Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].C(Cl)[Cl:36].Cl>O1CCOCC1>[ClH:36].[NH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6]([C:5]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[N:9]=2)=[CH:27][CH:26]=1
Reactant: ClCCl
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2csc(-c3ccc(CN)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 68a (200 mg) in 10 ml, CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for 4 h. The precipitate (2r) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.38 (br, 3H), 8.10 (d, 2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s, 2H), 4.11 (s, 2H), 3.87 (s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:30])([F:29])[CH2:26][CH2:27]I>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:27][CH2:26][C:25]([F:30])([F:29])[F:24])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(C2CCN(CCC(F)(F)F)CC2)c1F

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1,1,1-trifluoro-3-iodopropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 353 (M+, 11), 271 (15), 270 (bp), 152 (14) 133 (9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:20]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)(=[O:22])=[O:21])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: COc1cc(NS(=O)(=O)c2cccnc2)c2ncccc2c1
Yield: 38.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (50 mg, 0.29 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (76 mg, 0.43 mmol) gave the title compound (35 mg, 39%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([CH:15]3[O:19][C:18](=[O:20])[N:17]=[N:16]3)[CH:12]=[C:11]([Cl:21])[N:10]=2)[CH2:5][CH2:4]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:30])[NH:26][C:27]=1[CH3:28]>CC(N(C)C)=O>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[C:13]([CH:15]4[N:16]=[N:17][C:18](=[O:20])[O:19]4)[CH:12]=[C:11]([Cl:21])[N:10]=3)[CH2:5][CH2:4]2)=[O:30])[NH:26][C:27]=1[CH3:28]
Reactant: NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C4N=NC(=O)O4)cc(Cl)n3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
TEA (0.10 ml, 0.70 mmol) and 5-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]-1,3,4-oxadiazol-2(5H)-one hydrochloride (Intermediate 51, 0.10 g, 0.33 mmol) were added to a solution of pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17) (0.12 g, 0.33 mmol) in DMA (2 ml). The mixture was stirred at room temperature overnight and was purified by semi-preparative HPLC eluting with water/acetonitrile and TFA mixtures to give the title compound (18 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixed solution of the compound (1.5 g, 4.2 mmol) obtained in Example 36a in ethanol/tetrahydrofuran (v/v=1/1, 20 mL) was added palladium-carbon (10% wet., 150 mg), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere (1 atm). Palladium-carbon was removed by filtration and the solvent was evaporated under reduced pressure to give a crude title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([SiH](CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[NH:8][N:7]=1
Reactant: COC/C=C/c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
To the solution of crude (R,E)-1-(3-(3-methoxyprop-1-en-1-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (142 mg, 0.239 mmol) in DCM (0.8 mL) TFA (0.3 mL) and triethylsilane (0.1 mL) were added. The mixture was stirred at room temperature for 30 min and additional TFA (0.5 mL) and triethylsilane (0.3 mL) were added. The mixture was stirred at room temperature for 30 min, evaporated in vacuo and purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to afford (R)-1-(3-(3-methoxypropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (21.7 mg, 0.046 mmol, 19%). MS ESI calc'd. for C19H24N5O2 [M+H]+ 354, found 354. 1H NMR (600 MHz, DMSO-d6) δ 12.92 (s, 1H), 9.38 (s, 1H), 8.80 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.38-7.15 (m, 5H), 4.85 (m, 1H), 3.33 (t, J=6.3 Hz, 2H), 3.19 (s, 3H), 2.91 (t, J=7.6 Hz, 2H), 1.99-1.85 (m, 2H), 1.39 (d, J=6.9 Hz, 3H),
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-hydroxy-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one (0.13 g, 0.43 mmol) (from Example 53a supra) was suspended in a mixture of triethylsilane (0.15 g, 1.29 mmol) (Aldrich) and trifluoroacetic acid (0.73 g, 6.48 mmol) and heated in an 80° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one as a pale yellow solid. (Yield 0.11 g, 91%)
Reaction SMILES: [OH:1][CH:2]([CH2:24][O:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CN=C1.[Si:50](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[Si:50]([O:1][CH:2]([CH2:24][O:25][C:26]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 3 (5 mmol) in 30 ml of DMF is added imidazole (20 mmol) at 0° C. tert-Butyldiphenylsilyl chloride then is added dropwise to this mixture. The mixture is slowly warmed to room temperature. After 6 hours at room temperature, this is poured into ice water and extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by silica gel chromatography using isohexane/ethyl acetate (9:1). Yield: 95% of a colorless oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[C:8]([C:10](=[CH:13]OC)[C:11]#[N:12])=[O:9]>C(O)C>[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[C:8]([C:10](=[CH:13][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]#[N:12])=[O:9]
Reactant: COC=C(C#N)C(=O)c1ccc(Cl)cc1Cl
Reactant: NC1CC1
Solvent: CCO
Product: N#CC(=CNC1CC1)C(=O)c1ccc(Cl)cc1Cl
Yield: 86.9 %

