Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH3:26])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(N)c(C)c3O2)cc1

Procedure:
[(2R)-8-Formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methyl-benzenesulfonate (1.4 g, 2.74 mmole) in methanol (40 mL) was was treated with 60 psi of hydrogen on a Parr shaker in the presence of 0.10 g 20% palladium hydroxide on carbon (Pearlman's catalyst) for 24 hours. The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated in vacuum to give 0.94 g (93%) of the (R)-enantiomer of the title compound as a beige solid. 1H (DMSO) broad singlet 10.0 δ (2 H); doublet 7.8 δ (2 H); doublet 7.5 δ (2 H); doublet 6.9 δ (1H); doublet 6.8 δ (2 H); multiplet 4.0-4.6 δ (5 H); singlet 2.4 δ (3 H); singlet 2.1 δ (3 H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCBr)c1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCC(=O)c2ccccc2)CC1
Yield: 37 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (7 g) and 4-bromo-1-phenyl-1-butanone (4.93 g) were reacted and treated in the same manner as in Example 172 to give 3.1 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-oxo-4-phenylbutyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:30](O)(=[O:33])[CH:31]=[CH2:32].Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:30](=[O:33])[CH:31]=[CH2:32])=[C:24]([F:29])[CH:23]=4)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CC(=O)O
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)c(F)c3)ccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CC(=O)Oc1ccc(CCc2ccc3c(c2)Cc2cc(OCCCCC)ccc2-3)cc1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 17.6 %

Procedure:
2-Pentyloxy-7-(2-(3-fluoro-4-hydroxyphenyl)ethyl)fluorene (0.7 g) and acrylic acid (0.14 g) were dissolved in chloroform (30 mL) and cooled down to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.44 g) and 4-dimethylaminopyridine (0.01 g) were added thereto, and then the temperature was allowed to come back to a room temperature, followed by stirring for 24 hours. Water was added to separate the solution, and the chloroform layer was dried on anhydrous magnesium sulfate. A residue obtained by distilling chloroform off was purified by means of column chromatography (silica gel, eluting solvent: toluene), and it was further recrystallized to obtain 2-pentyloxy-7-(2-(3-fluoro-4-acryloyloxyphenyl)ethyl)fluorene (0.14 g) of the intended product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([N:14]2[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:32]=3)[C:15]2=[O:33])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([N:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:32]=3)[C:15]2=[O:33])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc([C@H](CC(=O)O)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCc3ccc4c(n3)NCCCC4)C2=O)cn1
Yield: 87.1 %

Procedure:
A mixture of 3-8 (0.40 g, 0.886 mmol), 20% Pd(OH)2 (0.40g), 1N NaOH (2 mL), and ethanol (20 mL) was shaken under 65 psig hydrogen in a Parr apparatus for 18 hours. The mixture was filtered through celite, and the filtrate concentrated. The residue was chromatographed on silica gel (25:10:1:1 to 15:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 350 mg of 3-9 as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.23 g, 1.40 mmol) and CDI (0.24 g, 1.50 mmol) in N,N-dimethylformamide (10 mL) was heated to 40° C. under nitrogen. After 1 h, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.5 g, 1.40 mmol) was added and the mixture was heated at 50° C. for 1.5 h. Water (20 mL) was added and the solids were isolated by filtration. The product was triturated in EtOAc (20 mL) for 18 h, then filtered and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.48 g, 84% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.15 min (97.48%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.41 (t, J=7.0 Hz, 3H, CH3), 1.86-2.11 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.59 (d, J=16.8 Hz, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 4.51-4.76 (m, 4H, CH2, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.35 (d, J=9.3 Hz, 1H, Ar), 7.49 (d, J=7.9 Hz, 1H, Ar), 7.56 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.09 (d, J=9.1 Hz, 1H, Ar), 9.73 (t, J=6.2 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 22.49, 31.18, 42.52, 47.10, 51.56, 63.44, 117.87, 122.14, 122.91, 127.15, 128.80, 130.38, 142.33, 143.63, 149.23, 162.74, 165.80, 167.90, 170.98, 172.85; LCMS: MH=424; Anal Calcd for C21H21N5O5: C, 59.57; H, 5.00; N, 16.54. Found: C, 59.26; H, 4.95; N, 16.53.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:17]3[C:16]([CH3:15])=[CH:36][CH:35]=[C:19]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:24]=4)=[O:21])[CH:18]=3)=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Agent: Br
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1-c1ccc(-c2csc(N)n2)cc1

Procedure:
Example 1 was prepared using 4-(4-bromophenyl)-2-thiazolamine monohydrobromide and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Intermediate 5).
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][CH2:40]Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:39][CH2:40][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 0.5 h

