Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.[O:26]1C[CH:27]1[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[OH:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:39]=[C:38]([C:40]3[O:44][N:43]=[C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:41]=3[C:51]([F:54])([F:53])[F:52])[O:37][N:36]=2)=[CH:31][CH:30]=1)[CH2:6][N:8]1[CH2:9][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)O)C1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 1.6 %

Procedure:
2-(1-(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (53.9 mg, 0.250 mmol) was treated with TFA/DCM for 1 hour. Solvents were removed in vacuo and the resulting material was dried. The solids were dissolved in 2-propanol (5 mL) and 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (50 mg, 0.125 mmol) and cesium carbonate (245 mg, 0.751 mmol) were added. The reaction mixture was treated at 90° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. After concentration, the material was repurified by HPLC to yield 1 mg of 2-(1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)azetidin-3-yl)acetic acid as a TFA salt. MS (m+1)=515. HPLC Peak RT=3.24 minutes(Analytical Method A). Purity=95%.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C=O.[CH2:19]([N:26]1[C:30]2[C:31]([Cl:35])=[N:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]1Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([N:26]1[C:30]2[C:31]([Cl:35])=[N:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccc2c1N(Cc1ccccc1)C(Cl)N2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccnc(Cl)c3n2Cc2ccccc2)CC1
Temperature: 150 °C
Yield: 14.9 %

Procedure:
0.094 g of t-butyl piperazine-1-carboxylate was added to a 1 ml N,N-dimethylformamide solution of 0.127 g of 3-benzyl-2,4-dichloro-1,3-dihydroimidazo[4,5-c]pyridine, and the mixture was heated at 150° C. for two hours. 25 ml of ethyl acetate was added to the mixture, and the organic layer was washed three times with 10 ml of water and then with 10 ml of an aqueous solution saturated with sodium chloride. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.029 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][CH:22]([O:36][CH3:37])[C:23]1[C:28](F)=[C:27]([N+:30]([O-:32])=[O:31])[C:26]([O:33][CH3:34])=[CH:25][C:24]=1[F:35]>C1COCC1>[CH3:37][O:36][CH:22]([O:21][CH3:20])[C:23]1[C:24]([F:35])=[CH:25][C:26]([O:33][CH3:34])=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: COc1cc(F)c(C(OC)OC)c(F)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(OC)OC)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-iodo-phenyl amine (2.97 g, 12.5 mmol) in THF (20 mL) was added LHMDS (24 mL, 1.0 M solution in hexanes 24 mmol) dropwise maintaining the temperature below −65° C. After stirring for 30 minutes a solution of 2-dimethoxymethyl-1,3-difluoro-5-methoxy-4-nitro-benzene (3.0 g, 11.4 mmol) in THF (20 mL) was added dropwise, the resultant mixture stirred cold (−78° C.) for 1 hour then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride and extracted twice with diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give an orange solid. The crude orange solid was triturated in diethyl ether to give the title compound as a yellow solid (4.2 g, 77%). 1H NMR (CDCl3) 7.36 (1 H, dd, J=10.09, 1.93 Hz), 7.28-7.17 (2 H, m), 6.59 (1 H, t, J=8.62 Hz), 6.44 (1H, d, J=11.47 Hz), 5.49 (1 H, s), 3.88 (3 H, s), 3.39 (6 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:43]1C(C)=CC=CC=1C>C(Cl)Cl.[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:43])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(N)=O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.7 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 100 mg, 0.19 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (100 μL, 0.20 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (44 μL, 0.38 mmol) was added. The reaction continued to stir at 0° C. for 20 min. Concentrated aqueous ammonium hydroxide (4 drops) was added. The ice bath was removed and the reaction continued to stir at 25° C. for 20 min. The reaction was diluted with ethyl acetate (20 mL), washed with water (2×5 mL), saturated aqueous brine solution (1×5 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzamide (49 mg, 49%) as an off white powder: ESI-LRMS m/e calcd for C26H29ClN4O4S [M+] 528.16, found 529.19 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.35-1.92 (m, 8H, 4×CH2), 2.11-2.26 (m, 1H, CH), 3.23 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1H, CH), 5.18 (s, 2H, NCH2), 6.08 (br.s., 2H, NH2), 6.74 (d, J=2.0 Hz, 1H, Ar), 7.15 (d, Jo=8.1 Hz, 2H, Ar), 7.37 (d, J=2.0 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.72 (d, Jo=8.1 Hz, 2H, Ar), 7.98 (d, Jo=8.1 Hz, 1H, Ar), 8.79 (s, 1H, NH).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1Br)(=[O:3])[CH3:2].[Cu](C#N)[C:11]#[N:12]>CN1C(=O)CCC1.O>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:11]#[N:12])(=[O:3])[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)c1sccc1Br
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1sccc1C#N
Yield: 99.8 %

