Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)#[N:18]>C1C(O)=CC=CC=1C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:3]([NH:2][C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[NH:18])[CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c(N)c1
Reactant: N#CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(-c2ccccc2)c(NC(=N)N2CCOCC2)c1

Procedure:
A mixture of 2-amino-4-methoxybiphenyl hydrochloride (4.4 g) and 4-cyanomorpholine (3.14 g) in m-cresol (25 ml) was heated at 90°-95° C. for 20 hours to yield N-(4-methoxy-2-biphenylyl)morpholine-4-carboxamidine (m.p. 140°-142° C.) which was recrystallised from ethylacetate. N-(4-Methoxy-2-biphenylyl)morpholine-4-carboxamidine (1.2 g) was dissolved in methanol (10 ml) and treated with fumaric acid (1.45 g) to give N-(4-methoxy-2-biphenylyl)morpholine-4-carboxamidine fumarate [m.p. 120° (dec)] which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: C(OC(=O)C[C@@H](N1C=CC(C2C=CC=CC=2)=C1)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([NH:69][C:70](OC(C)(C)C)=O)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])=[O:48])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC(C)(C)[C@H](NC(=O)[C@H](N1C=[CH:93][C:92]([C:95]2[CH:100]=[CH:99][C:98]([C:101]3[CH:106]=[CH:105][N:104]=[CH:103][CH:102]=3)=[CH:97][CH:96]=2)=[CH:91]1)CC(O)=O)CO.CO.C(Cl)Cl>ClCCCl>[CH2:36]([O:43][C:44](=[O:77])[CH2:45][C@@H:46]([N:69]1[CH:70]=[CH:91][C:92]([C:95]2[CH:100]=[CH:99][C:98]([C:101]3[CH:106]=[CH:105][N:104]=[CH:103][CH:102]=3)=[CH:97][CH:96]=2)=[CH:93]1)[C:47]([NH:49][C@@H:50]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:51][O:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])=[O:48])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C[C@H](C(=O)N[C@H](COC(=O)OCc1ccccc1)c1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Yield: 56 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, N-(2-benzyloxycarbonyloxy-1(S)-phenyl-ethyl)-3(R)-(t-butoxycarbonylarnino)succinamic acid benzyl ester and 2,5-dimethoxy-3-(4-pyridin-4-yl-phenyl)-tetrahydrofuran (prepared as described in Example 5(a)) were condensed in wet 1,2-dichloroethane at 80-90° C. after 18 hours. Flash column chromatagraphy with 4% MeOH/CH2Cl2 as eluant gave 140 mg (56%) of N-(2-benzyloxycarbonyloxy-1(S)-phenylethyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid, mp 138-40° C. 1H NMR (CDCl3): δ 8.66 (bs, 2H), 7.60 (s, 5H), 7.50 (d, 3H, J=5.3 Hz), 7.34-7.22 (m, 10H), 7.19 (d, 1H, J=2.2 Hz), 7.17 (d, 1H, J=1.9 Hz), 7.09 (t, 1H, J=1.9 Hz), 6.77 (dd, 1H, J=2.5, 2.8 Hz), 6.57 (bt, 1H, J=1.9, 2.5 Hz), 6.24 (d, 1H, J=7.8 Hz), 5.26 (m, 1H), 4.25 (dd, 1H, J=7.2, 11.5 Hz), 3.44 (dd, 1H, J=7.2, 16.8 Hz), 3.00 (dd, 1H, 8.7, 16.8 Hz). IR (KBr): 2985, 1738, 1657, 1598, 1560, 1495, 1202, 815, 697 cm−1. HRFABMS: Calculated for C42H37N3O6Cs (M+Cs+): 812.1737. Found: 812.1712. Anal. Calculated for C42H37N3O6•0.25 CHCl3: C, 71.51; H, 5.29. Found: C, 71.72; H, 5.60.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[OH:28][C@H]1CC[C@@]2(C)[C@]3(O[C@H]3C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]5[O:28][C@@:18]65[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]6)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45CCCC[C@]35C)[C@@H]1CC13OCCOC12OCCO3
Yield: 45 %

