Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:36][C:35]1[CH:34]=[CH:33][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:38][CH:37]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2cc1OC
Yield: 71.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 222.3 mg (1.2 mmol) of 4-phenoxyaniline to give 283.0 mg (71.3%) of the product as a light yellow solid, m.p. 239-241° C., mass (electrospray, m/e): M+H 397.9.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].[NH2:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:31]1[CH:32]=[CH:33][C:29]([NH:28][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:27])[CH3:1])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:22])=[N:30]1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Reactant: Nc1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccon3)cc3c2CC(C)(C)O3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (80 mg, 0.21 mmol), 3-aminoisoxazole (36 mg, 0.429 mmol) and triethylamine (0.0597 mL, 0.4294 mmol) in 2 mL of DMF was added HATU (163 mg, 0.429 mmol). The mixture was stirred at 50° C. overnight, and purified by reverse phase column chromatography to give a white solid (3.3 mg, 4% yield). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1 H) 7.39 (t, J=8.08 Hz, 1 H) 7.27 (s, 1 H) 7.20 (d, J=1.77 Hz, 1 H) 7.13 (d, J=4.55 Hz, 2 H) 6.82 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.51 (s, 6 H); LCMS for C23H22FN3O5 m/z 440.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:33]2[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]2)=[O:18])=[N:14][CH:15]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N2CCNC(=O)C2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.9 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (114 mg, 0.271 mmol) obtained in Example 12 in methylene chloride (3 ml), piperazin-2-one (33 mg, 0.325 mmol), 1-hydroxybenzotriazole (37 mg, 0.271 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg, 0.325 mmol) and 4-methylmorpholine (35 μl, 0.325 mmol) were added. The reaction mixture was stirred for 4 days at room temperature, and was concentrated under reduced pressure. Ethyl acetate was added to the resulting concentration residue, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. The resulting solid was washed with ether, and then was collected by filtration, to obtain the title compound (116 mg, 0.230 mmol, 85%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2cscn2)CC1
Temperature: 85 °C
Yield: 19.7 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.025 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a off-white solid (0.012 g, 20%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.65-2.73 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.64-3.72 (m, 4H), 3.77 (s, 2H, NCH2), 7.47 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 1.95 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1338, calculated for C25H29N7OSBr (M+H)+: 554.1339.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[O:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])=[N:16][N:17]=1.[CH3:23][NH2:24]>>[CH3:12][C:13]1[O:14][C:15]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]2[C:3]([NH:24][CH3:23])=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)=[N:16][N:17]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Cc1nnc(CSCCN)o1
Reactant: CN
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1nnc(C)o1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is treated with an equimolar amount of 2-[(2-methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamine [prepared in Step A] and an excess of methylamine by the general procedure described in Example 2, the title compound is thereby produced.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].F[C:12](F)(F)C(O)=O.[CH2:18]([N:25]([Si](C)(C)C)[CH2:26]OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:9]([O:8][C:1]([C@H:2]1[C@H:3]([C:4]([OH:6])=[O:5])[CH2:26][N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12]1)=[O:7])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)/C=C/C(=O)[O-]
Reactant: COCN(Cc1ccccc1)[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of mono ethyl fumarate (2.85 g, 19.8 mmol) and trifluoroacetic acid (1.98 mmol, 0.15 mL) in methylene chloride (50 mL), N-benzyl-N-(methoxymethyl)trimethylsilyl amine (Aldrich) (9.41 g, 39.6 mmol) is added at 0° C. under N2. The mixture is stirred at 0° C. for 30 min and then at RT over 48 h. The crude material is concentrated and purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 85:15 to 85:15+2% NH4OH) to give the title compound. MS (LC-MS): 278.0 [M+H]+. 1H-NMR (CD3OD, 400 MHz): δ=1.29 (t, 3H), 3.28 (m, 5H), 3.60 (m, 1 H), 4.07 (m, 2H), 4.20 (m, 2H), 7.47 (m, 5H) ppm.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])O.[Na+]>C(O)C.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.6 parts of sodium hydroxide was dissolved in ethanol. A solution of 5 parts of p-aminothiophenol in 20 parts of ethanol was added to the solution. The mixture thus obtained was cooled at 0° C. or below. A solution of 3.8 parts of chloroacetic acid and 3.4 parts of sodium hydrogencarbonate in 10 parts of water was added dropwise to the mixture, while the mixture was kept at 0° C. or below. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then adjusted at pH 3. A solid thus formed was filtered to obtain 5.4 parts of p-aminothiophenoxyacetic acid.
