Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=O)[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:5]1([CH2:21][CH2:22][CH2:23][CH3:24])[C:17]2[CH:16]=[C:15]([C:18](=[N:26][OH:27])[CH3:19])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc(C(C)=NO)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
After 5.45 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone (12) (17 mmol) was dispersed in 50 ml of ethanol and 1.42 g of hydroxylamine hydrochloride (20.4 mmol) and 1.67 g of sodium acetate (20.4 mmol) were added thereto, the reaction mixture was slowly heated and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and 100 ml of distilled water was added thereto and stirred for about 30 minutes. Then, the product was extracted with 200 ml of ethylacetate and sequentially washed with saturated aqueous sodium bicarbonate solution and 100 ml of distilled water, and the recovered organic layer was dried over anhydrous magnesium sulfate, followed by distilling the solvent under reduced pressure. The obtained solid product was dried, thereby obtaining 4.97 g of 1-(9,9-di-n-butylfluorene-2-yl)-ethanone oxime (13) (87.3%) as a light yellow product.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Yield: 84 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.20 g, 0.28 mmol) prepared in Example 127a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol (2.0 mL), to yield the title compound (0.11 g, 85%) as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCCCCCC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClC1CCCCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCC2=C(CC1)C(c1ccc(Cl)cc1)N(C1CCCCCCC1)N2
Product: Clc1ccc(-c2nn(C3CCCCCCC3)c3c2CCNCC3)cc1
Yield: 43.8 %

Procedure:
The title compound (47 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using chloro-cyclooctane (1.0 mmol) in place of chloro-cyclobutane according to Example 238. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H28ClN3, 357.20; found, m/z 358.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.44 (m, 4H), 4.49-4.45 (m, 1H), 3.51-3.48 (m, 2H), 3.38-3.36 (m, 2H), 3.33-3.32 (m, 2H), 3.05-3.04 (m, 2H), 2.21-2.18 (m, 2H), 1.97-1.88 (m, 4H), 1.72-1.64 (m, 8H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH2:20]([SH:22])[CH3:21].O>CN(C=O)C>[CH2:20]([S:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 2-fluoro-5-nitrobenzonitrile (5.00 g, 30.1 mmol) in DMF (100 mL), triethylamine (9.30 mL, 66.7 mmol) was added and followed by ethanethiol (2.80 mL, 37.9 mmol). After stirring at rt for 1 h, the reaction mixture was poured into water (500 mL). The resulting precipitate was filtered and dried on high vacuum overnight to provide 5A (6.08 g, 97%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([CH3:30])[CH:19]=3)=[C:15]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]4[CH2:43][NH:42][C:41](=[O:44])[N:40]4[C:45]([O:47]CC4C=CC=CC=4)=[O:46])=[CH:33][CH:32]=3)[S:14][C:13]=2[CH:55]=1)C1C=CC=CC=1.[CH3:56][OH:57].[NH4+].[OH-:59]>C(Cl)(Cl)Cl>[C:45]([OH:47])(=[O:46])[C:56]([OH:59])=[O:57].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:20]([CH3:30])[CH:19]=3)=[C:15]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]4[CH2:43][NH:42][C:41](=[O:44])[NH:40]4)=[CH:33][CH:32]=3)[S:14][C:13]=2[CH:55]=1
Reactant: Cc1cc(Cc2c(-c3ccc(OCC4CNC(=O)N4C(=O)OCc4ccccc4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: CO
Reactant: [OH-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cc2c(-c3ccc(OCC4CNC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Product: O=C(O)C(=O)O
Yield: 42 %

