Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)C.[BH4-].[Na+]>>[Br:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([CH2:5][CH2:4][OH:3])[S:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Agent: [BH4-]
Agent: [Na+]
Product: OCCc1nc2ccc(Br)cc2s1

Procedure:
Compounds of formula (22) can be prepared from 6-bromobenzothiazolone as shown in Scheme 3. 6-Bromobenzothiazolone is heated in the presence of NaOH base to provide a mixture of 2-amino-5-bromothiophenol (15) and its disulfide (16). The mixture is treated with chlorocarbonyl-acetic acid ethyl ester to provide 6-bromo-benzothiazol-2-yl-acetic acid ethyl ester (17) and 7-bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (18), which can undergo rearrangement by treatment with zinc and ethyl acetate to provide compound (17). Compound (17) is reduced with NaBH4 to provide 2-(6-bromo-benzothiazol-2-yl)-ethanol (19). Compound (19) is treated with mesyl chloride in the presence of triethyl amine to afford the corresponding methanesulfonic acid 2-(6-bromo-benzothiazol-2-yl)-ethyl ester (20), which is treated with an amine of formula HNRaRb wherein Ra and Rb each is as defined for R4 and R5, to provide compounds of formula (21). Compounds of formula (21) can be treated with a boronic acid, wherein Rc is aryl or heteroaryl, to provide compounds of formula (22).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12](=[S:14])[NH2:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.Cl[CH:16]([C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2ccc(Br)cn2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2c(C)nc3ccc(Br)cn23)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 65.5 %

Procedure:
To a suspension of 6-bromo-2-methylimidazo[1,2-a]pyridine-3-carbothioamide (700 mg, 2.59 mmol) obtained as described above in DMF (60 mL), was added ethyl 2-chloro-3-oxo-3-phenylpropanoate (1.76 g, 7.77 mmol), and the mixture was stirred at 90° C. for 21 h. The mixture was allowed to cool to rt, and the solvent was removed under reduced pressure. The residue was washed with water, EtOH and diethyl ether to give the titled compound (750 mg, 66%) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:31])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CN
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Product: CNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Yield: 78 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with methylamine to give the title compound as a white solid (156 mg, 78%); NMR Spectrum 1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: Br.[C:2]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([OH:4])=[O:3].[ClH:24].[CH3:25]O>>[ClH:24].[C:2]([C:5]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]([OH:22])[C:6]=1[OH:23])([O:4][CH3:25])=[O:3]
Reactant: O=C(O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1
Reactant: CO
Agent: Br
Agent: Cl
Product: COC(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1

Procedure:
A mixture of 3.0 g (0.0079 mole) of 6-carboxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in 200 ml of methanol saturated with hydrogen chloride gas was heated at reflux for 60 hours. The solvent was stripped off and the residue was triturated with ethyl acetate, then recrystallized from methanol-ethyl acetate to give 6-carbomethoxy-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 216°-219° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27].C(N(CC)C(C)C)(C)C>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:14]([C@@H:15]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1ncc(Br)cc1CBr
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1C[C@H](Cc1cccc(F)c1)N1Cc2cc(Br)cnc2C1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (500.0 mg, 1.618 mmol), 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (482.8 mg, 1.618 mmol) and N,N-diisopropylethylamine (0.564 mL, 3.24 mmol) in 1-butanol (10.0 mL) was stirred at 120° C. for 2 h under microwave. Purification by combi-flash chromatography gave 0.48 g (61% yield) of the desired product. LC-MS found: 494.1 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CSc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CSc1ncccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 0.48 g of 3-acetoxy-2-(methoxycarbonyl)methylthiopyridine, 0.15 g of potassium carbonate, and 3 ml of methanol was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][S:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH2:1]([C:8]1[C:9]2[CH2:30][S:29](=[O:39])[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CSCC3)cc1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CS(=O)CC3)cc1
Reaction time: 2 h
Yield: 13.8 %

Procedure:
4-Benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (90 mg, 0.22 mmol) and mCPBA (56.3 mg, 0.33 mmol) was dissolved in DCM (4 mL). The reaction was completed after 2 h. The solvent was evaporated and the crude product was purified on preparative HPLC yielding 4-benzyl-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine 6-oxide (13.0 mg, 13.0%). MS (ES+) m/z 430.0 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:22])=[N:8][N:9]2[C:14]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][C:12]([CH3:21])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[CH3:22][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH3:21])[CH:13]=[C:14]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]2[N:8]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCCC(C)C)n2nc(C)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of 220 mg (0.469 mmol, 72% pure) of 2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 122A in 4 ml of dioxane was admixed with 2 ml of 2 N sodium hydroxide solution. The resulting mixture was stirred at 100° C. for 15 h. The solvent was removed under reduced pressure. The residue was admixed with acetonitrile (5 ml), followed by the dropwise addition of trifluoroacetic acid (2 ml). The resulting precipitate was filtered off and dried under reduced pressure, which gave 45 mg (28% of theory, 90% pure) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N+:35]([O-])=O.[CH:38](O)=O>[Pd]>[NH:1]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]3)=[O:11])=[CH:4][C:3]=2[N:35]=[CH:38]1
Reactant: O=CO
Reactant: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)CC1
Agent: [Pd]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)CC1

