Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Yield: 94.9 %

Procedure:
A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanol-ethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydrogen for 8 hr. The mixture is filtered through diatomaceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.
Reaction SMILES: C1C2C(CO[C:16]([N:18]([CH2:34][C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:19][CH2:20][NH:21][C@@H:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC1C=CC([N+]([O-])=O)=CC=1>CN(C)C=O.ClCCCl>[CH3:31][C:30]([CH3:32])([CH3:33])[C@H:22]([N:21]1[CH2:20][CH2:19][N:18]([CH2:34][C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[C:16]1=[O:17])[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: Cn1c(CN(CCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)C(=O)OCC2c3ccccc3-c3ccccc32)nc2ccccc21
Agent: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCNCC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1c(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.7 %

Procedure:
A solution of the product of Example 59D (0.19 g) in N,N-dimethylformamide (3.5 mL) was treated with diethylamine (0.35 mL), stirred at 25° C. for 1.5 hours and concentrated. A solution of the residue in 1,2-dichloroethane (7 mL) was treated with bis-(p-nitrophenyl) carbonate (0.128 g, 1.2 eq.), stirred at 60° C. for 16 hours and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate:dichloromethane (3:2) to give 80 mg (64% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4](Cl)[CH:3]=1.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.O>CN(C)C=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH3:16])[CH:3]=1
Reactant: Cc1ncc[nH]1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cc(N)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 30 h
Yield: 61.9 %

Procedure:
To a solution of 20.0 g (~83 mmol) 4-amino-2-chloro-5-nitrobenzotrifluoride in 50 ml dry N,N-dimethylformamide was added 30 g (~370 mmol) 2-methylimidazole, and stirring was continued at 180° C. for 30 h. The reaction mixture was poured into 400 ml water to give the title compound (14.7 g; 62%). M.p. 222°-225° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(Cl)cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(Cl)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-chlorobenzoic acid
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2].[OH-:20].[K+]>O.C(O)C.CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([C:3]1[C:12]2[O:11][CH:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:20])=[O:2]
Reactant: O=Cc1cccc2c(=O)c(-c3ccccc3)coc12
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c(=O)c(-c3ccccc3)coc12

Procedure:
A solution of 38.22 g of silver nitrate in 75 ml of water was added dropwise, under stirring, at 20°-25° C., to a solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran (prepared as described by G. Atassi et al., Eur. J. Med. Chem. - Chim. Ter. 20, 393 (1985)) in 150 ml of 85% ethanol and 450 ml of N,N-dimethylformamide. Then, a solution of 32.67 g of 85% potassium hydroxide in 195 ml of water was added dropwise under stirring at 15°-20° C. After additional stirring at room temperature, the reaction mixture was filtered by suction; the mother liquor was acidified with 37% hydrochloric acid and diluted with 1.2 l of water. Filtration by suction and washing with water to neutrality gave the title compound as a crude. The crude was suspended in 150 ml of ethyl acetate and stirred with 444 ml of 0.3M aqueous sodium hydrogen carbonate solution until clear layers were obtained. The aqueous layer was washed with 75 ml of ethyl acetate, then made acidic with 37% hydrochloric acid, filtered and dried at 60°-65° C. to give 19, 12 g of the title compound that melted at (215) 218° C. A sample, crystallized from ethanol, showed the same melting point, m.p. (215) 218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.[H][H]>[Pd].[Ni].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Cn2c(OC3CCNCC3)nc3cncnc32)cc1
Yield: 82.2 %