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (3 grams) was added to about 40 ml of dry dimethylformamide (DMF) and stirred for about 30 minutes. Then 4.0 ml of chloromethyl pivalate in 5 ml of DMF was added. The mixture was stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13]C(=O)C2C=CC=CC=2)=[S:12])[N:7]([CH2:22][CH3:23])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH2:13])=[S:12])[N:7]([CH2:22][CH3:23])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCn1nc(C(C)(C)C)cc1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCn1nc(C(C)(C)C)cc1NC(N)=S
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A suspension of compound 24 (5 g, 15.1 mmol) in 30 mL of 5% NaOH aqueous solution was stirred in an oil bath of 90° C. for 8 hrs and cooled down to room temperature. Ice was added while stirring to the reaction mixture. The resulting suspension was filtered, and the cake was washed with cold water (10 mL×3) and further dried in vacuo to afford the desired product 8 as an off-white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:25][CH2:24][CH:23]([O:26]C3CCCCO3)[CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:26][CH:23]1[CH2:24][CH2:25][CH:21]([CH2:20][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])[CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(OC3CCCCO3)C2)C(=O)Nc2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(O)C2)C(=O)Nc2nccs2)cc1
Temperature: 60 °C
Yield: 85.8 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (450 mg, 0.94 mmol) in ethanol (9.4 mL) was treated with pyridinium p-toluenesulfonate (24 mg, 0.094 mmol). The resulting reaction mixture was heated at 60° C. for 4 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow residue was diluted with ethyl acetate (100 mL) and then washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 to 1/7 hexanes/ethyl acetate) afforded the 3-(3-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (318 mg, 86%) as a white foam: mp 69–72° C.; FAB-HRMS m/e calcd for C18H22N2O4S2 (M+H)+ 395.1099, 395.1091.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[CH:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2)[CH3:2].[CH3:22][C:23](=[O:26])[C:24]#[CH:25].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:23]([C:24]1[CH:25]=[C:5]2[N:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=13)[C:3]([CH2:1][CH3:2])=[C:4]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:26])[CH3:22]
Reactant: CCc1c(-c2ccc(OC)cc2)cn2ccc(OC)cc12
Reactant: C#CC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCc1c(-c2ccc(OC)cc2)c2cc(C(C)=O)c3cc(OC)cc1n32
Yield: 62.3 %

Procedure:
A solution of 1-ethyl-7-methoxy-2-(4-methoxyphenyl)indolizine (Compound 3) (2.0 g, 7.11 mmol) in 65 ml of toluene was stirred in an ice bath, while 3-butyn-2-one (0.64 ml, 8.17 mmol) was added dropwise. The cooling source was removed and stirring was continued for twenty hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.73 g, 7.61 mmol) was added in portions and stirring was continued for twenty hours. The solvent was evaporated and the residue chromatographed over aluminium oxide with heptane/tetrahydrofuran (1:1) as eluent to afford 1.54 g (63%) of the title compound. M.p. 137-39° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.39 (t, 3H), 2.64 (s, 3H), 3.15 (q, 2H), 3.87 (s, 3H), 4.09 (s, 3H), 7.19 (d, 2H), 7.80 (d, 2H), 7.82 (d, 1H), 7.89 (d, 1H), 8.15 (s, 1H). (Compound 6).
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2C2C=CC(C([O-])=O)=CC=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C[C@H]([O:42]C1C=CC(OC(=O)C2C=CC=CC=2)=CC=1[N+]([O-])=O)CCCCCC>>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:42])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[N+:31]([O-:33])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(-c2ccccc2-c2ccc(C(=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: CCCCCC[C@H](C)Oc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1[N+](=O)[O-]

