Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:26][CH3:27]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CC[C@H](N)CO
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@@H](CC)CO)s1
Yield: 79 %

Procedure:
As described for example 105, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using (S)-2-amino-1-butanol instead of (R)-2-amino-1-butanol, to the title compound (150 mg, 79%) which was obtained as a light yellow solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=378.4 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[C:8]([CH3:7])=[N:9][O:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cnc(Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nocc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Oxalyl chloride (0.06 ml, 0.69 mmol) was added to a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.06 g, 0.48 mmol) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.035 g, 0.24 mmol) in anhydrous pyridine (3 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (30 mg).
Reaction SMILES: [CH:1]([N:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH:4]1[C:13]([O:15]C)=[O:14])=[O:2].[OH-].[K+].Cl>O1CCOCC1>[CH:1]([N:3]1[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH:4]1[C:13]([OH:15])=[O:14])=[O:2]
Reactant: COC(=O)C1CC2(CCN1C=O)OCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=CN1CCC2(CC1C(=O)O)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.25 g of the compound obtained in Step A (62.7 mmol) are dissolved in 160 ml of dioxane. A solution of 125 mL of 1M KOH is added dropwise, and the whole is stirred at ambient temperature for one hour. There are subsequently added 125 mL of 1M HCl, and the compound is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of a powder.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:6]2[C:2](=[O:1])[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:4][NH:5]2)[CH:8]=1
Reactant: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1

Procedure:
150 mg (531 μmol) of the compound from Example 41 are dissolved in 20 ml methanol, 1 ml concentrated sulfuric acid are added and the mixture is heated under reflux overnight. After cooling, the precipitate formed is filtered off with suction, washed with methanol and dried.
Reaction SMILES: [NH2:1][C:2]1[C:23]([NH2:24])=[CH:22][C:5]2[CH2:6][C@@H:7]3[C:12]([CH3:14])([CH3:13])[C@:11]([CH3:15])([C:4]=2[CH:3]=1)[CH2:10][CH2:9][N:8]3[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18].[C:25](O)(=O)[CH3:26]>>[F:19][C:17]([F:20])([F:18])[C:16]([N:8]1[CH2:9][CH2:10][C@:11]2([CH3:15])[C:12]([CH3:13])([CH3:14])[C@H:7]1[CH2:6][C:5]1[CH:22]=[C:23]3[N:24]=[C:25]([CH3:26])[NH:1][C:2]3=[CH:3][C:4]=12)=[O:21]
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: CC(=O)O
Product: Cc1nc2cc3c(cc2[nH]1)[C@]1(C)CCN(C(=O)C(F)(F)F)[C@H](C3)C1(C)C
Temperature: 130 °C
Reaction time: 3 h

Procedure:
1-[(2R,6S)-8,9-Diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (600 mg) dissolved in glacial acetic acid is stirred at 130° C. for 3 h. After cooling to ambient temperature, the solution is concentrated under reduced pressure and the residue is taken up in ethyl acetate. The organic solution is washed with aqueous K2CO3 solution and brine and dried (MgSO4). The solvent is removed under reduced pressure to give the crude title compound as a foam-like solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:16]([CH2:15][CH:14]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:37])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COCOc1ccc(CC(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N(CC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A portion of 144 mg of 60% sodium hydride were suspended in 15 ml of dimethylformamide and cooled to 0° C., followed by dropwise addition of 1.34 g of N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide, and then followed by addition of 391 mg of ethyl chlorocarbonate. After stirring at room temperature for four hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.49 g of N-ethoxycarbonyl-N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1.C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:25]5[CH2:28][CH:27]([OH:29])[CH2:26]5)=[CH:20][CH:21]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN2CC(O)C2)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using azetidin-3-ol hydrochloride (21 mg, 0.20 mmol, Oakwood) and diisopropylethylamine (34 μL, 0.20 mmol) in the displacement, which was performed overnight (10.3 mg, 58%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(OCC)(=O)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 33.9 %

