Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1)(=[O:25])=[O:24]
Reactant: Nc1ccc(CCn2ccnc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(CCn2ccnc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a -10° C. solution of 8 g (0.064 mole) of 1-[2-(4-aminophenyl)ethyl]-1H-imidazole and 10 mL triethylamine in 200 mL of methylene chloride add 5 mL of methanesulfonyl chloride dropwise. Stir the resulting solution at -10° C. for about 30 minutes then warm to ambient temperature for about 30 minutes. Wash the reaction mixture with water (2×100 mL). Extract with 10% aqueous sodium hydroxide (2×50 mL). The combined aqueous extracts are neutralized with ammonium chloride then extracted with methylene chloride (2×100 mL) and combined. Remove the solvent in vacuo to provide the title compound, which may be recrystallized from tetrahydrofuran.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([O:29]CC)=[O:28])[CH2:7]1)(=[O:4])=[O:3].[Li+].[OH-].Cl>CO>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@H:8]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([OH:29])=[O:28])[CH2:7]1)(=[O:3])=[O:4]
Reactant: CCOC(=O)[C@@H]1C[C@H]1[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H]([C@@H]2C[C@H]2C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 80.4 %

Procedure:
A stirred solution of ethyl trans-2-[(2S, 4R)-4-methanesulfonyloxy-N-(4-nitrobenzyloxycarbonyl) pyrrolidin-2-yl]cyclopropanecarboxylate (750 mg, 1.64 mmol) and MeOH (15 ml) was treated with 2N LiOH (2.4 ml, 4.8 mmol) at room temperature over 12 hours. The reaction mixture was neutralized with 6N HCl (0.80 ml, 4.8 mmol) and extracted with CH2Cl2 (20 ml×2). The organic layers were combined, dried (MgSO4) and concentrated to afford trans-2-[(2S, 4R)-4-methanesulfonyloxy-N-(4-nitrobenzyloxycarbonyl)pyrrolidin-2yl]cyclopropanecarboxylic acid (565 mg, 80% yield) as a residue.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[SH:29]>>[CH3:18][C:19]1[CH:24]=[C:23]([C:25]([CH3:27])([CH3:26])[CH3:28])[CH:22]=[CH:21][C:20]=1[S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: Cc1cc(C(C)(C)C)ccc1S
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: Cc1cc(C(C)(C)C)ccc1SCCCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 2-methyl-4-tert. butyl-thiophenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:17]=[C:18]([C:20]([O-])=[O:21])[S:19][C:12]=12.[Li+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:20]([C:18]2[S:19][C:12]3[C:13](=[N:14][CH:15]=[CH:16][C:11]=3[Cl:10])[CH:17]=2)=[O:21])[CH:2]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCCc1cccnc1
Agent: [Li+]
Product: O=C(NCCc1cccnc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-pyridine-3-yl-ethyl amine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 318/320 (MH+); HPLC Rf: 4.27 min.; HPLC purity 76%.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[CH3:24][NH:25][CH3:26]>C(O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:25]([CH3:26])[CH3:24])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: CNC
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Product: CN(C)c1ccc2c(n1)C(c1ccccc1Cl)=NCc1n[nH]c(=O)n1-2

Procedure:
A mixture of 19 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine, 80 grams of dimethylamine and 500 ml. of ethanol were heated in the autoclave for 8 hours at 100°-110° C. The solution was evaporated to dryness, the residue stirred with water, filtered off with suction and washed several times with water. Then it was recrystallized from methanol. Yield 8 grams; M.P. 244°-246° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:17]=[CH:16]4)[CH:5]=[CH:4][C:3]1=2.C[N+]1([O-])CCOCC1.C(OCC)(=O)C>C(Cl)Cl.O.CCCCCC>[CH2:26]([O:25][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:28])([CH3:1])[CH2:11][CH2:10][C:9](=[O:12])[C:8]=4[CH:7]=3)[CH:14]=2)[CH:19]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(O)CCC4(C)C)ccc2c1
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(=O)CCC4(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 101 mg (0.27 mmol) of ethyl-6-[5,6,7, 8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate (Compound B4) in 1.5 mL of methylene chloride was added 50 mg (0.43 mmol) of N-methylmorpholine N-oxide and 6.0 mg (0.017 mmol) of tetrapropylammonium perruthenate(VII). The reaction was stirred at room temperature for 3 h, diluted with water, and extracted with CH2Cl2 (2×). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give a foam. The title compound was obtained as a 9 white solid after flash chromatography (silica, 10% ethyl acetate in hexane).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([Sn](CCCC)(CCCC)CCCC)=[N:38]1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:35])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:37]([CH3:36])[N:38]=4)[N:24]=3)[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccccc12
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2ccccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 125.1 %

