Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]([CH:52]([CH3:54])[CH3:53])=[C:50]=[O:51]>>[CH:52]([NH:49][C:50](=[O:51])[O:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)([CH3:54])[CH3:53]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Product: CC(C)NC(=O)O[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethyl-silyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol and 2-isocyanatopropane following a procedure analogous to that described for Intermediate 13. LC (method 5): tR=1.28 min.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)C1C=CC=CC=1.B(Br)(Br)Br.C1COCC1>C(Cl)Cl>[Br:19][C:11]1[CH:10]=[C:9]([OH:8])[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=1
Reactant: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc2cc(Br)cc(O)c21
Reaction time: 1 h

Procedure:
To a solution of 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51 (157 mg, 0.495 mmol) in DCM (3 mL) at 0° C. was added a solution of 1.0M BBr3 in THF (1.1 equiv). After 1 h at 0° C., the reaction mixture was diluted with DCM and washed with sat'd NaHCO3 and then the aqueous layer was then extracted with EtOAc (3×). Combined organic layers were washed successively with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 0% MeOH/EtOAc→10% MeOH/EtOAc) to give of 5-bromo-1-methyl-1H-benzo[d]imidazol-7-ol 2.56.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:18]=[O:19])=[C:5]([OH:17])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2].[OH-].[K+].S(OC)(O[CH3:26])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4]([CH:18]=[O:19])=[C:5]([O:17][CH3:26])[C:6]2[C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1)[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1cc2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1cc2c(c(OC)c1C=O)C(C)(C)CCC2(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
3-Ethyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde (48.2 g, 0.185 mol) was stirred with toluene (650 mL), and potassium hydroxide 85% (19.5 g, 0.296 mol) was added in one portion. The mixture was heated to 45° C. and dimethyl sulfate (35 g, 0.278 mol) was added during 0.5 h at 45°-50° C. The heating was continued for an additional 0.5 h at 50° C. The mixture was cooled to 20° C., neutralized with 5% hydrochloric acid, washed with water (50 mL), and then finally washed with brine (30 mL). Solvent was removed by distillation and the residue distilled to give 3-ethyl-1-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde (40.6 g), GLC purity 98%. Crystallization from hexane gave 27 g of material, GLC purity 99%, exhibiting the expected spectral data.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)=[O:13])=[C:10]([Cl:30])[CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:4]([S:5]([C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)=[O:13])=[C:10]([Cl:30])[CH:9]=1)(=[O:7])=[O:6])[CH:3]=[CH2:2]
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
115 mg of NBS was added to a solution of 200 mg of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide and 169 mg of triphenylphosphine in 3 mL of dichloromethane at 0° C. The reaction mixture was stirred at 0˜5° C. for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by prep TLC plate (60% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 60 mg of 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide and 111 mg of cesium carbonate in 0.5 mL of DMF were heated to 100° C. in a sealed microwave reactor for 20 min. The reaction mixture was evaporated, and the product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 448.0 (M)+.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[CH3:16][C:17]1[O:18][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:20][N:21]=1>>[CH3:16][C:17]1[O:18][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:23]2)=[N:20][N:21]=1
Reactant: Cc1nnc(C2CCCNC2)o1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Product: Cc1nnc(C2CCCN(C(=O)OC3C4CC5CC3CC(O)(C5)C4)C2)o1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 Step 1 using 1-hydroxy-4-adamantyl chloroformate solution and 2-methyl-5-(piperidin-3-yl)-1,3,4-oxadiazole. LC-MS Method 1 tR=1.35 min, m/z=362.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12](=O)[CH2:13][O:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:12]1[CH2:11][C:10]2[C:15](=[CH:16][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[O:14][CH2:13]1
Reactant: COc1ccc2c(c1)OCC(=O)C2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1COc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (459 mg, 5.49 mmol) was added to a solution of Example 3C (890 mg, 4.99 mmol) in pyridine (20 mL) and the mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure, taken up in ethyl acetate (100 mL) and 1N hydrochloric acid (100 mL). The separated organic layer was washed with brine, filtered, and dried over anhydrous sodium sulfate. Concentration and chromatography on silica gel eluting with 0-to-20% ethyl acetate in hexane afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.64 (s, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.49 (s, 2H), 6.47 (d, J=2.72 Hz, 1H), 6.57 (dd, J=8.48, 2.38 Hz, 1H), 7.10 (d, J=8.48 Hz, 1H). MS (DCI) m/z 208.05 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>N1CCCCC1.[Cu]I>[CH2:10]([N:9]([CH2:12][CH3:13])[CH2:8][CH2:7][O:6][C:5]1[CH:14]=[CH:15][C:2]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:3][CH:4]=1)[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CC)CCOc1ccc(Br)cc1
Agent: [Cu]I
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 70 °C