Procedure:
Heat a stirred solution of 2-acetyl-3-bromothiophene (1.49 g, 7.29 mmol) (Chem. Pharm. Bull. 2000, 48, 1558-1566) in dry NMP (72 mL) for 10 h at 150° C. in the presence of copper cyanide (3.26 g, 36.5 mmol). Dilute the mixture with water, extract three times with diethyl ether, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give the desired intermediate as a dark oil (1.1 g, 99%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[O:6]=[C:2]1[NH:3][CH2:4][CH2:5][N:1]1[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCNC1=O
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of imidazolidin-2-one (0.2 g; 2.3 mmol) in anhydrous DMF (5 ml) 60% NaH in mineral oil (0.18 g; 4.6 mmol) was added at room temperature, under N2. After stirring for 1 h, tert-butyl 2-bromoacetate (0.35 ml; 2.3 mmol) was added. The resulting mixture was stirred for additional 2 h and solvents were removed in vacuo. The residue was diluted to 15 ml with EtOAc, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, EtOAc) to give the title compound (0.12 g; 26%) as a colourless solid. 1H-NMR (CDCl3) 4.61 (broad s, 1H); 3.83 (s, 2H); 3.58-3.41 (m, 4H); 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:17]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: OCCCc1ccc(O)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(CCCO)cc1
Yield: 99.4 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (5.5 g, 27 mmol) (Alfa) was reacted with 3-(4-hydroxyphenyl)-1-propanol (4.5 g, 30 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-[4-(3-hydroxy-propyl)-phenoxy]-benzaldehyde as a brown oil (Yield 9 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[NH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C@@H:19]2[C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:40]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH3:40])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C@@H:19]2[C:30]2[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)cc(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2S[C@@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a solution of N2-[(3,5difluorophenyl)acetyl]-N1-[(2R,3R)-2-(3,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-alaninamide (16) (85 mg, 0.16 mmol) in DMF (1 ml) was added a 60% suspension of NaH (6.6 mg, 0.165 mmol). The reaction was stirred at RT for 5 min and methyl iodide (23 mg, 0.16 mmol) was added via syringe. The reaction was stirred at RT for 3 h and was quenched with dropwise addition of 1N HCl, diluted with water and extracted with ethyl acetate. The organic phase was collected and washed with H2O, dried, filtered and evaporated to yield a crude oil (85 mg). The crude product was purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound (17) (70 mg, 80%) as a 1:1 mixture with the 2S,3S diastereomer as a white solid. 1H NMR (300 MHz, CDCl3) δ0.99 (d, 1.5H), 1.17 (d, 1.5H), 3.44 (s, 1H), 3.46 (s, 1H), 3.50 (s, 3H), 4.24 (m, 1H), 4.70 (m, 1H), 5.15 (m, 1H), 5.77 (d, 0.5H), 5.91 (d, 0.5H), 6.46 (dd, 1H), 6.65-6.92 (m, 6H), 7.31 (m, 2H), 7.51 (m, 1H), 7.71 (m, 1H). MS APCI, m/z=546 (M+1). LC/MS: 2.80 min.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[NH:8][C:7]=1[NH2:19])=[O:5])C.[CH3:20][N:21](C=O)C.C(N)=O>C(O)=O>[OH:5][C:4]1[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)[NH:8][C:7]=2[N:19]=[CH:20][N:21]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)[nH]c1N
Solvent: NC=O
Solvent: O=CO
Product: N#Cc1ccc(-c2cc3c(O)ncnc3[nH]2)cc1
Temperature: 150 °C