Procedure:
In a dry round-bottomed flask 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.12 g, 0.21 mmol) and 1-methyl-3-tributylstannanyl-1H-indazole (117 mg, 0.28 mmol) were dissolved in DMF (2 ml). The reaction mixture was evacuated and backfilled with Argon then tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) and copper(I) iodide (9 mg, 0.047 mmol) were added. The reaction mixture was stirred at 80° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-3% MeOH) to afford 161 mg of 2-(1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow oil.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C.CCCCC>[CH3:17][C:16]1[S:18][C:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[C:3]([CH3:4])[N:19]=1
Reactant: CC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=S
Solvent: CCCCC
Solvent: CCO
Product: Cc1nc(C)c(Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 68.3 %

Procedure:
4.7 g of 3-chloro-4-(4-nitrophenyl)butan-2-one and 2.4 g of thioacetamide are dissolved in 60 ml of ethanol and refluxed for 12 hours. The reaction medium is concentrated, the residue is taken up in water and the solution is rendered basic with sodium carbonate and extracted with chloroform. After concentration of the organic phase, the solid obtained is taken up in hot pentane to give 3.5 g of 2,4-dimethyl-5-(4-nitrobenzyl)thiazole in the form of yellow crystals melting at 66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([F:22])[CH:15]=3)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([OH:29])[CH:3]=1.Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([F:22])[CH:15]=3)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([O:29][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:3]=1
Reactant: BrCC1CCCC1
Reactant: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1F
Product: N#Cc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-2-fluoro-benzonitrile and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless solid (50%). MS (Turbo Spray): m/z=496.3 (M+H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:38]=1)[C@@H:10]([O:31][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.44 g (3.90 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoic acid in 14 ml of DMF are stirred, under an N2 atmosphere, together with 2.70 g (17.6 mmol) of tert-butyldimethylchlorosilane and 2.18 g (32 mmol) of imidazole at RT for 18 h. The reaction mixture is poured onto ice-water, and this mixture is extracted with 3 portions of ethyl acetate; the organic phases are washed with 10% citric acid solution, H2O and saline, dried with Na2SO4 and evaporated. The resulting oil is taken up in 30 ml of methanol/THF/H2O 3:1:1, and this solution is treated with 3.2 g of K2CO3 and stirred at RT for 1 h. The reaction mixture is partially evaporated, and the aqueous residue is poured onto 10% citric acid solution and ice, and this mixture is extracted 3× with ethyl acetate; the organic phases are washed twice with H2O and, finally, with saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 2:1→1:1) of the crude product affords the title compound: TLC Rf (C)=0.53; FAB-MS (M+H)+ =740.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:27])[N:9]3[CH2:13][CH:12]([CH2:14][N:15]4[CH2:20][CH2:19][C@H:18]([OH:21])[C@H:17]([CH2:22][NH:23]C(=O)[O-])[CH2:16]4)[C:11]=1[C:10]=23.FC(F)(F)C(O)=O>ClCCl>[NH2:23][CH2:22][C@H:17]1[C@@H:18]([OH:21])[CH2:19][CH2:20][N:15]([CH2:14][CH:12]2[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:27])[N:9]([C:10]=43)[CH2:13]2)[CH2:16]1
Reactant: O=C([O-])NC[C@@H]1CN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@@H]1CN(CC2Cn3c(=O)ccc4ncc(F)c2c43)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
A suspension of 1,1-dimethylethyl({(cis-1-[(3-fluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-hydroxy-3-piperidinyl}methyl)carbamate (0.175 g, 0.405 mmol) in dichloromethane (2 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 20 min. The reaction mixture was evaporated and then redissolved using a 4:1 dichloromethane:methanol solution. The organic phase was then treated with aqueous sodium bicarbonate solution. The aqueous phase was extracted 10 times with a 4:1 dichloromethane:methanol solution and then the combined organic phases were dried and the solvent was removed under reduced pressure and the residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and ammonia gradient to provide the desired compound (0.08 g).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6](=[O:23])[NH:5][C:4](=[O:24])[CH:3]=1.[Na].[F:26][C:27]([F:31])([F:30])[CH2:28][OH:29]>>[O:23]=[C:6]1[NH:5][C:4](=[O:24])[CH:3]=[C:2]([O:29][CH2:28][C:27]([F:31])([F:30])[F:26])[N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(Cl)cc(=O)[nH]c2=O)cc1
Reactant: OCC(F)(F)F
Agent: [Na]
Product: N#Cc1ccccc1-c1ccc(Cn2c(OCC(F)(F)F)cc(=O)[nH]c2=O)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a mixture of 4′-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (2.7 g) and 2,2,2-trifluoroethanol (70 mL) was added a solution of sodium (0.28 g) in 2,2,2-trifluoroethanol (10 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with chloroform and 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.3 g, 30%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[N:18]2[C:19]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:20][O:21][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[NH:11]1>C(#N)C.C(O)(=O)C>[Br:1][C:15]1[C:16]2[O:21][CH2:20][C:19]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:18]3[C:10](=[O:9])[NH:11][C:12]([C:17]=23)=[CH:13][CH:14]=1
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)NCC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a mixture of N-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide in acetonitrile (5 mL) and acetic acid (3 mL), and cooled to 0° C. The reaction was stirred for 1 h, concentrated to remove residual acetic acid, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-[(7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide (0.040 g. 60%). LCMS calculated for C17H16BrN4O3 (M+H)+: m/z=403.1, 405.1. found: 402.9, 405.0.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:30][CH3:31])=[C:12]([CH3:17])[C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1C

