Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[C:39]4[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[C:25]([F:42])[CH:24]=2)=[O:21])[C:16](=[O:43])[N:15]1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O.CCO.NN.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:3][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[C:39]4[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[C:25]([F:42])[CH:24]=2)=[O:21])[C:16](=[O:43])[N:15]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN5C(=O)c6ccccc6C5=O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 50 °C
Yield: 82.1 %

Procedure:
To a solution of 1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.30 mmol) in 1:1 H2O/EtOH was added hydrazine (0.049 g, 1.5 mmol). The reaction was heated to 50° C. for 8 hours and then cooled to RT. The reaction mixture was then diluted with 20 mL of satd. NaHCO3 aq. solution and 60 mL of EtOAc. The organic phase was separated and washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 20% hexane in EtOAc to give the title compound as a light yellow solid (0.13 g, 81% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[N:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cn1nnc(-c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cn1nnc(-c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of ethyl [5-(4-(3-(2-quinolinylmethyl-oxy)phenoxymethyl)phenyl)tetrazol-3-yl]acetate in 5 ml ethanol and 40 ml of 1N NaOH is stirred at 70° C. for 4 hours. This is cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazol-3-yl acetic acid.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:53]=[CH:54]/[CH2:55][C:56]([NH:58][C:59]([CH2:63][OH:64])([CH3:62])[CH2:60][OH:61])=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:65])=[CH:42][C:41]=1[O:66]CC1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd].[OH-].[Pd+2].[OH-]>[OH:66][C:41]1[CH:42]=[C:43]([CH3:65])[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][CH2:55][C:56]([NH:58][C:59]([CH2:60][OH:61])([CH3:62])[CH2:63][OH:64])=[O:57])=[CH:49][CH:48]=2)=[CH:45][C:40]=1[C@@H:10]1[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)NC(C)(CO)CO)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCC(=O)NC(C)(CO)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a methanol solution (1 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[(1E)-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-4-oxobut-1-en-1-yl]benzyl]-4-methylphenyl]-D-glucitol (91 mg, 0.0926 mmol) was added 10% palladium-activated carbon (16 mg), and the mixture was stirred overnight under a hydrogen atmosphere at room temperature. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved in methanol (1 mL). And 20% palladium hydroxide (91 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature for 2 days. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=5:1) to obtain the title compound (32 mg, 65%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C@H:28]5[CH2:29][CH2:30][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:33]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl trans-4-formylcyclohexanecarboxylate (JP 490-48639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:14]([O-])=O)[C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:5]1[C:6]([CH3:13])=[C:7]([CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(OC)cc(N)c1C
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a stirred solution of methyl 5-methoxy-2-methyl-3-nitrobenzoate (1.7 g, 7.6 mmol) in ethanol (20 mL) was added ammonium chloride (1.7 g, 32 mmol) dissolved in water (20 mL) and iron powder (3.38 g, 60.44 mmol). The mixture was heated at 80° C. for 3 h, filtered and the residue washed well with hot ethanol. The filtrate was concentrated and the residue was basified with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water, dried, and concentrated under reduced pressure to give the crude title compound (1.2 g) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([NH:16][CH2:17][C:18]#[CH:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)C(C)C)(C)C>ClCCl.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]#[C:18][CH2:17][NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of 1-chloro-4-iodobenzene (6.40 g, 26.8 mmol) and N-boc propargylamine (5.00 g, 32.2 mmol) in dichloromethane (117 mL) was added copper (I) iodide (0.204 g, 1.07 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.754 g, 1.07 mmol). The solution was degassed with argon for 10 minutes, then N,N-diisopropylethylamine (14.3 mL, 81.9 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated, then the residue was diluted with EA and water. The layers were separated and the aqueous layer was extracted twice more with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified using column chromatography on silica gel (80 g Analogix column, gradient hexanes to 20% EA in hexanes over 20 minutes) to give the product (5.97 g, 84%). LCMS: (AA) ES+ 210, 212 (Boc group fragmentation). 1H NMR (400 MHz, d6-DMSO) δ: 7.47-7.39 (m, 4H), 7.35 (s, 1H), 3.97 (d, J=5.6 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1B(O)O>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1ccncc1B(O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: COc1ccncc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 28 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 4-methoxypyridin-3-ylboronic acid were reacted to give 266 (0.045 g, 28%). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J=2.1, 1H), 8.50 (d, J=6.0, 2H), 7.92 (s, 1H), 7.46 (dd, J=8.3, 2.2, 1H), 7.15 (d, J=8.4, 1H), 6.93 (d, J=5.7, 1H), 5.84 (dt, J=13.3, 6.6, 1H), 4.46 (t, J=5.0, 2H), 3.91 (s, 3H), 3.45 (t, J=5.0, 2H), 1.59 (d, J=6.7, 6H). MS (ESI(+)): m/z 420.1 (M+H)
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-])=O.[N+:12]([CH2:15][CH3:16])([O-])=O.C([O-])(=O)C.[NH4+].CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[NH2:12][CH:15]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:4][CH:5]=1)[CH3:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(N)Cc1ccccc1
Yield: 24.6 %