Procedure:
17,17-Bis(ethylendioxy)-5α,6α-epoxyandrostane was prepared in 45% yield from 3,3:17,17-bis(ethylendioxy)-5-androstene by the procedure described above for the preparation of 3β-hydroxy-5α,6α-epoxyandrostan-17-one (Prepn. 4). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 80/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.92-3.75 (m, 8H), 2.68 (m, 1H), 2.56 (d, 1H), 1.99-1.06 (m, 18H), 1.09 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17](Br)[CH:16]=1)#[N:2].[CH3:31][N:32](C)C=O>Cl.O>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[O:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]([C:31]#[N:32])[CH:16]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC)cc2C#N)cc1Br
Agent: Cl
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CCCC)cc2C#N)cc1C#N
Temperature: 25 °C

Procedure:
9.9 g (0.021 mol) of the (2'-cyano-4'-n-butylphenyl)-3-bromo-4-n-heptyloxybenzoate prepared in Step VI and 4 g of cuprous cyanide were added to 80 ml of N,N-dimethylformamide. The suspension was gently refluxed for four hours. The reaction mixture was cooled to room temperature, poured into a solution of 14.5 g ferric chloride hexahydrate dissolved in a mixed solution of 3.6 ml of concentrated hydrochloric acid and 22 ml of water, and was stirred with heating at 65° C. for 30 minutes in order to decompose any complexes. An organic layer was extracted from the suspension with toluene, was cleaned and was dehydrated. The toluene was distilled off. The residue was recrystallized in ethanol to yield 3.4 g of purified (2'-cyano-4'-n-butylphenyl)-3-cyano-4-n-heptyloxybenzoate. The yield was calculated to be 39.1%.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2c(Cl)cccc2CN1CCCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 3-phenyl-propylamine (0.081 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.120 g, 84%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.68 (t, 2H), 3.66 (t, 2H), 4.28 (s, 2H), 7.14-7.44 (m, 8H). GC-MS: m/z 285 (M)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>CN(C)C=O.C(N(CC)C(C)C)(C)C>[O:29]=[C:28]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:21][N:20]=1)[CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:31]
Reactant: Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Reactant: COC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 5-[(4-phenylphenyl)methoxymethyl]pyridin-2-amine (0.189 g) in N,N-dimethylformamide (6.0 mL), N,N-diisopropylethylamine (0.453 mL), 4-methoxy-4-oxobutanoic acid (0.174 g), and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.376 g) were added at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Yamazen Corporation, elution solvent: dichloromethane/ethyl acetate) to obtain the title compound (0.171 g).
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10]Cl)=[N:5][C:4]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[N:21]=1.O>CN(C=O)C>[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10][N:30]2[CH:29]=[CH:28][N:27]=[C:26]2[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=2)=[N:5][C:4]=1[CH3:12]
Reactant: CCn1c(CCl)nc(C)c1Br
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(Cn2ccnc2-c2cccc(F)n2)nc(C)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 74 mg (0.27 mmol) of 5-bromo-2-chloromethyl-1-ethyl-4-methyl-1H-imidazole hydrochloride in 1.5 ml of DMF is added 224 mg (1.62 mmol) of K2CO3 and 45 mg (0.27 mmol) of 2-fluoro-6-(1H-imidazol-2-yl)-pyridine. The mixture is stirred at room temperature for 24 hours. 5 ml water is added and the mixture was extracted with EtOAc (3×15 ml). The combined extracts are washed with 15 ml brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue is purified by preparative TLC, developing with 10:0.4:0.05 CH2Cl2—MeOH—NH4OH solution. The purified compound is then dissolved in 3 ml of EtOAc and to it is added 2 ml of 2N HCl in ether. The resulting suspension is stirred at room temperature for 15 minutes. Evaporation of the solvent provided the title compound as a white powder. LC-MS (M+1) 364.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[CH:6]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10](B(O)O)[CH:9]=1.C([O-])([O-])=O.[Na+].[Na+].N#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C(O)CC>[Cl:7][C:5]1[CH:6]=[C:2]([C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[S:3][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: Clc1csc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: ClCCl
Solvent: CCCO
Product: Clc1csc(-c2cccnc2)c1
Temperature: 85 °C
Yield: 51.5 %