Procedure:
By essentially following the conditions detailed in Example 8, Part F, the free base of the title compound was prepared as a solid from 6-benzyloxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-(3-benzyloxycarbonyl-2-oxo-imidazolidin-4-ylmethoxy)phenyl]benzo[b]thiophene (Part A) in 42% yield following radial chromatography (SiO2; 1% then 3% then 5% MeOH in CHCl3 sat'd with NH4OH). The product was converted to the oxalate salt according to the conditions described in Example 1; Part G.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Agent: NCCN(CCN)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, 4-chlorobenzenesulfonyl chloride (5 eq), and triethylamine (5 eq) in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional 4-chlorobenzenesulfonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris(2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl2. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)#[CH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:34]([CH:36]([CH3:38])[CH3:37])#[C-:35]>CO.O>[C:12]([C:14]1[CH:15]=[C:16]([C:17]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]3[C:35]=2[NH:34][CH:36]([CH3:38])[CH3:37])[CH:19]=[CH:20][CH:21]=1)#[CH:13]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: [C-]#[N+]C(C)C
Reactant: C#Cc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C#Cc1cccc(-c2nc3ccc(C(F)(F)F)cn3c2NC(C)C)c1
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (100 mg, 617 μmol, Eq: 1.00), 3-ethynylbenzaldehyde (84.3 mg, 648 μmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (35.2 mg, 185 μmol, Eq: 0.3) were dissolved in MeOH (1.00 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyanopropane (42.6 mg, 58.2 μL, 617 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 2 h. Upon addition of water a yellow precipitate was formed. The solid was filtered off, washed with MeOH/water (1:1) and dried under vacuum to yield the product as a yellow solid (153 mg, 72.2%). MS: 344.0 [M+H]+; 1H-NMR (D6-DMSO): δ 8.90 (s, 1H), 8.36 (s, 1H), 8.25 (d, 1H), 7.71 (d, 1H), 7.50 (t, 1H), 7.46-7.39 (m, 2H), 5.10 (d, 1H), 4.24 (s, 1H), 3.25 (m, 1H), 1.08 (d, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(Cl)Cl.C(OCC)C>[C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
N-Boc-3-pyrrolodinol (17.192 g, 0.092 mole) in 50 mL anhydrous methylene chloride was added to a solution of (60 g, 0.276 mole) of pyridinechlorochromate in 300 mL anhydrous methylene chloride which was surrounded by a water bath at room temperature. After stirring at room temperature for 4 hours an additional (60 g, 0.276 mole) of pyridinechlorochromate was added and the reaction was stirred over night. The reaction had gone to completion by the next morning and was diluted with 400 mL diethyl ether and filtered through a pad of celite 521 filter aid using excess diethyl ether to wash through. Evaporation gave a black oil which was flash chromatographed over silica gel eluting with 40% ethyl acetate in hexane to provide the title compound (12.5 g, 71%) as an oil. Mass Spec FD+MI=184.9, (MW=185) 1H NMR (300 MHz CDCl3) δ 1.49 (9H, s); 2.56-2.61 (2H, t); 3.75-3.80 (4H, t).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:33]=[C:14]3[CH2:15][CH:16]([N:23]([CH:30]4[CH2:32][CH2:31]4)C(=O)C(F)(F)F)[C:17]4[CH2:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(O)C>[C:1]1([S:7]([N:10]2[CH:33]=[C:14]3[CH2:15][CH:16]([NH:23][CH:30]4[CH2:31][CH2:32]4)[C:17]4[CH2:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC2=CN(S(=O)(=O)c3ccccc3)C=C3CC(N(C(=O)C(F)(F)F)C4CC4)C(=C23)C1
Solvent: CCO
Solvent: O
Product: O=C1C=CC2=CN(S(=O)(=O)c3ccccc3)C=C3CC(NC4CC4)C(=C23)C1
Reaction time: 23 h
Yield: 96 %

Procedure:
Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodium hydrogenborohydride 42 mg was added to the solution at room temperature and the mixture was stirred for 23 h. Water was added with cooling in ice to the reaction mixture, which was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil, 98 mg. Yield 96%. The titled compound was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from isopropanol-ether to give colorless crystals, m.p. 119-122° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:6]=2[CH:18]=1.[H-].[Na+].[CH3:22]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7]([N:12]([S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])[CH3:22])[C:6]=2[CH:18]=1
Reactant: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)C1CCCOc2c(C)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A solution of 0.6 g (2.0 mmol) of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine in 8 ml of THF was added dropwise under nitrogen to a suspension of 0.1 g (2.7 mmol) of 80 percent sodium hydride in 5 ml of THF. After stirring at RT for 1 h, 0.41 g (2.9 mmol) of methyl iodide was added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. After washing the organic phase with dil. hydrochloric acid and water, and drying over magnesium sulfate, it was concentrated in vacuo and the crude product was recrystallized from methylene chloride. 0.4 g of 7-chloro-9-methyl-5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 141-143° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C:15]2[S:19][C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29]C(=O)OC(C)(C)C)=[O:21])=[CH:17][CH:16]=2)[N:8]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20]([C:18]1[S:19][C:15]([CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:12]=[CH:11][N:10]=2)=[CH:16][CH:17]=1)=[O:21].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccccn3)n2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3ccccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 381 (35 mg, 0.07 mmol) in 1:1 mixture of DCM and TFA (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to produce a solid which was triturated with ether to afford the title compound as a TFA salt (26 mg, 75% yield). 1H NMR (MeOH-d4) 9.31 (s, 1H), 8.68 (s, 1H), 8.66 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 7.77 (d, J=3.9 Hz, 1H), 7.68 (m, 1H), 7.1-7.5 (m, 6H). LRMS: (calc) 402.2; (found) 403.3 (M+H1).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:37])[C@H:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C@@H:12]([CH3:26])[CH2:13][CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH2:2][CH2:3][CH3:4].[CH2:38](NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(S(CC)(=O)=O)C1)=O)[CH2:39][CH2:40]C>>[CH2:1]([NH:5][C:6](=[O:37])[C@H:7]([CH3:36])[CH2:8][C@@H:9]1[O:35][C:39]([CH3:40])([CH3:38])[N:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:10]1[CH2:11][C@@H:12]([CH3:26])[CH2:13][CH2:14][O:15][Si:16]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:24])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(S(=O)(=O)CC)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
The title compound is prepared in a manner analogous to that described in Example 72e) starting from 800 mg of 5(S)tert-butoxycarbonylamino-4(S)-hydroxy-9-triisopropylsilyloxy-2(R),7(R)-dimethyl-nonanoic acid (N-butyl)amide: Rf (A)=0.69.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCC[C@H](CC(=O)OC)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a flask containing 27.1 (0.900 g, 2.99 mmol) and cesium carbonate (1.27 g, 3.88 mmol) in 8 mL of DMF was added benzyl bromide (0.43 mL, 3.59 mmol), and the resulting mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (0 to 20% EtOAc/Hexanes) to provide 27.2 (1.00 g, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[OH:26][CH2:27][C:28]#[CH:29]>N1CCCC1.O.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>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:29]#[C:28][CH2:27][OH:26])[CH:20]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: O
Product: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C#CCO)c2)N=C1N
Temperature: 70 °C
Yield: 45 %

