CH3:30])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:28][C:21]=2[CH:22]=1)=[O:26]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)N(C)C)cc2c1
Yield: 97.9 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid (270 mg, 0.599 mmol) in CH2Cl2 (10 mL) and DMAP (220 mg, 1.80 mmol), EDC (172 mg, 0.898 mmol), and dimethyl amine hydrochloride (73 mg, 0.90 mmol) are reacted analogous to Example 5 to yield title compound (280 mg, 98%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(#N)C>[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=1[CH2:31][NH:32][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Reactant: NCc1ccc(OC(F)(F)F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (70.0 g, 0.28 mol), (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine (58.3 g, 0.28 mol), DIPEA (63.1 mL, 0.36 mol) and acetonitrile (350 mL) was stirred at 80° Celsius for 16 h. The reaction was cooled to RT, concentrated to dryness, and the resulting residue was recrystallized from ethanol (350 mL) and H2O (350 mL). The solid was collected by filtration and rinsed with a mixture of H2O/ethanol (3:1, 200 mL) followed by hexanes (2×300 mL) yielding the title compound as a yellow solid (116.3 g, 94.7%). MS (ESI): mass calcd. for C19H16F4N4O4, 440.1; m/z found, 441.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.68-8.52 (m, 1H), 8.20-8.14 (d, J=9.5, 1H), 7.39-7.34 (m, 1H), 7.34-7.31 (d, J=2.2, 1H), 7.06-6.97 (d, J=9.8, 2H), 6.42-6.33 (dd, J=9.5, 2.5, 1H), 6.33-6.24 (m, 2H), 5.09-5.01 (s, 2H), 4.60-4.52 (d, J=5.9, 2H), 3.93-3.85 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=CC=1>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:27]=[N:26][CH:25]=2)=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Brc1ccc(-c2cnco2)nc1

Procedure:
To a stirred suspension of 5-bromopicolinaldehyde (0.412 g, 2.215 mmol, Tetrahedron Letters 2008, 64, 3794-3801) and potassium carbonate (0.3358 g, 2.43 mmol, Rankem) in MeOH (20 mL) was added toluenesulphonylmethyl isocyanide (0.4757 g, 2.43 mmol). The reaction mixture was heated to reflux for about 4 h. The reaction mixture diluted with water (100 mL) and the product was extracted with EtOAc (2×75 mL). The combined organic layers were washed successively with water (2×50 mL) and brine (1×50 mL), dried over sodium sulphate and evaporated to dryness. The crude material obtained was purified by silica gel column chromatography eluted with 10% EtOAC in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 5-(5-bromopyridin-2-yl)oxazole as an off white solid 0.35 g (70.2%), 1H NMR (400 MHz, DMSO): δ 8.7 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.2 (dd, J=8.4 Hz, 1H), 7.8 (s, 1H), 7.7 (d, J=8.8 Hz, 1H), MS m/z: 226 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH3:30])[N:22]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1oc(-c2ccc(-c3ccc(F)cc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 10 mg (10%). MS (m/e) 365.2 (M+1)
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.[CH:14](OCC)(OCC)OCC>O1CCCC1.C(OCC)(=O)C>[O:12]1[C:11]2[C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=[CH:14]1
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Reactant: CCOC(OCC)OCC
Agent: Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCc2ccc3ncoc3c21
Yield: 61.7 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (50 mg, 0.205 mmol) and triethyl orthoformate (128 μL, 0.769 mmol) were heated under reflux in tetrahydrofuran (2.5 mL) for 0.5 hr. The mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (21.9 mg, yield from Reference Example 362%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCCNC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(C2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a solution of (RS)—N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide (1.0 g, 2.5 mmol) in 1,4-dioxane (9.5 ml) was added a solution of hydrogen chloride (4M in 1,4-dioxane, 9.5 ml, 38 mmol) and the mixture stirred at ambient temperature for 6 hours. The solid formed was collected by filtration, washed with diethyl ether and dried in vacuo. It was treated with a 2M solution of aqueous sodium hydroxide and extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated to afford the product as a colourless solid (0.73 g, 99%); NMR Spectrum: (DMSO-d6) 1.71 (m, 4H), 2.61 (m, 2H), 2.75 (m, 1H), 3.03 (m, 2H), 4.92 (s, 2H), 6.65 (t, 1H), 6.83 (d, 1H), 7.02 (t, 1H), 7.23 (d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 9.61 (s, 1H); Mass Spectrum: M+H+ 296.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:21])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C.CC(OC)(C)C>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:9](=[O:21])[O:10][C:11]=2[CH:18]=1
Reactant: COc1ccc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Solvent: COC(C)(C)C
Product: COc1ccc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 29 %

Procedure:
Process A; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 26) and 1-(2-methoxyphenyl)piperazine; yield 29%; m.p. 129°-130° C. (from ethanol/TBME).
Reaction SMILES: CS(O[C@@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[N:21]([C@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 90 °C

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.686 g, 5.71 mmol) from Step C and sodium azide (0.557 g, 8.56 mmol) were combined in N,N-dimethylacetamide (10 mL). The reaction was heated at 90° C. for 15 hours. The reaction was cooled and diluted with 200 mL of ethyl acetate and then quenched with 30 mL water. The organic layer was removed and washed with 2×20 mL of water, then 20 mL of brine. The solvent was removed in vacuo to give (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole: 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.22 (dd, J=2.9, 5.8, 1H), 3.72-3.61 (m, 1H), 3.54 (s, 2H), 2.76-2.60 (m, 1H), 2.55-2.40 (m, 4H), 2.35 (dd, J=3.5, 9.1, 1H), 2.07-1.86 (m, 2H), 1.72-1.60 (m, 1H), 1.49-1.38 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:53])[C@H:10]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:11][C:12](=[O:48])[C@H:13]([C:44]([CH3:47])([CH3:46])[CH3:45])[NH:14][C:15](=[O:43])[C@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])[NH:17]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:53])[C@H:10]([CH2:49][CH:50]([CH3:51])[CH3:52])[NH:11][C:12](=[O:48])[C@H:13]([C:44]([CH3:45])([CH3:46])[CH3:47])[NH:14][C:15](=[O:43])[C@H:16]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccccc1C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Yield: 99.8 %

Procedure:
A solution of 10 g (13.95 mmol) of N-[N-[N-[(9-fluorenyl)-methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanolin dichloromethane for the elution. Evaporation gave 6.9 g of N-[N-[2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester inthe form of an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[NH2:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Nc1c(C(=O)O)ccc(F)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(O)c1N
Temperature: -78 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
To a solution of 2-amino-4-fluoro-3-hydroxybenzoic acid (2.44 g, 9.7 mmol) in methanol (200 mL) was added thionyl chloride (3.8 mL, 50 mmol) at −78° C. The mixture was stirred in the boiling solvent for 17 h. The solvent was removed under reduced pressure; the residue was dissolved in methanol (200 mL). The solution was cooled to −78° C. and treated with thionyl chloride (8 mL, 100 mmol). The mixture was stirred in boiling solvent for 48 h. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 0 to 70% ethyl acetate in hexanes) to afford methyl 2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 44%) as off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.48-7.43 (m, 1H), 6.40 (t, J=9.3 Hz, 1H), 3.87 (s, 3H); MS (ESI+) m/z 186 (M+H).