Procedure:
The benzoyl ester of (S)-4'-(1-methylheptyloxy)-3'-nitro-4-biphenylylbenzoate was saponified using the same procedure as that used for saponification of (S)-[4-(1-methylheptyloxy)-3-nitrophenyl]-benzoate except that the reaction was carried out at 60° C. to give (S)-4'-(1-methylheptyloxy)-3'-nitro-4-hydroxybiphenyl (Compound 17, Scheme II, R2 =(S)-OCH(CH3)C6H13) as a very viscous orange liquid after flash chromatography with hexanes/ethyl acetate [88/12]; Rf [hexanes/ethyl acetate 85/15]: 0.17; 1H NMR (300 MHz, CDCl3): δ o.86(t, 3 H, J=6.6 Hz), 1.18-1.52(m, 8 H), 1.35(d, 3 H, J=6.1 Hz), 1.62(m, 1 H), 1.78(m, 1 H), 4.50(m, 1 H), 5.22(broad s, 1 H), 6.89(d, 2 H, J=8.5 Hz), 7.07(d, 1 H, J=8.8 Hz), 7.39(d, 2 H, J=8.5 Hz), 7.62(dd, 1 H, J=2.4 Hz, J=8.8 Hz), 7.92(d, 1 H, J=2.4 Hz); 13C NMR (300 MHz, CDCl3): δ 13.99, 19.49, 22.50, 25.19, 29.10, 31.65, 36.17, 76.57, 115.94, 116.17, 123.30, 127.99, 131.21, 131.64, 133.09, 141.00, 15.42, 155.52; IR (CHCl3); 350, 3300(broad), 3020, 2920, 2840, 1610, 1540, 1510, 1485, 1350, 1260, 1220, 1160, 1110, 1040, 925, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 343(M+ 5), 231(100), 185(6), 57(6), 43(12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([F:30])[CH:3]=1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][C:10]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:33])[CH:12]=2)=[O:18])=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(=O)c1cccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccc(Cl)cc2F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 161, step 1, ethyl 3-(1-(4-chloro-2-fluorophenyl)-3-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)propyl)benzoate was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=442.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10]2)[CH3:3].[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]#[C:30][CH3:31].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:16][CH:30]([CH2:29][C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH2:31][N:15]=1)=[CH:10]2)[CH3:1]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)C)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (857 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.6 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was stirred at 60° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/99 to 40/60, volume ratio) to give the title compound (381 mg, 41%) as a yellow amorphous solid. MS 517 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1)[CH:2]=C.[O:13]=[O+][O-]>ClCCl>[O:13]=[CH:2][CH2:1][C@H:4]1[O:9][CH2:8][O:7][C@@H:6]([CH2:10][C:11]#[N:12])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OCO1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OCO1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -b 78° C. under nitrogen. Ozone (Welsbach 9generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 2.3 g of pure (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[N:41]1([CH:27]2[CH2:28][CH2:29][N:23]3[N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:12]5[CH:13]=[C:9]([Cl:8])[N:10]=[CH:11]5)=[C:15]([O:39][CH3:40])[CH:16]=4)[N:38]=[C:24]3[CH:25]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:26]2)[CH2:44][CH2:43][CH2:42]1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3n(n2)CCC(N2CCC2)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (50 mg, 0.107 mmol, from example 137) was added to a mixture of azetidine (6.11 mg, 0.107 mmol), and sodium cyanoborohydride (1.0M in THF, 428 μL, 0.428 mmol) in ethanol (0.535 mL). The mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (18.7 mg, 27% yield) as a TFA salt. LC-MS (M+H)+ 508.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.63 (1 H, d, J=3.7 Hz), 7.89-7.98 (1 H, m), 7.31-7.38 (1 H, m), 7.07-7.22 (5 H, m), 7.01 (2 H, dd, J=8.5, 4.9 Hz), 4.92 (2 H, d, J=4.6 Hz), 4.64-4.77 (1 H, m), 4.42 (2 H, br. s.), 3.98-4.10 (1 H, m), 3.66-3.97 (5 H, m), 2.58-2.90 (2 H, m), 2.14-2.44 (4 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][NH:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][N:11]([CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:44]([O:46][CH2:47][CH:48]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=2[C:55]2[C:60]1=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
The product from Example 26B (1.28 g, 2.6 mmol) in tetrahydrofuran (11 mL) was treated with triethylamine (0.39 mL, 2.8 mmol) and 9-fluorenylmethyl chloroformate (0.72 g, 2.8 mmol) at ambient temperature. After stirring for 1 hour, the mixture was concentrated and the residue was dissolved in ethyl acetate (10 mL), wash with 10% NaHCO3 (2×10 mL), 10% citric acid (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with chloroform (1.68 g, 90%). 1H NMR (CDCl3) δ 7.82-6.94 (m, 18H), 4.93 (br s, 1H), 4.66-4.43 (m, 2H), 4.20 (t, 1H), 3.87-3.35 (m, 4H), 3.00-2.20 (m, 7H), 1.38-1.23 (m, 18H); MS (ESI+) m/z 706 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([C:26]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27]1)[CH2:24][CH3:25]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4](=[O:21])[NH:32][S:29]([C:26]2([CH2:23][CH2:24][CH3:25])[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CCCC1(S(N)(=O)=O)CC1
Product: CCCC1(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc2ccc(F)cc2)OC)CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-propyl-cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. MS (M−H) calcd for C18H22FN2O6S: 413.1. Found: 413.0. 1H NMR (500 MHz, CDCl3) δ: 0.92 (t, 3, J=8), 1.00 (m, 2), 1.54 (m, 2), 1.74 (m, 2), 1.84 (m, 2), 3.68 (s, 3), 4.79 (s, 2), 6.54 (s, 1), 7.04 (m, 2), 7.29 (m, 2), 8.79 (s, 1). Anal calcd for C18H23FN2O6S: C, 52.16; H, 5.59; N, 6.76. Found: C, 52.20; H, 5.69; N, 6.66.