Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[N+:24]([O-:26])=[O:25])[CH2:3][CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl cis-4-aminocyclohexanecarbamate (1.27 g, 5.93 mmol) and 4-fluoro-3-nitrotoluene (0.92 g, 5.93 mmol) in DMF (20 mL) was added potassium carbonate (1.64 g, 11.88 mmol). The mixture was heated at 85° C. and stirred overnight. The mixture was cooled to room temperature and the solid was filtered. The filtrate was evaporated to dryness. The residue was extracted with ethyl acetate and brine. The organic layer was dried over sodium sulfate and solvents were evaporated. The resulting material was purified through flash column chromatography using hexanes and ethyl acetate (4:1) to give an orange colored solid as cis-[4-(4-methyl-2-nitro-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.88 g). This material (1.80 g, 5.17 mmol) was suspended in a mixture of methanol (50 mL) and water (25 mL). To this suspension was added ammonium chloride (4.15 g, 77.6 mmol) and zinc dust (3.36 g, 51.6 mmol). The mixture was stirred at room temperature for 20 minutes and THF (20 mL) was added. The mixture was stirred an additional 1 hr during which the orange color disappeared. The mixture was filtered and rinsed with THF and ethyl acetate. The filtrate was extracted with brine and ethyl acetate. Solvents were evaporated to give cis-[4-(2-amino-4-methyl-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.65 g). LC-MS showed a single peak, C18H29N3O2 (m/e) calcd 319.2260, obsd 320.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@:7]2([CH3:27])[N:11]3[C:12]([C:15](O)=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl.[CH2:31]([O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([O:34][C:35]([C:37]1([NH:40][C:15]([C:12]2[N:11]3[C@@:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:29][CH:28]=4)([CH3:27])[C:8](=[O:26])[N:9]([C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[C:10]3=[N:14][CH:13]=2)=[O:16])[CH2:39][CH2:38]1)=[O:36])[CH:32]=[CH2:33]
Reactant: C=CCOC(=O)C1(N)CC1
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(Br)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a suspension of (R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (1.00 g, 2.02 mmol) and 1-amino-cyclopropanecarboxylic acid allyl ester hydrochloride (430 mg, 2.42 mmol) in 6 mL of DMF at room temperature was added diisopropylethylamine (1.05 mL, 6.06 mmol), and the reaction mixture (became mostly clear) was stirred for 10 min. HATU (845 mg, 2.22 mmol) was then added, and the clear yellow reaction mixture was stirred at room temperature for 21 h. The reaction mixture was partitioned between 150 mL of ethyl acetate and 50 mL of 1 M HCl. The organic phase was washed with satd. NaHCO3 solution, water (2×), and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (50 g, 10-30% EtOAc in hexanes), to furnish 1.16 g of 1-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (93%) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH2:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH2:33][CH2:34][C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCCc1cccs1
Product: O=C(NCCc1cccs1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(2-aminoethyl)thiophene as in General Procedure 10 to give the title compound. LCMS: m/z=556.91 (M+H+); retention time=0.92 minutes.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
21.6 g (79.5 mmol) 3-iodo-1H-indazole-5-carbaldehyde (Example 4A), dissolved in DMF (100 ml), and 31.1 g (95.4 mmol) cesium carbonate were slowly treated with 15.9 g (95.4 mmol) 2-(trimethylsilyl)ethoxymethyl chloride at 0° C. The mixture was warmed to room temperature, and stirring was continued for 12 h. The solids were then filtered off, and the filtrate was evaporated to dryness yielding the title compound (26.4 g, 82% of th.).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=2[S:5](=[O:9])(=[O:8])[C:6]=1[CH3:7].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:3]2[CH:2]=[C:6]([CH2:7][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[S:5](=[O:9])(=[O:8])[C:4]=2[CH:10]=1
Reactant: C1CCNCC1
Reactant: CC1=C(Cl)c2ccc(Cl)cc2S1(=O)=O
Solvent: O
Product: O=S1(=O)C(CN2CCCCC2)=Cc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3.75 g 3,6-dichloro-2-methyl-benzo[b]-thiophene-1,1-dioxide and 35 ml piperidine is stirred for 4 hours at 80° C., water is subsequently added and it is extracted with ethyl acetate. The extract is concentrated by evaporation and it is ground with ethyl acetate. 1.6 g of the title compound (36% of the theoretical yield) of melting point 154°-156° C. is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Cl[CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27]
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 0.65 g (2.25 mmol) of 2-chloro-4-(4-trifluoromethylphenoxy)-phenol in 20 ml of N,N-dimethylformamide, there are added 0.38 g (2.47 mmol) of ethyl 2-chloroethylcarbamate and 0.69 g (4.95 mmol) of potassium carbonate with stirring, and the resultant mixture is stirred at 50° C. for 8 hours. The reaction mixture is poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give ethyl 2-[2-chloro-4-(4-trifluoromethylphenoxy)phenoxy]ethylcarbamate.
Reaction SMILES: C([O-])C.[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[CH2:10]([O:12][C:13](=[O:28])[C:14]([C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])=[CH:15]N(C)C)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:8][C:6]([CH3:7])=[N:9][CH:15]=1)=[O:28])[CH3:11]
Reactant: CC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Br
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1-c1ccccc1Br
Yield: 84 %