Procedure:
A mixture of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (2.4 g, 5.85 mmol), 3-hydroxy-1-propyne (3.27 g, 58.5 mmol) and Pd(PPh3)4 (670 mg, 0.585 mmol) in pyrrolidine is heated at 70° C. under a nitrogen atmosphere for 16 h, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by chromatography on a silica cartridge, to give 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, 1 g (45% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)=O)=CC=1[N+]([O-])=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[OH:33])=[CH:28][C:27]=1[N+:44]([O-:46])=[O:45].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)=[O:33])=[CH:28][C:27]=1[N+:44]([O-:46])=[O:45]
Reactant: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: c1cc[nH+]cc1
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Yield: 82.2 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone using (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 11.5 mmol) and pyridinium chlorochromate (3.7 g, 17.0 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanone (3.0 g, 82%) as a white solid: 1H NMR (CDCl3) δ 8.33 (d, J=2 Hz, 1H), 8.09 (d, J=9.1 Ha, 1H), 7.20-7.15 (dd, J=3, 8 Hz, 1H), 6.84 (d, J=2 Hz, 2H), 6.69 (m, 1H), 4.06 (s, 3H), 3.83 (s, 6H).
Reaction SMILES: CS[CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].O[O:18][S:19]([O-:21])=O.[K+].[CH3:23]O>O>[CH3:23][S:19]([CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])(=[O:21])=[O:18]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSCCCN1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione (440 mg) in methanol (10 mL) was added a solution of oxone (1.73 g) in water (10 mL) and the reaction stirred at room temperature for 16 h. The reaction was then diluted with water (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(3-methanesulfonyl-propyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>C(#N)C>[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][N:15]([S:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)c1cccs1)CC2
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.4 %

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry acetonitrile (15 mL) was treated with dry triethylamine (0.11 mL), then with 2-thiophenesulfonyl chloride (52 mg). After stirring at 60° C. for 7 hours the reaction mixture was allowed to cool to room temperature and then stand overnight. The solvent was removed under reduced pressure and the residue then treated with water and dichloromethane. The organic phase was separated, then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of methanol and dichloromethane (1:19, v/v) to give 7-chloro-6-phenyl-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (100 mg) as a white solid, m.p. 240–242° C. [Elemental analysis: C, 50.95; H, 4.06; N, 9.98%; Calculated for C18H16ClN3O3S2: C, 51.24; H, 3.82; N, 9.96%].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([F:30])=[CH:32][CH:33]=3)=[O:25])=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Reactant: Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)cc1)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 31.9 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-56, 0.050 g, 0.138 mmol), thionyl chloride (2.0 mL), 4-fluoro aniline (0.052 g, 0.138 mmol), THF (5.0 mL) and 60% NaH (0.017 g, 0.692 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.20 (t, J=7.8 Hz, 2H), 7.40-7.46 (m, 3H), 7.63 (s, 1H), 7.80-7.82 (m, 2H), 9.34 (s, 1H), 10.08 (s, 1H), 11.63 (s, 1H); MS [M−H]−: 452.23.