Procedure:
Under a nitrogen atmosphere a mixture of 5.44 g (20 mmol) [2-(4-bromo-phenoxy)-ethyl]-diethyl-amine, 3.11 mL (22 mmol) ethynyl-trimethyl-silane, 462 mg (0.4 mmol) tetrakis-triphenylphosphane-palladium, 76 mg (0.4 mmol) CuI in 50 mL piperidine is heated to 70° C. for 21 h. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[NH3:24]>CO>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:8]1[CH:9]=[C:5]([C:3]([NH2:24])=[O:2])[NH:6][N:7]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: N
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(N)=O)[nH]n1
Yield: 16 %

Procedure:
As described for example 6, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using ammonia in methanol instead of ethanolamine, to the title compound (15 mg, 16%), which was obtained as a white solid. MS: m/e=299.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.Cl[C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.O.[H-].[Na+]>CN(C=O)C>[CH3:30][C@@:28]1([CH2:31][N:13]2[CH2:12][CH:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[O:29][C:19]2=[N:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][N:20]2[CH2:27]1
Reactant: FC(F)(F)Oc1ccc(C2=CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CC=C(c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
4-(4-Trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridine (0.985 g, 4.05 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.839 g, 3.86 mmol) were added to DMF (15 ml), and the solution was stirred at 60° C. for 8 hours. The reaction mixture was added water and extracted with ethyl acetate. The organic phases was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford as oil. The oil was dissolved in DMF (20 ml), and sodium hydride (94 mg, 2.35 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-2-methyl-6-nitro-2-[4-(4-trifluoromethoxyphenyl)-1,2,3,6-tetrahydropyridin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (0.192 g, yield 23%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([S:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:33])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2ccncc2Cl)c1
Solvent: ClCCl
Product: O=S(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1ccncc1Cl
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a methylene chloride (10 ml) solution of the 3-chloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (75 mg, 0.20 mmol) obtained in Example 53 was added 3-chloroperbenzoic acid (33 mg, 0.20 mmol). Under ice cooling, the resulting mixture was stirred for 3 hours. After dilution with ether (80 ml), the diluted mixture was washed with water and brine and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (48 mg, 60%) as a diastereomer mixture (1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH3:21])[N:14]=3)=[CH:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].[Na]>N1C=CC=CC=1>[CH2:20]([NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:39]([C:33]4[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=4[F:31])(=[O:41])=[O:40])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)[CH3:21]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)n1
Agent: [Na]
Solvent: c1ccncc1
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
340 mg (0.85 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-ethylpyrimidin-2-amine were dissolved in 10 ml of dry pyridine and 114 μl (0.85 mmol) of 2,5-difluorobenzensulfonyl chloride were added. The resulting solution was stirred at room temperature overnight. The mixture was then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was finally dried over sodium sulphate and evaporated, giving 450 mg (91%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])O[C:6]2=[O:15].[NH2:16][CH2:17][C:18]([OH:20])=[O:19]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:15])[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:8]2=[O:14]
Reactant: NCC(=O)O
Reactant: COc1cc2c(cc1OC)C(=O)OC2=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)N(CC(=O)O)C2=O
Temperature: 180 °C
Yield: 53.5 %

Procedure:
A suspension of 5,6-dimethoxyisobenzofuran-1,3-dione (491 mg, 2.359 mmol) and 2-aminoacetic acid (195 mg, 2.59 mmol) in toluene (10 ml) was heated under MW irradiation at 180° C. for 7 hours. The precipitate was collected by filtration, washed with toluene (5 ml) and dried to afford 2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid as a off-white powder (335 mg, 1.263 mmol, 54% yield). MS/ESI+ 265.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCCCCC
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)N2CCCCC2)cc1
Yield: 48.6 %

