Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N:19]2[CH:20]=[N:21][N:22]=[CH:23]2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-n1cnnc1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-n1cnnc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (10 mg, 0.050 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine (15 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.091 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H19ClFN8 (M+H)+: m/z=449.1. found: 449.1.
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=4)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.[H-].[Na+].Br[CH2:35][CH3:36]>CN(C=O)C>[CH2:35]([N:21]([C@@H:18]1[CH2:19][CH2:20][N:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:31])([CH3:30])[CH3:1])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:17]1)[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1)[CH3:36]
Reactant: C[Si](C)(C)CCOCn1ccc2c(N3CC[C@@H](Nc4ccc(C#N)cn4)C3)ncnc21
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccc(C#N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino)nicotinonitrile (200 mg, 0.46 mmol) in DMF (5.0 mL) was added NaH (55 mg, 2.3 mmol) in portions at 0° C. The reaction mixture was stirred at ambient temperature for 30 minutes, bromoethane (60 mg, 0.55 mmol) was then added dropwise and the reaction mixture was stirred at ambient temperature for additional 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 464 (M+H)+.
Reaction SMILES: [NH3:1].Br[C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].O>CS(C)=O>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([NH2:1])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: N
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a sealed reaction tube, add cautiously 6 mL of an aqueous solution of ammonia (32%) to a solution of 2,4-dibromonitrobenzene (1,6 g) in 2 mL of DMSO. Stir for 18 hours at 100° C. and cool to room temperature. Pour the heterogeneous mixture into water and filter the title compound (1.1 g, 92%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9](Cl)=[O:10])=[O:5])[CH3:2].[CH:25]1[C:30]([C:31]([O:33][OH:34])=[O:32])=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:8]=1[C:9]([O:34][O:33][C:31](=[O:32])[C:30]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:10])=[O:5])[CH3:2]
Reactant: O=C(OO)c1ccccc1
Reactant: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)Cl)c1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)OOC(=O)c2ccccc2)c1
Yield: 26 %

Procedure:
In a manner similar to that of Example 1-4, starting with 5.79 g (16.3 mmol) of 2-ethoxycarbonyloxy-5-octanoylbenzoyl chloride and 3.38 g (24.5 mmol) of perbenzoic acid (prepared as described in Example 1-3), 2 g of (2-ethoxycarbonyloxy-5-octanoyl)benzoyl peroxide are obtained in the form of a colourless oil in a yield of 26%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4]C=[C:2]1C(O)=O.[O-:9]CC.[Na+].N#N.S1C=CC=C1CC(O)=O.ClC[Si:26]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>COCCOCCOC>[C:5]([S:1][CH2:2][Si:26]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])(=[O:9])[CH3:4]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: O=C(O)c1cccs1
Reactant: CC[O-]
Agent: N#N
Agent: O=C(O)Cc1cccs1
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCO[Si](CSC(C)=O)(OCC)OCC
Temperature: 8 °C
Yield: 55 %

Procedure:
This example illustrates the preparation of a thiocarboxylate alkoxysilane from a salt of a thiolcarboxylic acid using as a nonprotic solvent. 88 grams of powdered sodium ethoxide and 600 ml diglyme were charged into a 1 liter, 3 neck round bottomed flask equipped with magnetic stir bar, temperature probe/controller, heating mantle, addition funnel, condenser, N2 inlet, and ice water bath. The solution was cooled to 8° C. and 105 grams of thiolacetic acid was added slowly via the addition funnel, keeping the temperature below 60° C. The solution was allowed to cool to 35° C., and 250 grams of chloromethyltriethoxysilane was added via the addition funnel. After addition was complete, the solution was heated to 70° C., where a brief exotherm to 120° C. was observed. The solution was heated at 70° C. for an additional 3 hours. A white solid formed which was filtered first through a 0.1 μm pressure filter and then a 0.01 μm filter to give a clear, black solution. The solvent was removed under reduced pressure, and the remaining liquid vacuum distilled to yield 163 grams of a clear and colorless liquid, a 55 percent yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][OH:31])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.[C:32]([N:36]=[C:37]=[O:38])([CH3:35])([CH3:34])[CH3:33].O.[OH-].[Na+]>CN(C=O)C.Cl[Cu]>[NH4+:2].[OH-:8].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][O:31][C:37](=[O:38])[NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:28]=2)=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CC(C)(C)N=C=O
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(CCO)cc4)nc32)CC1
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(CCOC(=O)NC(C)(C)C)cc4)nc32)CC1
Product: [NH4+]
Temperature: 50 °C