Procedure:
To a fresh prepared solution of sodiumethanolate (prepared from 0.77 g (33.7 mmol) Na in 100 ml Ethanol) 3.18 g (33.7 mmol) acetamidinhydrochloride was added. After 10 Min. a solution of 10.0 g (30.6 mmol) 2-(2-bromo-benzoyl)-3-dimethylamino-acrylic acid ethyl ester in 120 ml ethanol was added and the reaction mixture heated for 16 hrs. at 80°. The solvent was evaporated, the residue distributed between 100 ml H2O and 100 ml CH2Cl2. The aqueous phase was extracted twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtrated and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) to give 8.3 g (84%) 4-(2-bromo-phenyl)-2-methyl-pyrimidine-5-carboxylic acid ethyl ester as a pale brown oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:41]=[CH:40][C:34](C(OCC)=O)=[CH:33][CH:32]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Mg]Br>O1CCCC1.C1(C)C=CC=CC=1.O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:32]=[CH:33][C:34]([C:9]([OH:8])([CH3:18])[CH3:10])=[CH:40][CH:41]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc([C@H]2OC3(CCCC3)c3c2c(C(C)C)nc2c3[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(C)(C)O)cc1)OC31CCCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -5 °C

Procedure:
110 mg Ethyl 4-((3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-3′-yl)benzoate are dissolved in 3 ml tetrahydrofurane, cooled to −5° C. and treated dropwise with 820 μl of a 1.4 M solution of methylmagnesium bromide in toluene/tetrahydrofurane (72:25). The mixture is warmed to room temperature during 1 hour, then recooled to 0° C. and the reaction is quenched by addition 1 ml methanol. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (petrole ether/ethylacetate 90:10 to 50:50).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[N:26]1([CH2:24][CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:21][CH:20]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: c1ccc(-c2cnn3cc(-c4ccc(CCCN5CCOCC5)cc4)cnc23)cc1

Procedure:
A solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5, 150 mg, 0.458 mmol, 1 equiv), morpholine (0.048 mL, 0.55 mmol, 1.2 equiv), acetic acid (0.026 mL, 0.55 mmol, 1.0 equiv), and sodium triacetoxyboro-hydride (116 mg, 0.547 mmol, 1.20 equiv) in dichloroethane (8 mL) was stirred in the presence of 4 angstrom molecular sieves for 15 minutes. The reaction mixture was partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (50% hexane in chloroform saturated with ammonia gas, grading to 100% chloroform saturated with ammonia gas) to give 6-[4-(3-morpholin-4-ylpropyl)phenyl]-3-phenylpyrazolo[1,5-a]pyrimidine (2-6) as a yellow solid (mp=147-149° C.). 1H NMR (400 MHz, CDCl3) δ8.82 (s, 2H), 8.45 (s, 1H), 8.06 (br d, 2H, J=7.8 Hz), 7.53 (d, 2H, J=8.2 Hz), 7.47 (t, 2H, J=7.8 Hz), 7.35 (d, 2H, J=8.2 Hz), 7.29 (t, 1H, J=7.8 Hz), 3.73 (m, 4H), 2.73 (t, 2H, J=7.5 Hz), 2.46 (m, 4H), 2.40 (t, 2H, J=7.2 Hz), 1.87 (pentet, 2H, J=7.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CC#N>[CH2:21]([N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10. mg, 0.054 mmol, from Step 5) in DMF (1.5 mL) was treated with K2CO3 (22 mg, 0.16 mmol) and a solution of benzyl bromide (6.4 μL, 0.054 mmol, Aldrich) in DMF (0.10 mL). After stirring for 2 hours, the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (12 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])=[C:11]([Br:24])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])=[C:11]([Br:24])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.24 g (2.70 mmol) of ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate were dissolved in 10 ml of THF and 10 ml of H2O, and 0.117 g of NaOH was added. After stirring at RT for 12 h the mixture was admixed with 6 N HCl and extracted with CH2Cl2. Drying of the organic phase over Na2SO4 gave 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoic acid as a viscous colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1(C)C=CC(S(O[CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=O)=O)=CC=1>ClCCl>[CH3:1][N:2]([CH3:3])[CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
190 ml (4.2 mmol) of dimethylamine dissolved in 2.5 ml of dichloromethane are added dropwise at 0° C. to a solution of 0.7 g (2.1 mmol) of 4-[3-(p-tolylsulphonyloxy)-prop-1-ynyl]-nitrobenzene in 10 ml of dichloromethane. The cooling is stopped and the mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is washed with water and freed from solvent. The residue is chromatographed on silica gel (dichloromethane/methanol=10:1). The product is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][NH2:19])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[CH2:22]([NH:26][C:27]([NH:19][CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:8]=[CH:9]2)=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN=C=O
Reactant: NCCOc1ccc2c(ccn2Cc2ccc(Cl)cc2)c1
Solvent: c1ccncc1
Product: CCCCNC(=O)NCCOc1ccc2c(ccn2Cc2ccc(Cl)cc2)c1
Reaction time: 0.25 h