Procedure:
A mixture of 16.25 parts of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with b 3 parts of palladium-on-charcoal catalyst 10% and 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in trichloromethane and water was added. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The precipitated product was filtered off and dried, yielding 10.5 parts (82.2%) of 9-[(4-fluorophenyl)methyl]-8-(4-piperidinyloxy)-9H-purine; mp. 79.3° C. (compound 56).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].C(N1C(C)=NC=N1)(C)C.C([Li])CCC.[Br:24][C:25]1[C:26]([CH3:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32](I)=[CH:33]3)[C:29]=2[CH:39]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:24][C:25]1[C:26]([CH3:40])=[CH:27][C:28]2[O:37][CH2:36][CH2:35][N:34]3[C:30](=[N:31][C:32]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:9])[N:7]=4)=[CH:33]3)[C:29]=2[CH:39]=1
Reactant: Cc1cc2c(cc1Br)-c1nc(I)cn1CCO2
Reactant: Cc1ncn(C(C)C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncnn1C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(C)cc2OCC3)n(C(C)C)n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.292 g, 1.4 mmol) in THF (5 mL) was cooled to −30° C. and treated with n-butyllithium (2.5M in hexanes, 0.56 mL, 1.40 mmol). Stirring was continued for 1 h maintaining the internal temperature between −30° C. and −20° C. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 1.66 mL, 0.83 mmol) was added over 2 min. The reaction mixture was then slowly warmed to RT over 1 h. A solution of 9-bromo-2-iodo-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (404 mg, 1.0 mmol) in THF (5 mL) was added followed by Pd(PPh3)4 (58 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and water. The aqueous phase was further extracted with EtOAc (300 mL) and the combined organic layers were washed with water followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 1-10% MeOH in EtOAc) affording the title compound (0.168 g, 35%). LCMS: RT 3.71 min [M+H]+ 402.0/404.0. 110178153
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[C:3]=1[I:11].[NH2:12][OH:13]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[C:4]([F:10])[C:3]=1[I:11]
Reactant: O=Cc1ccc(Cl)c(I)c1F
Reactant: NO
Solvent: CCO
Product: ON=Cc1ccc(Cl)c(I)c1F
Reaction time: 12 h

Procedure:
A solution of 4-chloro-2-fluoro-3-iodobenzaldehyde (4.60 g, 16 mmol) in ethanol (25 mL) at RT was treated with hydroxylamine (4.5 mL, 162 mmol) and the reaction was to stir for 12 h. The volatiles were removed and the residue was treated with water (25 mL), and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to provide an off white solid 4-chloro-2-fluoro-3-iodobenzaldehyde oxime. MS (ESI, pos.ion) m/z: 299.9 (M+1)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccccn2)CC1

Procedure:
A stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.15 g, 0.61 mmol, Example 30B) and 2-fluoropyridine (0.3 mL, 3.5 mmol) was heated to 175° C. under microwave conditions for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 20% to 35% ethyl acetate in hexane) to provide (4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 326 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.06 (dd 1H), 7.52 (m, 1H), 7.37-7.26 (m, 5H), 6.80 (d, 1H), 6.62 (t, 1H), 5.04 (s, 2H), 4.84 (s, 1H), 3.78 (m, 2H), 3.25-3.16 (m, 2H), 2.08 (m, 2H), 1.64-1.55 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1

Procedure:
1.8 g (3.7 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred into 100 l of ethanol saturated with hydrogen chloride for 16 hours first at 0° C. and then at room temperature until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off, the oily residue was taken up in 50 ml of absolute ethanol and mixed with 3.6 g (37 mMol) of ammonium carbonate. After 4 hours the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; gradient:dichloromethane/ethanol 19:1 to 4:1) and evaporated down again. Yield: 1.6 g of beige solid (80% of theory), Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia=90:5:5)
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:14]=[CH:13][C:12]2[NH:11][C:10]3[N:15]=[CH:16][C:17]([Br:19])=[CH:18][C:9]=3[C:8]=2[CH:7]=1)=O>CO>[NH3:11].[Br:19][C:17]1[CH:16]=[N:15][C:10]2[NH:11][C:12]3[CH:13]=[N:14][C:6]([C:4]([NH2:1])=[O:3])=[CH:7][C:8]=3[C:9]=2[CH:18]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: N
Solvent: CO
Product: NC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 140 °C
Yield: 85 %