Procedure:
4,4′,4″-trimethoxytrityl chloride (0.51 g, 1.38 mmol) (Aldrich) was dissolved in acetonitrile (8 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.70 g, 8.22 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour, and then the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):n-hexane (Wako Pure Chemical Industries, Ltd.)=1:4 as an eluent), to thereby obtain the title compound (0.28 g, 49% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[NH:18][C:17](=[S:19])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:15]1=[O:31].[C:39]([C:41]1[CH:50]=[CH:49][C:44]([C:45](=[O:48])[CH2:46]Br)=[CH:43][CH:42]=1)#[N:40]>C1COCC1>[OH:11][CH2:12][CH2:13][C:14]1([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[C:15](=[O:31])[N:16]([CH2:20][CH:21]2[CH2:26][CH:25]3[CH2:27][CH:23]([C:24]3([CH3:29])[CH3:28])[CH:22]2[CH3:30])[C:17]([S:19][CH2:46][C:45]([C:44]2[CH:49]=[CH:50][C:41]([C:39]#[N:40])=[CH:42][CH:43]=2)=[O:48])=[N:18]1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1C(CN2C(=O)C(CCO)(Cc3ccncc3)N=C2SCC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Potassium bis-(trimethylsilyl)amide (286 mg, 1.43 mMol) was dissolved in anhydrous THF (20 mL) under an atmosphere of dry N2. The mixture was cooled to -40° C. and then 5-(2-hydroxy-ethyl)-5-pyridin-4-ylmethyl-2-thioxo-3-((+)-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl))-imidazolidin-4-one (548 mg, 1.37 mMol) was added. The mixture was warmed to ambient temperature and 4-cyanophenacyl bromide (350 mg, 1.43 mMol) was added. The reaction mixture was stirred for one hour after which time it was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried over Na2SO4, filtered and concentrated under vacuum to give a red foam. The foam was chromatographed on flash silica gel eluting with EtOAc-hexanes (50:50) to give 700 mg of the titled compound as a yellow foam as a 1:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]=[C:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([NH:25][C:45]([CH:43]2[CH2:44][C:41](=[CH2:40])[CH2:42]2)=[O:46])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)O)C1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C1CC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)C1

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (690 mg, 1.99 mmol) was dissolved in 6.0 mL of CH2Cl2 followed by the addition of EDC (600 mg, 2.98 mmol) and HOBT (300 mg, 1.99 mmol). 3-Methylenecyclobutanecarboxylic acid (300 mg, 2.59 mmol) was dissolved in 1.0 mL of CH2Cl2 and added to the homogenous reaction mixture. After 24 h the reaction was concentrated in vacuo and dissolved in EtOAc and the organic layer was washed with sat. NaHCO3. The organic layer was washed with H2O and brine. The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc:Hex] to obtain the desired product as a white fluffy solid; 1H NMR (400 MHz, CDCl3): δ=2.82-2.92 (m, 2H), 2.99-3.06 (m, 2H), 4.77-4.80 (m, 2H), 6.81 (d, 1H, J=7.8 Hz), 7.45-7.54 (m, 3H), 7.83-7.88 (m, 3H), 8.10 (d, 2H, J=7.1 Hz), 8.22-8.23 (brm, 1H), 8.39 (d, 1H, J=1.79 Hz), 8.59 (d, 1H, J=2.5 Hz); MS (ES+): 440.93 (M+1), 442.91 (M+3).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.N1C=CC=CC=1.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1
Reactant: BrBr
Reactant: C1=Cn2cnnc2Cc2ccccc21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Brc1nnc2n1C=Cc1ccccc1C2

Procedure:
To 1.83 g of 11H-s-triazolo[3,4-b][3]benzazepine in 40 ml of chloroform was added 0.1 ml of pyridine and 0.55 ml of bromine was added dropwise under stirring. The mixture was stirred for 2 hours, after which it was washed with water and dried over Na2SO4. After evaporation of the solvent, the residue was treated with ether. By the above procedure was obtained 3-bromo-11H-s-triazolo[3,4-b][3]benzazepine as crystals. These crystals were recrystallized from ethanol and methanol in the order mentioned to obtain pale-brown platelets melting at 169°-170° C.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([OH:35])=O)[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([NH:2][CH3:1])=[O:35])[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
HATU (0.606 g, 1.594 mmol) was added to a solution of 6-methoxy-5-nitropicolinic acid (Preparation 190, 0.243 g, 1.226 mmol), DIPEA (0.320 mL, 1.840 mmol) and 2M methylamine solution in THF (1.2 mL, 2.453 mmol) in THF (3.3 mL). The reaction mixture was stirred at room temperature for 3 hours. Further methylamine (0.6 mL) was added and the mixture was stirred for 18 hours. The reaction was quenched with water and concentrated in vacuo. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed twice with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 99/1 to 90/10 to afford the title compound as a yellow solid (182 mg, 70%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([O:20]C)=O.[NH3:22]>>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH2:22])=[O:20]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: N
Product: NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Yield: 64 %

Procedure:
A solution of methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (1.007 g, 3.38 mmol) in ammonia (7 N in MeOH, 12 mL, 84 mmol) was heated under microwave heating conditions at 100° C. for 5 min. After that time the reaction was cooled to room temperature and concentrated to give a yellow solid. This was recrystallized from EtOAc to give 0.613 g (64%) of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide as colorless crystals.