Procedure:
To a mixture of 1-(4-chlorobenzyl)-5-(aminoethoxy)-indole (1.0 g) in pyridine (I ml), butyl isocyanate (0.5 ml) was added at ambient temperature. After stirring for 15 minutes, excess pyridine was evaporated in vacuo and the residue recrystallized from ethanol to yield the title product, m.p. 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (9.35 g, 34.1 mmol) in THF (170 mL) was added ethylmagnesium bromide (1M solution in THF) (136 mL, 136 mmol) dropwise at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for 4 hr. At this time, only 50% of the starting material was consumed. The reaction mixture was cooled again to 0° C. To push the reaction to completion, a 3M solution of ethylmagnesium bromide in diethyl ether (50 mL, 150 mmol) was added slowly to the cooled reaction mixture. The reaction was quenched with an aqueous solution of 1N HCl at 0° C. and was extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography (100% hexanes ramped to 6% ethyl acetate in hexanes) to give 1-(4-fluoro-2-phenylamino-phenyl)-propan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:20]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(O)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (30.1 g; manufactured by Wako Pure Chemical Industries, Ltd.) and imidazole (18.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated DMF (436 mL; manufactured by Kanto Chemical Co., Inc.), and the solution was cooled to 0° C. Subsequently, TBDMSCl (48.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto, and the mixture was stirred for one hour while the temperature was raised to room temperature. The solvent was evaporated under reduced pressure from the reaction solution, subsequently water was added thereto, and the mixture was extracted two times with ethyl acetate. The organic layer was washed two times with water and with brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by column chromatography (“COLUMN-A.”; n-hexane:ethyl acetate=100:0→94:6). Thus, the title compound (40.3 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21]>C1CCCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][C:8]([C:20]([F:21])([F:22])[F:23])=[C:7]([Cl:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: C1CCCCC1
Product: COCCNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting 2-methoxyethylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product melting at 106.5°-107.5° C.
Reaction SMILES: Cl[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[NH:11][C:10]3[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=3[N:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
8-Chlorotheophylline (3.5 g) and piperazine-1-carboxylic acid tert-butyl ester (11.69 g) were mixed, and stirred at 110° C. overnight. Then, the reaction mixture was diluted with ethyl acetate and water, insoluble white solid was collected by filtration, and washed with ethyl acetate to give 3.65 g of the title compound.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[CH3:17][O:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[CH:21][CH:20]=1.O>C(O)CCC>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:25]=2)[N:24]=1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Reactant: COc1ccc(N)nn1
Solvent: CCCCO
Solvent: O
Product: COc1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (600 mg, 2.2 mmol) and 6-methoxypyridazin-3-amine (550 mg, 4.4 mmol) in 1-butanol (20 mL) was heated at reflux overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a light brown solid (500 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.73 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J=1.5, 8.4 Hz, 1H), 6.64 (d, J=9.6 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[Cl:15])(=[O:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:16])[C:7]=1[Cl:15])(=[O:5])[CH3:4]
Reactant: CI
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)n(C)c2ccccc12
Reaction time: 72 h

Procedure:
To a slurry of 310 mg of NaH in 15 ml THF was added 1 g of (75), and then 625 μl of methyl iodide. The reaction was left with stirring for 3 days. Water was added, the product extracted with diethylether, and the ether phase dried and evaporated to dryness to give (76). Yield 870 mg.