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 6.92 (d, 1H), 6.86 (d, 1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s, 3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[CH3:36][O:37]C1C=C(S)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:36][O:37][C:8]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(S)c1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1cccc(SCCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 3-methoxy -thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([F:18])[C:6]2[O:10][N:9]=[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][CH:33]=O)[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([O:23][C:24](=[O:35])[NH:25][C@H:26]1[CH2:27][CH2:28][C@H:29]([CH2:32][CH2:33][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:17]=[C:3]([F:2])[CH:4]=[C:5]([F:18])[C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:30][CH2:31]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Fc1cc(F)c2onc(N3CCNCC3)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4c(F)cc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution in CH2Cl2 (20 ml) of 5,7-difluoro-3-piperazin-1-yl-benzo[d]isoxazole hydrochloride (1.35 g, 4.9 mmol) and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.77 g, 7.3 mmol; prepared according to WO2007/093540) was stirred 15 min at r.t. before addition of Na(AcO)3BH (1.87 g, 8.8 mmol). The reaction mixture was stirred 2 h at r.t., then sat. aq. NaHCO3 was added and the product was extracted with 3 portions of CH2Cl2. After drying (Na2SO4) and evaporation of the solvent the product was purified by flash chromatography (50 g SiO2, EtOAc/MeOH 100:0→90:10) to obtain 2.59 g (quant.) of title compound as a white solid. m/z=465.3 ([M+H]+); 409.3 ([M+H—C4H8]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cc(C)cc(C)c4)CC3)nc2c1
Yield: 65 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 65%). 1H NMR (300 MHz, CDCl3): δ 2.28 (s, 6H), 3.26 (s, 4H), 3.76-3.87 (m, 6H), 4.11 (s, 4H), 6.59 (s, 2H), 6.90 (m, 1H), 7.14 (d, J=8.7 Hz, 1H), 7.32 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].CN(C)[CH:19]=[O:20]>O1CCCC1>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([CH:19]=[O:20])=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: FC(F)(F)c1ccncc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cnccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (1.65 mL, 0.00265 mol, 1.6 M) was added to a solution of 3-bromo-4-(trifluoromethyl)pyridine (E; 0.5 g, 0.022 mol) in anhydrous tetrahydrofuran (15 mL), at −78° C. The reaction mixture was stirred for 10 min followed by the addition of dimethylformamide (0.2 mL, 0.00265). It was stirred for 30 min at same temperature. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (25 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic extracts were combined and then washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulphate and concentrated to afford 4-(trifluoromethyl)nicotinaldehyde. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.25 (s, 1H), 9.10-9.09 (d, J=4 Hz, 1H), 7.95-7.94 (d, J=4 Hz, 1H).