Procedure:
A mixture of 36.6 g (0.143 mol) 2-amino-5-(4-cyano-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester, 140 ml DMF, 305 ml formamide and 14.6 ml 85% formic acid is heated for 16 h at 150° C. The resulting yellow suspension is cooled to 10° C. and filtered. The solid is washed with methanol (120 ml) and ether (150 ml) and dried. The title compound is obtained as yellowish crystals; m.p.>410° C.; MS-ES+: (M+H)+=254.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=[CH:31]3)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[C:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=[CH:31]4)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 80 °C
Yield: 55.8 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.110 g, 0.35 mmol) (from multiple batches), ethyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.102 g, 0.35 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and diisopropyl azodicarboxylate (0.063 mL, 0.35 mmol) in toluene (3.5 mL) was placed in microwave reaction tube and heated to 80° C. for 1000 seconds. The solution was concentrated and purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.115 g, 51.6% as 0.7EtOAc). 1H NMR (DMSO-d6): δ 8.79 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.09 (d, J=7 Hz, 1H), 7.98 (dd, J=2, 9 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.60 (m, 1H), 7.42 (d, J=8 Hz, 2H), 7.25 (t, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 2H), 4.98 (s, 2H), 4.40 (q, J=7 Hz, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.24-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.37 (t, J=7 Hz, 3H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 588 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12](Cl)=[N:13][CH:14]=1>COCCOC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:7][CH2:6][CH2:5][O:4][CH3:3])=[N:13][CH:14]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCOc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of NaH 55% (133 mg, 3.06 mmol) in DME (3 ml) was cooled to 0° C., then 2-methoxyethanol (Aldrich, Buchs, Switzerland, 0.362 ml, 4.58 mmol) was added. The solution was stirred at rt for 15 min. After that 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 294 mg, 1.528 mmol) was added and the RM was heated by microwaves at 150° C. for 10 min. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were evaporated together to give the title compound as a colorless oil. (LC-MS: tR 1.20 min (Method B); M+H=232, 234 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.28.8.21 (m, 1H), 7.91-7.84 (m, 1H), 6.86-6.79 (m, 1H), 4.31 (t, 2H), 3.62 (t, 2H), 3.26 (s, 3H))
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[C:31]1([CH:37]([NH2:45])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([CH:37]([NH:45][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(Cc1ccccc1)c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Example 3(b) was repeated, except that S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1,2-diphenylethylamine were employed as starting materials, in relative proportions similar to those used in that Example, to give the title compound in a quantitative yield.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br.C(Cl)Cl.CO>C(Cl)Cl>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:12][CH:13]=1)=[O:6]
Reactant: COc1ccc(C(=O)Nc2ccc(-c3nc4ccc(OC)cc4s3)cc2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccc(-c2nc3ccc(O)cc3s2)cc1)c1ccc(O)cc1C(F)(F)F
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Prepared as described in the Demethylation section using 2-trifluoromethyl-N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-4-(methoxy)benzamide (0.30 g, 0.655 mmol) in dry DCM (15 ml) and BBr3 (1.0M in DCM, 1.4 ml, 1.4 mmol) at −78° C. under an atmosphere of argon. Stirring was continued at −78° C. for 1 h, and then the reaction mixture was allowed to rise to room temperature overnight. A further volume of BBr3 (1.0 M in DCM, 1.4 ml, 1.4 mmol) was added and the reaction mixture stirred at room temperature for 24 h to give the title compound (0.175 g, 62%) as a colourless solid after work-up and flash chromatography (15:1 DCM/MeOH).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:18])[F:17])=[O:12])[CH2:2][CH2:3]2)=[O:30])=[CH:27][CH:26]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a stirred mixture of 3-(piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (3.07 mmol, 1.01 g), 4-aminobenzoic acid (3.07 mmol, 0.421 g) and triethylamine (6.13 mmol, 0.855 mL, 0.621 g) in dichloromethane (30.7 mL) was added 1-propanephosphonic acid cyclic anhydride (6.13 mmol, 3.63 ml, 3.90 g, 50% solution in ethyl acetate). After 2 hours stirring, dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (640 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH2:18])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[O:25]>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH:18][C:20](=[O:25])[CH2:21][S:22][CH2:23][CH2:24][OH:19])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CSCCO1
Reactant: NC/C=C\COc1cc(CN2CCCC2)ccn1
Product: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCC2)ccn1

Procedure:
Following a procedure similar to that described in Example 68, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, N-{4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenyl}-2-(2-hydroxyethylthio)acetamide was obtained. This product was reacted with acetic anhydride in the same manner and same relative proportions as described in Example 67(c), to give the title compound in a 42% yield.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[N:28]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31][CH:30]2[CH2:34][NH:35][CH2:36][CH:29]12.C(N(CC)CC)C>C(#N)C>[NH2:18][C:16]1[N:17]=[C:12]([N:35]2[CH2:34][CH:30]3[CH:29]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31]3)[CH2:36]2)[C:13]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[C:14]=2[N:15]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC21

Procedure:
A solution of the product from Example 59C (76 mg, 0.2 mmol), t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS #159877-36-8) (59 mg, 0.22 mmol) and triethylamine (0.1 mL) in acetonitrile (1 mL) was heated in a microwave reactor at 160° C. for 1 hour. The mixture was concentrated and chromatographed on silica gel eluting with EtOAc:hexane (1:1) mixture to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[OH:10][C:9]1[C:2]([O:1][CH2:18][CH2:19][CH3:20])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(O)cccc1C=O
Yield: 42.3 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.16 g, 8.40 mmol), potassium carbonate (1.16 g, 8.40 mmol) and 1-iodopropane (0.82 mL, 1.43 g, 8.40 mmol) in dry DMF (10 mL) were stirred at ambient temperature for 20 h. The reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with water (2×), then extracted with 1N sodium hydroxide solution (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with diethyl ether. The ether layer was washed with 10% sodium hydrogen carbonate (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 3-hydroxy-2-propoxybenzaldehyde (0.64 g, 42%) as a yellow solid.