Procedure:
A solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén Chemica Scripta, 1971, 1, 33) (1.45 g, 7.34 mmol), pyridine-3-boronic acid (0.95 g, 7.71 mmol), 2 M Na2CO3 (5.50 mL, 11.01 mmol) and, n-PrOH (3 mL), is degassed with N2 for 10 minutes. Pd(OAc)2 (0.033 g, 0.15 mmol) and PPh3 (0.12 g, 0.44 mmol) are added and the solution is heated at 85° C. for 48 hours, diluted with CH2Cl2 (50 mL), washed with 10% Na2CO3 (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (0.74 g, 3.78 mmol, 51%). 1H NMR (CDCl3), δ 7.12-7.13 (m, 1H), 7.20 (d, J=1.4 Hz, 1H), 7.31 (dd, J=8.0, 4.9 Hz, 1H), 7.78-7.82 (m, 1H), 8.55 (d, J=4.9 Hz, 1H), 8.82 (d, J=2.2 Hz, 1H).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][O:48][CH3:49].[I-].[K+]>CN(C)C=O.O>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([O:36][CH2:46][CH2:47][O:48][CH3:49])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (39 mg) and potassium carbonate (47 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, 1-bromo-2-methoxyethane (38 mg) and potassium iodide (1.1 mg). The reaction mixture is stirred at 80° C. for 3 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(2-methoxyethoxy)-phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (17 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].Cl>O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: II
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 23 h
Yield: 78.9 %

Procedure:
To a solution of 2-bromo-3-hydroxypyridine (10 g, 57.5 mmol) and potassium carbonate (15.9 g, 114.9 mmol) in water (130 mL) was added iodine (15 g, 59.2 mmol) and the reaction mixture stirred at room temperature for 23 hours. A small amount of solid sodium metabisulfite was added to the reaction mixture. The reaction mixture was then cooled to 0° C. and acidified to pH 6 by the addition of 1 M aqueous hydrochloric acid. The resulting suspension was stirred at 0° C. for 1 hour then filtered to give 2-bromo-6-iodopyridin-3-ol (13.6 g, 79% yield) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][N:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][N:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (3.18 g, 12.12 mmol) and diisopropylazodicarbocylate (2.39 μL, 12.12 mmol) in 10 mL of THF was stirred at 0° C. for 30 min and combined with a solution of 2-(2-methyl-pyridin-4-yl)-ethanol and phthalimide (1.33 g, 9.7 mmol) in 10 mL of THF. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions. The organic layer was dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica using a dichloromethane/methanol gradient (2-10%) gave 2.5 g of the title product. MS(ES): m/e (EI*) 267.1 [M+H]
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 73 (303 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to get 271 mg (68%) of white solids. M.P. 228° C. 1H NMR (DMSO-d6): δ 3.56 (s, 3H), 3.64 (m, 4H), 3.94 (m, 4H), 6.65 (m, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 7.79 (dd, J=1.9, 9.0 Hz, 1H), 7.86 (m, 2H). EIMS m/z 419 (M+23). Anal. (C20H17ClN4O3) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12].O>ClCCl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: O=Cc1ccnnc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of pyridazine-4-carboxaldehyde (3.646 mmol, 1 eq) in dry dichloromethane (25 ml), (methoxycarbonylmethylene)triphenylphosphorane (5.550 mmol, 1.2 eq) was added portionwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured into water (200 ml) and extraction with DCM (3×100 ml) followed. Organic layers were combined, dried over phase separator cartridge to giving crude product which was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of MeOH in DCM: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 3-pyridazine-4-yl-acrylic acid methyl ester (4.142 mmol, yield=89%, purity=96%). [M+H]+=165.11 1H NMR (300 MHz, CDCl3) δ/ppm 3.82 (s, 3H), 6.64-6.68 (m, 1H), 6.72 (s, 1H), 9.22 (dd, J=5.3, 1.0 Hz, 1H), 9.27 (s, 2H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC.O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: OB(O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: COCCOC
Solvent: O
Product: Brc1ccccc1-c1ccc2ccccc2c1
Temperature: 85 °C
Yield: 79.6 %