Procedure:
A mixture of the above described 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (800 mg, 2.248 mmol) and 1-methylpiperazine (5 ml, 45 mmol) was stirred at 23° C. for 18 h. Diluted with ethyl acetate, washed with sat. sodium hydrogen carbonate-solution, dried the organic layer over sodium sulfate. Filtration and removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with ethyl acetate to ethyl acetate +10% methanol-ammonium hydroxide (10:1) and trituration with diethyl ether to give the title compound as a white foam (320 mg, 34%), MS (ISP) m/e=420.2 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)=[N:22][N:21]=[C:20]2[CH2:36][N:37]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:19]3[C:20]([CH2:36][NH2:37])=[N:21][N:22]=[C:23]3[CH2:24][N:25]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-nitro-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-nitro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]enzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Nc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
Add 4-bromophenyl boronic acid (5.0 g, 24.82 mmol), tetrakis(triphenylphosphine)palladium (0) (0.717 g, 0.620 mmol) and 2 M Na2CO3 (10 mL) to a solution of 2-iodoaniline (4.5 g, 20.69 mmol) in toluene (2 mL):ethanol (20 mL), degas and heat at 80° C. under nitrogen. After 4 h, add water and extract with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography (silica gel) eluting with ethyl acetate:hexane 1:12 to provide the title compound (3.53 g, 69%): Mass spectrum (m/e): 248 (M+1); 249 (M+2). 1HNMR (CDCl3), δ3.62 (s, 2H); 6.75-6.89 (m, 2 H); 7.08-7.18 (m, 2H); 7.21-7.40 (m, 2H); 7.55-7.63 (m, 2H):
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[NH4+].[OH-].[N+:19]([O-])([OH:21])=[O:20].O>O>[N+:19]([C:12]1[CH:11]=[C:10]([CH:6]2[O:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)[CH:15]=[CH:14][C:13]=1[OH:16])([O-:21])=[O:20]
Reactant: CCCN1CCOC(c2ccc(O)cc2)C1
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCOC(c2ccc(O)c([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
The phenol from example 29 (100 mg, 0.45 mmol) was dissolved in nitric acid:water (1:3) (2 ml) and stirred at room temperature for 10 minutes. The reaction mixture was then diluted with water (5 ml) and basified with NH4OH (1 ml), before extracting into ethyl acetate (3×10 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow solid (95 mg, 0.35 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ: 0.97 (t, 3H), 1.33 (t, 2H), 1.43-1.79 (bm, 4H), 2.02 (d, 3H), 4.06 (m, 2H), 7.17 (d, 1H), 7.60 (d, 1H), 8.16 (s, 1H), 10.55 (bs, 1H). LRMS: m/z 267 (M−H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:12](=[NH:16])[N:13]([OH:15])[CH3:14])[CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:12]2[N:13]([CH3:14])[O:15][C:23](=[O:24])[N:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(O)C(=N)/C(=N\OCc1cccc(Br)n1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1oc(=O)nc1/C(=N\OCc1cccc(Br)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a solution of (2Z)-2-{[(6-bromopyridin-2-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (4.0 g, 11 mmol, 1 eq.) in acetonitrile (100 ml), was added 1,1′-carbonyldiimidazole (2.14 g, 13.2 mmol, 1.2 eq.). After stirring at 80° C. for 1 hours and 2 hours at room temperature, the reaction was diluted with EtOAc (500 mL), subsequently washed with H2O (500 mL) and brine. After separation, the organic phase was dried over MgSO4 then concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(6-bromopyridin-2-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (4.40 g, 95% yield).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH:30](CS([O-])(=O)=O)([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:30]([CH3:32])[CH3:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)CS(=O)(=O)[O-]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3C(C)C)CC1
Temperature: 95 °C
Reaction time: 22 h
Yield: 47.3 %

Procedure:
To a mixture of (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2, 100 mg, 1.0 eq.) and isopropyl-methanesulfonate (67 mg, 2.0 eq.) in dimethylformamide (4 mL) was added cesium carbonate (156 mg, 2.0 eq.). The solution was stirred 22 h at 95° C. The reaction mixture was concentrated in vacuo and the residue partitioned between water and methyl-tert-butylether. The aqueous layer was extracted with methyl-tert-butylether. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and then purified on silica, eluting with cyclohexane/ethyl acetate. One fraction was isolated and dried in vacuo, to yield 52 mg (47%) of the desired product as off-white solid. MS (m/e): 462.5 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C@H:11]2[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH:18]=[O:19])[CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]([C@H:11]2[CH2:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][OH:19])[CH2:12]2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CC=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(CCO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
2-Chloro-4-{[(2-methylphenyl)methyl][(3S)-5-oxo-1-(2-oxoethyl)-3-pyrrolidinyl]amino}benzonitrile from the previous step was dissolved in THF, and NaBH4 (1.2 eq) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with H2O and extracted three times with ethyl acetate (5 mL). The organics were dried over anhydrous MgSO4 and concentrated to give the titled compound as white solid (3.5 g, 33% for two steps). LC-MS (ES) m/e 384.6 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)=[CH:7][C:6]([NH:21][C@H:22]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:23]([NH2:25])=[O:24])=[C:5]([F:30])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:25][C:23](=[O:24])[C@H:22]([NH:21][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:7]=1)[CH2:26][CH:27]1[CH2:28][CH2:29]1
Reactant: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)-3-cyclopropylpropanamide (75 mg) in EtOH (1 mL) and DMSO (0.5 mL) at room temperature, aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. After being concentrated in vacuo, the residue was purified by HPLC to give the titled compound (13 mg). MS 424.4 (M+H); UV 201.0, 244.9, 289.1 nm; t 0.668 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].Cl[C:20]1[N:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[NH2:4][C:3]1[C:5]([CH3:18])=[CH:6][C:7]([C:20]2[N:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=2)=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: Cn1cnc(Cl)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(=O)n(C)cn2)cc(C)c1N
Temperature: 65 °C
Reaction time: 12 h