Procedure:
2.5 g of cyclopropylamine are added dropwise to a solution of 11 g of 2-(2,4-dichloro-benzoyl)-3-methoxyacrylonitrile in 40 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 25 minutes and then heated at the boiling point for 15 minutes. The solvent is removed in vacuo and the residue is recrystallized from ethanol/light petrol. 10.5 g of 2-(2,4-dichloro-benzoyl)-3-cyclopropylaminoacrylonitrile of melting point 93°-94° C. are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O)([CH3:3])[CH3:2].[N-:21]=[C:22]=[O:23].[K+].C(O)(=O)C>O>[CH:1]([N:4]1[C:5]2[C:6](=[CH:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:21][C:22]1=[O:23])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)c(NC(C)C)c1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(-c3ccc(F)cc3)nc(=O)n(C(C)C)c2c1

Procedure:
A solution of 8.5 g. of 2-isopropylamino-4-methyl-4'-fluoro-benzophenone and 4.2 g. of potassium isocyanate in 100 ml. of glacial acetic acid is stirred at 60°-70°C. for 20 hours. The resulting mixture is treated with a mixture of ice and water and extracted three times with methylene chloride. The organic phases are combined, washed twice with water, once with sodium bicarbonate solution and again with water followed by drying and evaporation in vacuo. The residue is dissolved in a small amount of methylene chloride and precipitated by adding pentane. The resulting solid is redissolved in methylene chloride, treated with charcoal and diethyl ether exchanged for the methylene chloride to obtain a solid which is dried in a high vacuum at 60°C. to yield 1-isopropyl-7-methyl-4-(p-fluorophenyl)-2(1H)-quinazolinone, m.p. 172°-174°C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:12]1)=[O:10].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:42])[C:36]=3[NH:35][C:34]3[CH:43]=[CH:44][CH:45]=[CH:46][C:33]2=3)=[O:31])=[CH:26][CH:25]=1>C(#N)C>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:41][C:40]4[CH:39]=[N:38][N:37]([CH3:42])[C:36]=4[NH:35][C:34]4[CH:43]=[CH:44][CH:45]=[CH:46][C:33]3=4)=[O:31])=[CH:26][CH:25]=2)[CH2:12][CH2:13]1
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(O)cc1)C2
Reactant: CC(C)(C)CCN1CCN(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(OCC(=O)N3CCN(CCC(C)(C)C)CC3)cc1)C2
Yield: 11 %

Procedure:
Potassium carbonate (104 mg, 0.76 mmol) was added to a mixture of 2-bromo-1-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-ethanone from Example E37 (110 mg, 0.38 mmol) and (4-hydroxy-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E75.2 (90 mg, 0.28 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for 20 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with 5% KHCO3 solution, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white powder identified as the title compound (21 mg, 11%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 833.4 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 4.85 mmol) in DCM (60 mL) and DIPEA (1.33 mL, 7.76 mmol) is added methane sulfonylchloride (0.452 mL, 582 μmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. Another portion of methane sulfonylchloride (0.452 mL, 5.82 mmol) is added and stirring is continued for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.15 min, [M+1]+=491.34.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1)[CH3:2].[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])=[CH:16][C:15]=2[CH2:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(N)cc2CSC(C)(C)C)c1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1