Reaction SMILES: C(N[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.Cl.C([OH:34])C>O>[OH:34][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:27])([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CCO
Reactant: CC(=O)NC(=Cc1ccc(Oc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Agent: Cl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc(C=C(O)C(=O)O)cc3)ccc21

Procedure:
1.6 g of (4 mmol) of α-acetamido-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)cinnamic acid, 25 ml of concentrated hydrochloric acid and 25 ml of ethyl alcohol were introduced into a round-bottomed flask and the mixture was heated at reflux for eight hours. The reaction medium was poured into water and extracted with ethyl acetate, and the organic phase was decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was triturated in a mixture of hexane and ethyl ether (80:20)and the mixture was filtered. 1.06 g (72%) of the expected acid was recovered, having a melting point of 207°-10° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:42]([C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@:26]2([C:27]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:33][C:25]2=[O:24])[CH2:41]3)=[O:43])[CH2:10]1
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.42 h
Yield: 76.9 %

Procedure:
To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (7.0 mg, 0.023 mmol) in N,N-dimethylforinamide (105 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (6.5 mg, 0.023 mmol), 1-hydroxy-7-azabenzotriazole (0.3 mg, 2.1 μmol), N-methylmorpholine (2.56 μL, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 mg, 0.023 mmol). The mixture was stirred 25 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (10.5 mg). HRMS 594.1931 (M+1). 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H); 8.84 (d, J=8.6 Hz, 1H); 8.07 (dd, J=5.3, 1.6 Hz, 1H); 7.83 (s, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.40-7.36 (m, 2H); 7.32-7.28 (m, 2H); 7.22 (dd, J=7.3, 1.6 Hz, 1H); 6.92 (s, 1H); 6.88 (dd, J=7.3, 5.3 Hz, 1H); 4.34 (d, J=7.9 Hz, 1H); 3.80 (t, J=10.3 Hz, 4H); 3.40 (d, J=16.3 Hz, 2H); 3.19 (dd, J=16.4, 3.5 Hz, 2H); 2.33-2.29 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNCCN
Solvent: CN(C)C=O
Product: CNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 11.2 %

Procedure:
To a solution of 5 g (67.45 mmol) N1-methyl-ethane-1,2-diamine in 50 mL DMF a solution of 16.72 g (60 mmol) trityl-chloride in 50 mL DMF was added slowly over a period of 10 minutes at room temperature. The mixture was stirred overnight then it was evaporated to dryness, the oil was dissolved in 100 mL ethylacetate, was washed three times with water, dried with sodium sulfate then was evaporated. The components of the oil were separated on a silicagel column using chloroform-methanol gradient elution to give 2.13 g (10%) 197.). 1H-NMR (CDCl3) 7.48–7.44 (m, 6H), 7.27–7.21 (m, 6H), 7.18–7.12 (m, 3H), 3.44 (s, 1H), 2.78–2.74 (m, 2H), 2.42–2.38 (m, 5H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18](=[O:46])[N:19]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[N:32]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18](=[O:46])[N:19]([C:31]1[CH:36]=[CH:35][C:34]2[NH:37][C:1](=[O:2])[N:39]([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[CH2:38][C:33]=2[N:32]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNC3CCCCC3)n2)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc3c(n2)CN(C2CCCCC2)C(=O)N3)c(OC)c1
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol, 1.2 equiv) in THF (5 mL) was added a solution of (5-amino-6-cyclohexylaminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (390 mg, 0.83 mmol, 1.0 equiv) in THF (5 mL) and the reaction mixture was stirred for 2 h. The solvent was evaporated, the residue was dissolved in EtOAc, washed with water, brine, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from methanol to afford (3-cyclohexyl-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (282 mg) as a white solid. MS: [M+H]+=496.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][OH:19])[C:9]=2[CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@H:15]1[C:14]1[C:9]2[CH2:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Methane sulfonyl chloride (6.5 mmol) was added dropwise to a solution of (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methanol (5.0 mmol) and triethylamine (7.5 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The crude reaction mixture was then diluted with CH2Cl2 (50 mL) and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate solution (2×50 mL) and then brine (1×50 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.38 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](Br)=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1cc(Br)c(F)cc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)c(F)cc1N