Procedure:
In a microwave vial 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.6 g) and 6-chloro-3-methylpyrimidin-4(3H)-one (3 g) are suspended in N,N-dimethylformamide (30 mL) and Na2CO3 (26 mL of a 2M aqueous solution). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (508 mg) is added, the vial is sealed and the mixture is stirred at 65° C. for 12 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated to give the title compound. Yield: 2.6 g; LC (method 11): tR=0.71 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]([F:22])([F:21])[C@@H:16]([OH:20])[CH2:17][CH2:18][OH:19].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH:11]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=2[O:20][C@H:16]([C:15]([F:22])([F:21])[F:14])[CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cl)n1
Reactant: OCC[C@H](O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 48 h
Yield: 5.5 %

Procedure:
6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 180 mg, 901 μmol), (S)-4,4,4-trifluorobutane-1,3-diol (394 mg, 2.73 mmol) and potassium tert-butoxide (307 mg, 2.73 mmol) were combined with DMF (3 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 48 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (15 mg, 5.4%) and its regioisomer; MS (EI) 304.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cc(C(=O)Cl)ccc1Br

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid (5.0 g, 23.25 mmol) and thionylchloride (50 ml) was refluxed for 5 hours. After removal of thionyl chloride, the residue was dried under high vacuum and used in next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:28]=2[F:37])[CH2:23][CH2:22]1)=[O:20])C1C=CC=CC=1.C(Cl)(Cl)Cl>[Pd].CO>[F:37][C:28]1[CH:29]=[C:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=[CH:32][C:27]=1[N:24]1[CH2:23][CH2:22][N:21]([C:19]([C:10]2[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[O:20])[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCc3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3O)CC2)c(F)c1
Reaction time: 2 h

Procedure:
A mixture of 0.915 mmol (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone, 0.05 mmol palladium on charcoal (10%) in 12.5 ml methanol was hydrogenated at atmospheric pressure at room temperature for 2 hours. After addition of chloroform, the mixture was filtered, and the solvent was evaporated to provide the title compound. MS (m/e): 474.3 (M+NH4+, 100%)
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:20].C[O:22][B:23](OC)[O:24]C.Cl>O1CCCC1>[CH3:13][C:12]1[C:7]([B:23]([OH:24])[OH:22])=[C:8]([CH3:20])[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
tert-Butyllithium (1.7 M solution in hexanes, 36.2 ml, 62.6 mmol) is added dropwise to a solution of 4-bromo-3,5-dimethylbiphenyl (7.27 g; 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. and stirred under an atmosphere of nitrogen for 30 minutes. Trimethylborate (9.54 ml; 84 mmol) is added and the resulting mixture is stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is acidified with aqueous hydrochloric acid and extracted with ether (2×150 ml). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a yellow solid. The crude product is triturated with iso-hexane and filtered to give 3,5-dimethylbiphen-4-ylboronic acid (5.89 g) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=C(C#N)[CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[O:1]=[C:2]1[C:8]2[CH:9]=[C:20]([C:19]([OH:22])=[O:21])[CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Reflux a mixture of 7.43 gm. (0.0316 mole) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-9-carbonitrile, 130 ml. of acetic acid, 13 ml. of water and 13 ml. of concentrated hydrochloric acid for 156 hours. Cool the reaction mixture, separate the solids by filtration and dry (yield 6.20 gm., m.p. 264°-269° C.). Recrystallize from acetic acid to obtain the title product (m.p. 270.5°-271.5° C.).