Procedure:
To a solution of 2-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-ethanol (example 192) (53 mg, 0.127 mmole) in DMF (1 mL) are added tertbutylisocyanate (16 mg, 0.26 mmole) and CuCl (13 mg, 0.13 mmole). The reaction mixture is heated at 50° C. for 24 hours. Water is added, and 1N NaOH to reach pH 9-10. The aqueous phase is extracted three times with AcOEt, and the organic phase is washed with water, brine, dried over MgSO4, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) with a gradient from (98:2) to (9:1) then (CH2Cl2:MeOH:NH4OH) (9:9:1) to give tert-butyl-carbamic acid 2-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-ethyl ester.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH2:12].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C([BH3-])#N.[Na+]>CC(O)=O.CO.C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:16][C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=O
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Preparation I6, Step 2: A solution of 5-(trifluoromethyl)-1H-indazol-3-amine (2.08 g, 10.3 mmol) in 50 mL of 1% AcOH/MeOH was charged with ethyl glyoxylate (2.05 mL of a 50% solution in toluene, 10.3 mmol; note: the commercially available material is polymeric and was heated at 100° C. for 90 min before being used immediately in this reaction) and sodium cyanoborohydride (777 mg, 12.4 mmol). The mixture was stirred for 2.5 h, quenched with sat. NaHCO3, and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by flash chromatography provided ethyl 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetate (819 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1.CC(C)=O>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)ncn2)c1

Procedure:
A stirred mixture of 4,6-dichloropyrimidine (18.6 g, 125 mmol), 3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL) and H2O (90 mL) is kept at reflux for 3 h. Acetone is removed in vacuo, the remaining aqueous layer is basified with conc. aqueous ammonia solution and extracted with ethyl acetate. The organic extract is dried over Na2SO4 and evaporated. The residue is suspended in a small amount of acetone, filtered and the filter cake dried in vacuo to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClC(Cl)C>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:38]([OH:40])=[O:39])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (30 mL) was added dropwise to a stirring slurry of 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (10 g, 20 mmol) in dichloroethane (30 mL) under N2. The clear dark green solution was stirred at rt for 2.5 h, concentrated to dryness and stirred with EtOAc (100 mL) overnight. The solids were collected by filtration, washed with EtOAc and Et2O to yield 13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (8.35 g, 18.8 mmol, 94%) was as a yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.13-2.16 (m, 10H), 2.74-2.88 (m, 1H), 3.84 (s, 3H), 3.89 (s, 3H), 4.06-4.19 (m, 1H), 5.54-5.76 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.4, 2.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.78 (dd, J=8.8, 1.1 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H). LCMS: m/e 446 (M+H)+, ret time 3.21 min, column B, 4 minute gradient.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][CH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CCCCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 106.8 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (82.6 mg, 0.142 mmol), 6-bromo-2-methyl-2-hexanol (139 mg, 0.710 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to give 87.2 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 6-bromo-2-methyl-2-hexanol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=C.N1C(C)=CC=CC=1C.C(Cl)Cl.[O:21]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[O:21]=[CH:5][CH2:4][CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7]
Reactant: C1COCCO1
Reactant: C=CCCCC(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COC(=O)CCCC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A colorless solution of commercially available methyl hex-5-enoate (5.000 g; 39.01 mmol) in dioxane (290 ml) and water (95 ml) was treated successively with 2,6-lutidine (8.360 g; 78.02 mmol), a solution of osmium tetroxide (2.5 wt. % in 2-methylpropan-2-ol; 0.50 ml), and NaIO4 (33.375 g; 156.04 mmol). The resulting beige heterogeneous reaction mixture was further stirred at rt, under nitrogen, for 16 h. The resulting milky heterogeneous mixture was treated with water (100 ml) and DCM (500 ml). The layers were separated, and the aq. layer was further extracted with DCM (200 ml/150 ml). The mixed slightly yellow organic layers were then washed with brine (200 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude methyl 5-oxopentanoate as a green oil which was directly used for the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:31]2[N:33]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:32]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(Cl)nc3)ncc1CC2
Temperature: 100 °C
Yield: 16 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 0.76 mmol), N-(6-chloro-pyridin-3-yl)-guanidine nitrate (196 mg, 0.84 mmol), NaOH (34 mg, 0.84 mmol) and 2-methoxyethanol (2 mL) was heated at 100° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the pure title product as a white solid (40 mg, 16%): mp 252-253° C. Anal. RP-HPLC: tR 16.8 min (10-70% MeCN, purity 92%). 1H-NMR (DMSO-d6) δ 9.98 (s, 1H, NH), 8.90 (d, 1H, J 2.9, Ph-H), 8.44 (s, 1H, Py-H), 8.29 (dd, 1H, J 8.7, 2.4, Ph-H), 7.50 (d, 1H, J 8.7, Ph-H), 3.10 (m, 4H, CH2—CH2), 2.82 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 169.08, 159.26, 158.47, 156.22, 155.35, 141.23, 139.69, 137.05, 128.55, 127.52, 123.55, 117.05, 24.60, 23.07, 19.39. MS (ESI+): m/z 330.06 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>>[F:19][C:18]([F:21])([F:20])[C:16]([O-:22])=[O:17].[C:13]([C@H:10]1[CH2:11][CH2:12][NH2+:8][CH2:9]1)([OH:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CC[NH2+]C1
Product: O=C([O-])C(F)(F)F