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate (4.00 g, 13.88 mmol), xantphos (0.402 g, 0.694 mmol)9), tris(dibenzylideneacetone)dipalladium (0.318 g, 0.347 mmol), 1,4-Dioxane (13.9 ml), and DIPEA (4.83 ml, 27.8 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to RT and benzyl mercaptan (1.724 ml, 14.58 mmol) was added and the reaction was continued heating at 80° C. for an additional 90 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford (E)-ethyl 3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (2.75 g, 8.30 mmol, 59.8% yield). m/z (ESI) 332.1 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:35])([CH3:34])[CH2:7][C@H:8]([N:25]([C:27](OC(C)(C)C)=[O:28])[CH3:26])[CH2:9][O:10][C:11](=[O:24])[NH:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=2)(=O)C.Cl.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[C:66]([F:67])=[CH:65][CH:64]=[CH:63][C:48]=1[CH2:49][NH:50]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[N:14][C:13]([NH:12][C:11](=[O:24])[O:10][CH2:9][C@@H:8]([N:25]([CH3:26])[C:27]([NH:50][CH2:49][C:48]1[CH:63]=[CH:64][CH:65]=[C:66]([F:67])[C:47]=1[Cl:46])=[O:28])[CH2:7][C:6]([CH3:35])([CH3:34])[CH2:5][OH:4])=[CH:22]2
Reactant: CC(=O)OCC(C)(C)C[C@@H](COC(=O)Nc1cc2cc(F)ccc2cn1)N(C)C(=O)OC(C)(C)C
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl(methyl)amino)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl acetate (1.9 g, 3.8 mmol) in THF (50 mL) was added HCl (4 N in 1,4-dioxane, 19 mL, 76 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (100 mL). To the suspension were added DIEA (2.0 mL, 11.4 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (1.2 g, 3.8 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxy-4,4-dimethylpentyl 6-fluoroisoquinolin-3-ylcarbamate (1.1 g, 53%). LRMS (M+H+) m/z 535.5
Reaction SMILES: [OH:1][C@@:2]1([CH3:29])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C:17]([C@@H:18]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)[CH2:19][C@:3]12[CH3:4])=[C:16]1[C:11](=[CH:12][C:13](=[O:28])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:12]1[C:13](=[O:28])[CH2:14][CH2:15][C:16]2[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C:17]=2[C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[CH2:19][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@:2]2([OH:1])[CH3:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Solvent: C1CCOC1
Product: C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(Br)C(=O)CCC4=C3[C@@H](c3ccc(C=O)cc3)C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
781 mg of 4-(17β-hydroxy-17α-methyl-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is dissolved in 25 ml of tetrahydrofuran and mixed with 356 mg of N-bromosuccinimide. The mixture is stirred for 2 hours at room temperature, then poured into 200 ml of ice water. The precipitate is filtered off, washed neutral and dried. After purification by means of preparative layer chromatography, 475 mg of 4-(4′-bromo-17β-hydroxy-17α-methyl-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is obtained as a foam, which is incorporated directly into the oximization analogously to Example 1 with hydroxylammonium hydrochloride in pyridine.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[NH:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.C([BH3-])#N.[Na+]>ClC(Cl)C.CO.C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:22]([C:13]=3[O:12][N:11]=2)=[CH:21][CH:20]=[C:19]([CH2:23][N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)[CH:18]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2noc3c2CCc2cc(C=O)ccc2-3)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCc1ccc(-c2noc3c2CCc2cc(CN4CC(C(=O)O)C4)ccc2-3)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
To 3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazole-7-carbaldehyde (Preparation 20E, 0.191 g, 0.602 mmol) in dichloroethane (2 mL) and methanol (2.0 mL) was added azetidine-3-carboxylic acid (0.073 g, 0.722 mmol) and 8 drops of acetic acid. The reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (0.045 g, 0.722 mmol) was added in one lot. The reaction mixture was stirred at room temperature for 20 min., and then concentrated. Acetonitrile (10 mL) was added to the resulting residue. The contents were sonicated for ˜2 min. and filtered. The solid was washed with acetonitrile (2×10 mL), water (2×10 mL), acetonitrile (5 mL), and dried to yield 1-((3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid as a grey solid (90 mgs). The compound had an HPLC retention time=3.08 min (condition C); LC/MS M+1=403.