Procedure:
Prepared from N-[1-((4-amino-3-nitro-phenyl)-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-biphenylylsulphonamide and cyclising with formic acid in the presence of palladium/charcoal analogously to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=1.[NH2:16][NH2:17]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:16][NH2:17])[N:11]=[N:12][CH:13]=1
Reactant: CSc1nncc(-c2ccccc2F)n1
Reactant: NN
Solvent: C1CCOC1
Solvent: CO
Product: NNc1nncc(-c2ccccc2F)n1

Procedure:
To a solution of 27.6 g. of 5-(o-fluorophenyl)-3-(methylthio)-1,2,4-triazine in 100 ml. of 1:1 methanol-tetrahydrofuran is added 6.4 ml. of 95% hydrazine. The mixture is refluxed for about 22 hours and then cooled. The solid is recovered by filtration, giving 5-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[S:14]1[CH:18]=[N:17][N:16]=[C:15]1[NH2:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:15]2[S:14][CH:18]=[N:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1nncs1
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Product: O=C(Nc1nncs1)c1ccc(F)c([N+](=O)[O-])c1
Yield: 67 %

Procedure:
The product from Example 172a was reacted with [1,3,4]Thiadiazol-2-ylamine (149 mg, 1.474 mmol) according to the procedure from Example 172b to provide the title compound (272 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC(=O)c1c(Cl)ccc([N+](=O)[O-])c1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ether, the combined organic layers washed with sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate/hexanes in 83% yield as a white solid. m.p. 147-149° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[F:12][C:13]1[CH:27]=[CH:26][C:16]2[CH2:17]C3C=CC=CC=3C=[CH:21][C:15]=2[CH:14]=1>C(Cl)(Cl)Cl.C1(O)C=CC(O)=CC=1>[F:12][C:13]1[CH:27]=[CH:26][C:16]2[CH2:17][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[CH:8]3[O:10][CH:21]3[C:15]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc2c(c1)C=Cc1ccccc1C2
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C1OC1c1ccccc1C2
Temperature: 60 °C
Yield: 110.4 %

Procedure:
Metachloroperbenzoic acid (0.0501 mol) was dissolved in CHCl3 (40 ml). The organic solution was dried, filtered and the filtrate was added dropwise to a solution of intermediate 1 (0.0417 mol) and 1,4-benzenediol (0.26 g) in CHCl3 (70 ml), stirred at 60° C. The reaction mixture was stirred for 2.5 hours at 60° C., then cooled on an ice-bath, washed with a 10% aqueous Na2CO3 solution and brine, dried, filtered and the filtrate was evaporated, yielding 10.42 g of 3-fluoro-6,10b-dihydro-1aH-dibenzo-[3,4:6,7]cyclohept[1,2-b]oxirene (intermediate 2)
Reaction SMILES: Cl[Si:2](Cl)([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[F:10][C:11]([F:17])([F:16])[S:12]([OH:15])(=[O:14])=[O:13].Cl>>[F:10][C:11]([F:17])([F:16])[S:12]([O:15][Si:2]([O:15][S:12]([C:11]([F:17])([F:16])[F:10])(=[O:14])=[O:13])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])(=[O:14])=[O:13]
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cl
Product: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(OS(=O)(=O)C(F)(F)F)C(C)C
Yield: 58.2 %

Procedure:
An oven-dried 100 mL-RB flask is charged with dichlorodiisopropylsilane (9.2 g, 0.05 mol). Then 15 g of trifluoromethanesulfonic acid (15 g, 0.10 mol) is added dropwise. The mixture is heated at 60° C. until no further HCl evolves. The residue is distilled to yield 12 g (60%) of the product as clear liquid. 1H NMR (500 MHz, CDCl3, in ppm) δ 1.58 (heptet, 2H, J=7.2 Hz), 1.24 (d, 12H, J=7.2 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([NH:15][CH3:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([N:15]([CH3:16])[S:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)(=[O:8])=[O:7])=[CH:13][CH:12]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1c[nH]cn1