Procedure:
In a steel bomb, a saturated solution of ammonia in methanol was prepared by passing gaseous ammonia through methanol (250 mL) then 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (14.0 g, 38.3 mol) was added. The vessel was sealed, then the reaction mixture was heated at 140° C. (15 bar) for 18 h. After this time, the reaction vessel was allowed to cool to ambient temperature then the reaction mixture was transferred to a round-bottomed flask and the solvent was removed in vacuo to afford a solid residue. The resultant solid residue was collected by filtration, washed with methanol (50 mL) and then dried to yield the desired product as a grey solid (9.47 g, 85%). 1H NMR (DMSO-D6, 400 MHz): 11.53 (s, 1H), 9.14 (d, J=2.3 Hz, 1H), 8.96 (d, J=1.1 Hz, 1H), 8.91 (d, J=1.1 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.07 (s, 1H), 7.52 (s, 1H). LCMS (Method B): RT=2.49 min, M+H+=291/293.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[C:33]([C:37]1[CH:70]=[CH:69][C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:58]=[C:57]4[C:53]([CH2:54][N:55]([C:60]5([C:65]([O:67]C)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61]5)[C:56]4=[O:59])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:37]1[CH:70]=[CH:69][C:40]([C:41]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]3[CH:58]=[C:57]4[C:53]([CH2:54][N:55]([C:60]5([C:65]([OH:67])=[O:66])[CH2:61][CH2:62][CH2:63][CH2:64]5)[C:56]4=[O:59])=[CH:52][CH:51]=3)=[CH:48][CH:49]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(C)(C)C)cc5)cc4)cc3C2=O)CCCC1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)O)CCCC3)C4)cc2)cc1
Yield: 62 %

Procedure:
The compound of example 531 was prepared analogous to compound of example 98 by hydrolysis of compound of example 530.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH:39]=[O:40])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:38][C:36]1[CH:35]=[CH:34][C:33]([CH:39]=[O:40])=[C:32]([C:31]#[C:30][C:27]2[CH:26]=[CH:25][C:24]([S:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)(=[O:23])=[O:22])=[CH:29][CH:28]=2)[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C#Cc3cc(F)ccc3C=O)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccc(F)cc1C#Cc1ccc(S(=O)(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
Trifluoroacetic acid (1.18 mL, 15.87 mmol) was added to a stirred solution of 4-[4-(5-fluoro-2-formyl-phenylethynyl)-benzenesulfonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.500 g, 1.06 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure. The viscous liquid was washed with ether (3×5 mL) to obtain 0.310 g (60.2%) of 4-fluoro-2-[4-(piperazine-1-sulfonyl)-phenylethynyl]-benzaldehyde as a yellow solid. MS cald. for C19H17FN2O3S [(M+H)+] 373, obsd. 373.3.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8](=[O:34])[N:9]=[C:10]([S:32][CH3:33])[C:11](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([F:31])[CH:24]=1)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([OH:20])[C:13]=1[F:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>O>[CH3:6][O:7][C:8](=[O:34])[N:9]=[C:10]([S:32][CH3:33])[C:11](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([F:31])[CH:24]=1)[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH2:42][CH2:43][O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[C:13]=1[F:21]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1cc(OC)cc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2 ml of a DMF solution containing 200 mg of [2-(4-cyano-3-fluorophenylimino)-2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester, 300 mg of potassium carbonate and 0.2 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran were added. The resulting mixture was stirred at room temperature for 18 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and then with 5 saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give (2-(4-cyano-3-fluorophenylimino)-2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1-methylsulfanylethylidene)carbamic acid methyl ester (150 mg) as a yellow oil.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]=[O:19].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1([CH3:17])[C:12]([CH:18]=[O:19])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccccc1
Reactant: C=O
Agent: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1ccccc1C=O