Procedure:
As described for Example 21, [3-(2-bromomethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and 2-methyl-2-propanethiol were reacted to provide [3-(2-tert-butylsulfanylmethyl-4-nitro-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-tert-butylsulfanylmethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester. The amine was treated with trimethylacetyl chloride to provide {3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-chloro-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided the acid.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1ccc(F)c2c1CCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCc1ccc(F)c2c1CCO2)C1CC1
Reaction time: 0.33 h
Yield: 10.4 %

Procedure:
A mixture of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (114 mg), triethylamine (0.089 ml), dichloromethane (5 ml) and cyclopropanecarbonyl chloride (67 mg) was stirred in ice for 20 minutes and stirring continued at room temperature overnight. The mixture was partitioned between 2N hydrochloric acid and dichloromethane and the organic phase washed with 8% sodium bicarbonate and evaporated. Purification of the residue by preparative hplc gave the title compound as a white solid (16 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CC#N>[N+:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15]2)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCn1c(-c2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-phenyl-5-nitroindole (prepared as described in J. Org. Chem. (1966), 31(1), 65-9) (1.5 g; 6.3 mmol) in CH3CN (50 ml) was added K2CO3(1.7 g; 12.6 mmol). To the mixture thus obtained was then added dropwise ethyl 4-bromobutanoate (3.3 g; 16 mmol) and the resulting mixture was heated to 120° C. under stirring for 18 hours. After cooling, the mixture was poured into water (500 ml) and the crude product was filtered, dried under vacuum to give ethyl 4-(5-nitro-2-phenyl-1H-indol-1-yl)butanoate which was used in the following reaction without any further purification.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][C:15](=[O:18])[C:14]3[S:13][C:12]([C:19]([NH2:21])=[O:20])=[N:11][C:10]=3[C:9]=2[CH:22]=1.[BH4-].[Na+].O>CO>[OH:18][CH:15]1[C:14]2[S:13][C:12]([C:19]([NH2:21])=[O:20])=[N:11][C:10]=2[C:9]2[CH:22]=[C:5]([C:4]#[C:3][C:2]([OH:1])([CH3:23])[CH3:24])[CH:6]=[CH:7][C:8]=2[O:17][CH2:16]1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (80 mg, 0.23 mmol) in MeOH (5 mL) at 0° C., NaBH4 (9 mg, 0.23 mmol) was added. The mixture was allowed to warm to room temperature, and stirred for 2 h, then water (2 mL) was added. The mixture was extracted with EtOAc (10 mL×3) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a white solid (29 mg, 36%). 1H NMR (400 MHz, DMSO-d6): 8.57 (d, J=2.1 Hz, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.31 (dd, J1=8.3 Hz, J2=2.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.38 (d, J=7.2 Hz, 1H), 5.45 (s, 1H), 5.09-5.14 (m, 1H), 4.08-4.35 (m, 2H), 1.49 (s, 6H); LC-MS (ESI & APCI): 345.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH2:24][C:23]#[N:25])[CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: O=Cc1cccc(OCCCCCOCc2ccccc2)c1
Product: N#CCC(O)c1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(5-benzyloxypentoxy)-benzaldehyde gave 3-[3-(5-benzyloxypentoxy)-phenyl]-3-hydroxypropionitrile as yellow oil. Yield (0.74 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.23-7.41 (m, 6H), 6.90-6.98 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0 (t, J=6.0 Hz, 1H), 4.51 (s, 2H), 3.98 (t, J=7.0 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.75 (d, J=6.0 Hz, 2H), 1.75-1.84 (m, 2H), 1.67-1.73 (m, 2H), 1.53-1.62 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[NH:29][C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:10]2=[N:11][C:12]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2[nH]1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCn1c(CCOC(C)=O)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate (step 3)(12 mg, 0.031 mmol) was dissolved in dry DMF (1 ml) at RT and treated with K2CO3 (12.91 mg, 0.093 mmol) and ethyl 7-bromoheptanoate (0.012 ml, 0.062 mmol). The resulting brown suspension was stirred at RT for 16 hours. The mixture was then heated at 60° C. for 5 hours and after cooling to RT, stirred overnight. The mixture was added to water (30 ml) and extracted with DCM (×3). The combined organic extracts were passed through a phase separating column and concentrated under reduced pressure to afford the title compound;