Procedure:
(3S)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (0.5 g, 2.34 mmol) was stirred in TFA (20 mL) for 3 h. The solvent was removed to provide the title compound as yellow oil that was used for the next step without further purification. Yield: 0.50 g (99%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[C:7]=1[CH:8]=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: O=S(=O)(O)O
Product: COc1cc(F)c(C=O)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cold (−5° C.) nitric acid (2.7 mL) was added concentrated sulfuric acid (1.75 mL, 32 mmoL) dropwise keeping the temperature below 5° C. The solution was added to a cooled solution of 2,6-difluoro-4-methoxy benzaldehyde (5.0 g, 29 mmoL) in sulfuric acid (20 mL) over 15 minutes keeping the temperature below 5° C. After stirring at 0° C. for 2 hours the orange solution was poured on to ice, the white precipitate which formed was collected by filtration to give the title compound as a white solid (6.33 g, 100%). 1H NMR (CDCl3) 10.20 (1 H, t, J=1.17 Hz), 6.69 (1 H, dd, J=11.68, 1.93 Hz), 4.03 (3 H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][C:29]4([CH3:28])[CH2:32][O:31][CH2:30]4)=[O:24])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: CC1(N)COC1
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cc2)cn1
Yield: 64 %

Procedure:
As described for example 3b, 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) was converted, using 3-methyl-3-oxetanamine instead of isopropylamine, to the title compound (57 mg, 64%) which was obtained as a white solid after trituration from ethyl acetate. MS: m/e=433.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][O:12][C@@H:13]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:14][N:15]3[CH:19]=[CH:18][NH:17][CH2:16]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[N+:29]([O-:32])([OH:31])=[O:30]>C(O)C>[N+:29]([O-:32])([OH:31])=[O:30].[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][O:12][C@@H:13]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H](CN2C=CNC2)OCc2csc3c(Cl)cccc23)c(Cl)c1
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Clc1ccc([C@@H](Cn2ccnc2)OCc2csc3c(Cl)cccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
2.35 mg (5.37 mmol) of (S)-(+)-1-[2-(7-chlorobenzo[b]thiophen-3-yl-methoxy)-2-(2,4-dichlorophenyl )-ethyl]-2H-imidazole are dissolved in 17 ml of 96% ethanol. 3 ml of water are added and heated at a temperature between 35 and 40° C. To the obtained solution, 0.61 ml of 60% nitric acid (8.06 mmol, 1.5 eq.) are added. Then 13 ml of water are added and cooled first at room temperature and thereafter at 10° C. for 1 hour. The formed solid is filtered, washed twice with 10 ml of water and dried at vacuum for 24 hours to give 2.65 g (R=98.5%) of (S)-(+)-1-[2-(7-chloro-benzo[b]thiophen-3-yl-methoxy)-2-(2,4-dichlorophenyl)-ethyl]imidazole mononitrate.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=2[F:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>B#[Ni].CO>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[F:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: B#[Ni]
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(c1ccc(N)cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Yield: 95.3 %

Procedure:
A mixture of ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)-acetate (6.0 g, 14.1 mmol) [prepared as in Example 1, Step (b)], nickel boride (8.0 g, 62.4 mmol), hydrochloric acid (50 ml, 1 M) and methanol (150 ml) was heated at reflux for 1 h. The reaction mixture was cooled and filtered through Celite®. After removing the methanol in vacuo, the resulting aqueous mixture was made basic with ammonium hydroxide, and the product was extracted into ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the organic layer gave ethyl 2-(5-benzoyl-1,4dimethyl-pyrrol-2-yl)-2-(2-fluoro-4-aminophenyl)acetate (5.3 g, 95%). ##STR21##
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=1.O>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([S:29][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(Sc2cccc([N+](=O)[O-])c2C#N)c1
Temperature: 0 °C
Yield: 73011.2 %

Procedure:
A mixture of 2,6-dinitrobenzonitrile (1.4 g 7.2 mmol) and K2CO3 (1.1 g, 7.9 mmol) in 10 ml of DMF was chilled to 0° C. A solution of 3,5-dimethylthiophenol (1.1 g 0.0079 mmol) in 10 ml of DMF, was added dropwise over 30 min with stirring under nitrogen. After stirring an additional 30 min, the reaction mixture was poured into 150 ml of water and stirred for 1 hr. The solid was collected by vacuum filtration. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 1.64 g (80%) of 2-[(3,5-dimethylphenyl)thio]-6-nitrobenzonitrile: mp 155°-156° C.