Procedure:
To a mixture of 13.8 parts of salicylic acid, 18.4 parts of toluene, 6.9 parts of 87% paraformaldehyde and 30 parts of acetic acid was added 1.0 part of sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted toluene and water were removed by vacuum distillation to give 31 parts of salicylic acid-toluene-formaldehyde co-condensation product. 10 parts of the co-condensation product was added to 41 parts of aqueous 10% sodium hydroxide solution and dissolved at 80° C. The resulting solution was cooled to 40° C., and 7.0 parts of zinc chloride was added thereto. After the reaction had been allowed to proceed at 40° C. for 1 hour, precipitates formed were collected by filtration, washed with water and then dried to give 12 parts of zinc salt of salicylic acid-toluene-formaldehyde co-condensation product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:23][N:22]=1>CC(O)(C)C>[CH3:2][O:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:23][N:22]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Product: COc1ccc(CNc2nnc(-c3ccccc3)c3ccccc23)c(OC)c1
Temperature: 25 °C

Procedure:
In a nitrogen purged 75 mL sealed tube, dissolved 2,4-dimethoxybenzylamine hydrochloride (2.54 g, 12.5 mmol), cesium carbonate (4.06 g, 12.5 mmol) in tBuOH (15 mL). Added 1-chloro-4-phenylphthalazine (2.0 g, 8.31 mmol)and the tube was stirred at 100° C. for 17 h. The tube was cooled to RT, and the mixture was concentrated in vacuo. Dissolved the crude material in DCM, and filtered the solution to remove cesium carbonate. Performed silica gel chromatography using 0-100% EtOAc/Hex and concentrated to yield N-(2,4-dimethoxybenzyl)-4-phenylphthalazin-1-amine as orange oil. MS [M+H]=372; Calc'd 371.4 for C23H21N3O2.
Reaction SMILES: C([C:5]1[CH:17]=[C:16](CCl)[C:15]2[C:14]3[C:9](=[CH:10][C:11](C(C)(C)C)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=CC(C=O)=CC=1)([O-])=O>>[CH:10]1[C:9]2[CH2:8][C:7]3[C:15](=[CH:16][CH:17]=[CH:5][CH:6]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)cc(CCl)c1-2
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
2,7-Di-t-butyl-4-chloromethylfluorene was reacted with triphenyl phosphine. The reaction product was condensed with 4-nitrobenzaldehyde to obtain a fluorene compound having the following structural formula. ##STR12##
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1([CH3:16])[O:15][C:13](=O)[C:10](=CO)[C:8](=[O:9])[O:7]1>C1(C)C=CC=CC=1>[CH3:5][C:6]1([CH3:16])[O:7][C:8](=[O:9])[CH:10]=[CH:13][O:15]1
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)OC=CC(=O)O1
Yield: 82.8 %

Procedure:
Acetone (2.9 g) was added to sufficiently dehydrated toluene (500 ml) and the mixture was heated under reflux in a reaction flask equipped with a reflux condenser. While the reflux was continued, a warm solution obtained by dissolving formyl Meldrum's acid (8.6 g) in toluene (500 ml) on heating was dropwise added over about 2 hours, followed by subjecting the reaction mixture to heating under reflux for additional one hour and then subjecting the resulting reaction mixture to purifying operation in the same manner as in Example 1 to obtain 2,2-dimethyl-1,3-dioxin-4-one (5.3 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=O)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1.O1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[S:40])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(Cl)nc2)c2ncccc2c1=S
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-chloropyridin-3-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (490 mg, 1.42 mmol) was suspended in toluene (5 mL) and dioxane (5 mL) and placed into a preheated oil bath at 110° C. The mixture was treated with Lawesson's Reagent (316 mg, 0.782 mmol, 0.55 equiv) portionwise over 45 minutes and stirred for an addition 30 minutes at 110° C. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 50:50; hexanes:ethyl acetate), providing the titled compound as a brown foam.