Procedure:
A mixture of 7.56 g (50 mmol) of 3-nitrobenzaldehyde, 11.25 g (150 mmol) of nitroethane and 4.24 g (55 mmol) of ammonium acetate was heated in 2 mL of acetic acid in a 110° C. oil bath for 2 1/2 hours. Subsequent examination of the mixture by preparative thin layer chromatography with hexane/ethyl acetate showed almost no starting material remaining. Volatile materials were removed with a rotary evaporator, and the residue was partitioned between dichloromethane and water, with washing of the organic layer twice with 10% sodium bicarbonate. Caution was necessary because gas evolution occurred during the first bicarbonate wash. Drying was performed with magnesium sulfate. Filtration and removal of solvent left 9.13 g of crude product. Half of this was chromatographed on a 3×35 cm flash silica column, packed with hexane and eluted with 7:1 hexane/ethyl acetate to give 1.66 g (32%) of pure title compound.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19].[OH:23][CH:24]([CH:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1)[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:18]([O:20][CH:21]([O:23][CH:24]([CH:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1)[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:22])[CH3:19]
Reactant: O=C1CCC(C(O)COc2ccccc2)CC1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(COc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridinium tosylate (15 mg, 0.06 mmol) and ethyl vinyl ether (339 mg, 450 μl, 4.70 mmol) were added to a solution of 4-(1-hydroxy-2-phenoxyethyl)cyclohexanone (919 mg, 3.92 mmol) in anhydrous methylene chloride (20 ml) and the mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was then added to the mixture and the mixture was washed with water, 5% strength sodium bicarbonate solution and saturated sodium chloride solution (50 ml of each). The organic phase was dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 56.5 %

Procedure:
A mixture of 1-benzhydrylpiperazin (4.13 g), 1-bromo-3-chloropropane (5.18 g) and anhydrous potassium carbonate (2.26 g) in anhydrous acetone (82 ml) was refluxed for 10 hours under stirring. The insoluble materials were filtered off and the filtrate was evaporated to dryness. The residue was subjected to column chromatography on alumina (50 g) using benzene as an eluent. The fractions containing the object compound were collected and evaporated to give oil of 1-benzhydryl-4-(3-chloropropyl)piperazine (3.04 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:18][O:19][C@H:20]1[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([N:28]2[C:37]3[C:38]4[NH:46][C:45]5[C:44]([Cl:47])=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]=4[C:48]4[C:53](=[O:54])[NH:52][C:50](=[O:51])[C:49]=4[C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]2=3)[O:22][C@@H:21]1[CH2:55][OH:56]>O1CCCC1>[Cl:47][C:44]1[C:45]2[NH:46][C:38]3[C:37]4[N:28]([C@@H:23]5[O:22][C@H:21]([CH2:55][OH:56])[C@@H:20]([O:19][CH3:18])[C@H:25]([OH:26])[C@H:24]5[O:27][S:7]([C:10]5[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=5)(=[O:9])=[O:8])[C:29]5[C:30](=[CH:31][CH:32]=[CH:33][C:34]=5[Cl:35])[C:36]=4[C:49]4[C:50](=[O:51])[NH:52][C:53](=[O:54])[C:48]=4[C:39]=3[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: CO[C@H]1[C@H](O)[C@@H](O)[C@H](n2c3c(Cl)cccc3c3c4c(c5c6cccc(Cl)c6[nH]c5c32)C(=O)NC4=O)O[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@H]1[C@H](O)[C@@H](OS(=O)(=O)c2ccc(C)cc2)[C@H](n2c3c(Cl)cccc3c3c4c(c5c6cccc(Cl)c6[nH]c5c32)C(=O)NC4=O)O[C@@H]1CO

Procedure:
1 equivalent of potassium carbonate and 1 equivalent of tosyl chloride are added to a solution of 1.7 mmol of rebeccamycin in 200 ml of tetrahydrofuran. After 48 hours' reflux and concentration under reduced pressure, chromatography of the residue over silica gel (cyclohexane/ethyl acetate 70/30) enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Br
Yield: 64.3 %