Procedure:
To a 250-mL round bottom flask equipped with a magnetic stir bar was added water (25 mL) and 1,2-dimethoxyethane (25 mL). The solution was sparged with nitrogen for 20 minutes, and then potassium carbonate (6.67 g, 48.3 mmol, 3 equiv), 2-bromophenylboronic acid (3.80 g, 18.9 mmol, 0.98 equiv) and 2-bromonaphthalene (4.00 g, 19.3 mmol, 1 equiv) were added. The flask was purged with N2 for 10 minutes before finally adding palladium(II)acetate (87 mg, 0.39 mmol, 0.02 equiv) and triphenylphosphine (405 mg, 1.55 mmol, 0.08 equiv). The reaction mixture was heated to 85° C. under a positive pressure of nitrogen for 7 hours. After cooling to room temperature, the phases were partitioned and the organic layer was collected. The aqueous layer was washed with ethyl acetate (3×30 mL), and the combined organic fractions were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude orange oil was purified by column chromatography on an Isco CombiFlash system (120-g column; gradient: 0.5 column volumes heptane, ramp up to 99:1 heptane:dichloromethane over 0.5 column volumes, hold at 99:1 for 1 column volumes, ramp up to 92:8 heptane:dichloromethane over 7 column volumes, hold at 92:8 for 6 column volumes) to afford the title compound as a colorless oil (4.26 g, 97 area % by HPLC, 78% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.93-7.85 (m, 4H), 7.72 (dd, J=8.0, 1.0 Hz, 1H), 7.57 (dd, J=8.5, 1.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.46-7.38 (m, 2H), 7.28-7.21 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[N:16][OH:17])[CH3:15])=[CH:4]1)[CH3:2].[Li][CH2:19]CCC.CN(C=O)C.O>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:15]=[CH:19][O:17][N:16]=2)=[CH:4]1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCn1cc(C(C)=NO)c2ccc(OC)cc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccon2)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) was dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) was added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of was then added dropwise. This was stirred at 0° C. for 1 h, then at room temperature for 1 h. The reaction mixture was pipetted into a mixture containing 1 mL of H2O, 1 mL of THF, and 100 μL of concentrated H2 SO4. This mixture was heated at 75° C. for 1 h and then was partitioned between H2O and EtOAc. The organic phase was dried and concentrated. Purification by column chromatography (CH2Cl2) yielded 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).
Reaction SMILES: [Na].F[C:3]1[C:8]([F:9])=[C:7](F)[C:6]([F:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15][O-:16].[Na+:17].[CH3:18][OH:19]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:15][O-:16].[Na+:17].[F:9][C:8]1[C:3]([O:19][CH3:18])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]([F:11])[C:7]=1[O:16][CH3:15]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Reactant: CO
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: COc1c(F)cc([N+](=O)[O-])c(OC)c1F

Procedure:
Sodium methoxide (1.0M) is prepared by adding freshly cut sodium metal (rinsed with toluene) portionwise to anhydrous methanol (Aldrich Chemical Co.) under nitrogen in flame-dried glassware with stirring; an ice-water bath is used to control the reaction temperature. To 9.8 g (50 mmol) of 2,3,4,5-tetrafluoronitrobenzene (Aldrich) under nitrogen at room temperature in flame-dried glassware is added sodium methoxide solution (2.2 equivalents) via syringe over the course of 5-10 minutes, with stirring. The resulting reaction mixture is stirred at room temperature, while monitoring the progress of the reaction by thin layer chromatography (TLC). Additional sodium methoxide solution is added as necessary. Once the reaction reaches completion (1-24 hours), several drops of 1M citric acid are added, and the reaction mixture is partitioned between ether and water. The aqueous layer is extracted once with ether. The combined organic portions are washed once with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 1 as 10.92 g (99%) of a pale yellow solid: m.p. 32.0°-32.5° C.; 1H NMR (CDCl3) 7.52 (dd, 1H), 4.12 (s, 3H), 4.04 (s, 3H); 19F NMR (CDCl3) 132.0 (m, 1F), 141.9 (d, 1F). Anal. calc. for C8H7NO4F2 : C, 43.85; H, 3.22; N, 6.39. Found: C, 43.84; H, 3.15; N, 6.15.