Procedure:
Imidazole-4-sulphonyl chloride was reacted with 4-chloro-N-methylaniline to give 4-[N-(4-chlorophenyl)-N-methylsulphamoyl]imidazole, m.p. 217°-9°. This was then treated with dimethylsulphamoyl chloride in a similar manner to that described in Example 1, to give 1-dimethylsulphamoyl-4-[N-(4-chlorophenyl)-N-methylsulphamoyl]imidazole, m.p. 131.5°-132°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl>[O:20]=[C:19]([N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:1])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: C1CCNC1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (113 mg, 0.35 mmol) in dichloromethane (4 ml) in a sarstedt tube was treated in one portion with solid 1,1′-carbonyldiimidazole (60 mg, 0.37 mmol). This mixture was shaken at room temperature for 30 minutes. Pyrrolidine (34 mg, 0.48 mmol) in dichloromethane (2 ml) was then added and the shaking continued for 16 hour at room temperature. The reaction mixture was washed with a mix of saturated sodium bicarbonate solution (4 ml) and brine (2 ml). The organic layer was then added to a 2 g SCX column and eluted with ethyl acetate (25 ml), the solvent removed under reduced pressure and the residue purified by mass directed auto-prep to give the title compound as a yellow oil (30 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+]>C1COCC1.CO.[Zn]>[Cl:19][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:14][C:13]([F:15])=[C:12]([NH2:16])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (1.31 g, 4.31 mmol) was dissolved in THF (108 mL) and MeOH (108 mL). Ammonium chloride (2.31 g, 43.1 mmol) was added, followed by zinc dust (2.82 g, 43.1 mmol). The reaction mixture was stirred at RT for 1 h. The solids were filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to yield 5-chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine as a brown solid which was used without purification assuming a 100% yield. MS (ESI) m/z: 273.0 (M+H+).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH:12]=O)=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:15][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CN
Reactant: O=Cc1cccc2c1OCCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2c1OCCCO2
Reaction time: 3 h
Yield: 86 %

Procedure:
3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carbaldehyde (269 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 hours. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.3 mg, 1.54 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (251 mg, 86%) as a brown oil: 1H NMR (400 MHz, DMSO-d6) δ 6.96 (dd, J=8.0, 4.0 Hz, 1H), 6.88-6.82 (m, 2H), 4.10-4.05 (m, 4H), 3.60 (s, 2H), 2.25 (s, 3H), 2.10-2.06 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:4]([C@H:5]2[CH2:6][CH2:7][C@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH2:10]2)[CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(C)N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)N(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from trans-N-isopropyl-4-phenylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:19]([NH:18][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)=[O:20])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Example 35 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-isocyanato-4-(trifluoromethoxy)benzene (20.6 μl) to give the title compound (0.0371 g). LC-MS (System A): Rt 2.57 mins, Mass Spectrum m/z 478 [MH+].
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:9]O>>[O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([O:6][CH3:9])=[O:5]
Reactant: CCC(=O)CC(=O)O
Reactant: CO
Product: CCC(=O)CC(=O)OC

Procedure:
The β-keto acid (14) is then esterified with an alkanol of formula R3 -OH to yield a β-keto ester (15). For example, 3-oxopentanoic acid is heated at reflux with methanol to yield methyl 3-oxopentanoate (15) (Scheme V, Step 3).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N[C@@H](Cc1ccc(NC(=O)c2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 4 h

Procedure:
A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine (10 g) obtained in Example 62 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of N-methylpyrrolidinone. The slurry was agitated for 4 hr. The mixture was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). To the washed resin was added a solution of 25% piperidine in N-methylpyrrolidinone (80 mL), the mixture was agitated at room temperature for 20 minutes and filtered. The process was repeated and the resulting slurry was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). Filtration afforded 4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine on Wang resin suitable for use in the next step.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5](=[O:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]>CO.C(O)(=O)C>[Cl:3][CH2:4][CH:5]([OH:16])[C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH3:7]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (621 mg, 16.42 mmol) was added to a mixture of (R)-tert-butyl (4-chloro-3-oxobutan-2-yl)carbamate (910 mg, 4.10 mmol) in methanol (9 mL) at 0° C., and the mixture was stirred for one hour at 0° C. A few drops of acetic acid were added then the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl ((2R)-4-chloro-3-hydroxybutan-2-yl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 6.65 (d, J=8.1 Hz, 1H), 5.24 (d, J=5.6 Hz, 1H), 3.58-3.53 (m, 1H), 3.50-3.44 (m, 2H), 3.44-3.34 (m, 1H), 1.36 (s, 9H), 0.99 (d, J=6.3, 3H).