Procedure:
A mixture of 3-bromopyridine N-oxide (26.09 g; 150 mmol), trimethylsilyl cyanide (50 g; 504 mmol), and triethylamine (30.36 g, 300 mmol) in dry acetonitrile under nitrogen was refluxed for 20 hours. The mixture was concentrated in vacuo, the residue partitioned between methylene chloride (600 ml) 3 N sodium carbonate solution (250 ml), and the aqueous layer was extracted with 200 ml of methylene chloride. The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography (25% ethyl acetate in hexane) to afford 17.65 g (64.5%) of 3-bromo-2-cyano-pyridine as a solid, m.p. 93°-95° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)=[O:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:8][C:7]2[CH:9]=[CH:10][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CS(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Product: CS(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
A mixture of 3.0 g (19 mmol) of 4-methylsulfinylaniline (obtained in reference example 3), 2 mL (19 mmol) of 4-fluorobenzaldehyde and 80 mL of benzene was refluxed in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:31]([C:27]5[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=5)=[O:32])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cn1ccnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) in N,N-dimethylformamide (4.0 mL) were added 1-methyl-1H-imidazole-2-carboxylic acid (154 mg, 1.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (351 mg, 1.83 mmol) and 1-hydroxybenzotriazole (248 mg, 1.83 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to give the title compound (31 mg, 12%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: Clc1ccc(Cl)nc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccc(C#Cc2ccccc2)nc1
Yield: 36 %

Procedure:
A mixture of 2,5 dichloropyridine (3.7 g, 25 mmol), phenylacetylene (3.02 ml, 1.1 eq), bis triphenylphosphine palladium dichloride (II) (Aldrich, 500 mg), copper (I) iodide (250 mg) and triethylamine (50 ml) was heated to reflux under N2 for 18 h. The cooled reaction mixture was diluted with water, extracted with diethyl ether, dried and concentrated to a black oil which was partially purified by SPE Si chromatography with gradient elution cyclohexane:ethyl acetate (100:0 to 10:1) gave the title compound as a brown solid (1.94 g, 36%). MH+ 213; 1H NMR (CDCl3) δ 7.37 (3H, m); 7.48 (1H, d, J 8 Hz); 7.59 (2H, m); 7.67 (1H, dd, J 8 & 2 Hz); 8.57 (1H, d, J 2 Hz); TLC SiO2 Cyclohexane: ethyl acetate (15:1) Rf 0.36.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].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>[CH2:21]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(OCc2ccccc2)ccc(C=O)c1[N+](=O)[O-]
Reaction time: 16 h
Yield: 97.4 %

Procedure:
4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (Step 2, 155 g, 786 mmol) was dissolved in DMF (1500 mL) and the stirred solution was treated with potassium carbonate (217 g, 1.57 mol) followed by benzyl bromide (161 g, 0.94 mol). After stirring for 16 h the reaction mixture was concentrated under reduced pressure and separated between water (2 L) and EtOAc (2 L). The organic layer was washed with brine (3×2 L), dried (sodium sulfate) and concentrated under reduced pressure. The resulting solids were triturated with Et2O (1 L) to give the title compound (220 g, 97%): 1H NMR (DMSO-d6) δ: 9.77 (1H, s), 7.87 (1H, d), 7.58 (1H, d), 7.51 (1H, m), 7.49 (1H, m), 7.39 (3H, m), 5.36 (2H, s), 3.05 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19](SC)[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:43]([NH2:45])[CH3:44].C1COCC1>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:45][CH2:43][CH3:44])[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Reactant: CCN
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
(S)-5-(4-Cyanobenzyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.927 g, 2.54 mmol) obtained in Step 2 was dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding 3-chloroperbenzoic acid (65%; 1.01 g, 3.81 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was dissolved in THF (20 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ethylamine/THF solution (12.7 mL, 25.4 mmol). The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and crystallized from ethanol/diethyl ether to give the title compound (Compound 1) (0.620 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[N+:11]([O-])=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Product: COc1cc(Br)c(N)cc1F

Procedure:
Combine 1-bromo-4-fluoro-5-methoxy-2-nitrobenzene (20.5 g, 82 mmol)and Pt-on-carbon (sulfided) in THF (600 mL) and hydrogenate at 60 psi (414 kPa) over for 4 hours. Filter the reaction through celite to remove the catalyst and remove the solvent to give 2-bromo-5-fluoro-4-methoxyaniline as a brown solid which may taken on without further purification.