Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].C[O-].[Na+]>CO>[C:1]([C@@H:5]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](Cc2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](Cc2ccccc2)C[C@@H]2CC[C@H]1N2C

Procedure:
To a solution of (1R,2S,3S)-2-carbomethoxy-3-benzyltropane (5.6 g, 20.5 mmol) in absolute methanol (100 ml) was added a solution of sodium methanolate in methanol (2M, 2 ml) and the mixture was refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the remanescens was dissolved in diethyl ether and was washed with water. The organic phase was dried and concentrated in vacuo. The crude product was purified by column chromatography using a mixture of diethyl ether and pentane (1+1)+1% triethyl amine as eluent yielding (1R,2R,3S)-2-carbomethoxy-3-benzyltropane as an oil. By dissolution of this product in diethyl ether and subsequent addition of a solution of hydrochloric acid in diethyl ether the title compound precipitates as white crystals, m.p. 188°-190° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:10]=[CH:11][C:3]=12.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:4]2=[N:5][C:6]([NH2:8])=[N:7][C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[C:3]2[CH:11]=[N:10]1
Reactant: Nc1nc(Cl)c2cnn(Cc3ccccc3F)c2n1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2cccs2)c2cnn(Cc3ccccc3F)c2n1
Yield: 19.7 %

Procedure:
A stirred solution of 4-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (139 mg, 0.5 mmol) in dry THF (10 mL) was treated with 2-thiopheneboronic acid (128 mg, 1.0 mmol), Pd(PPh3)4 (50 mg, 10 mol %) and saturated aqueous NaHCO3 solution (2 mL), refluxed for 30 min, diluted with H2O, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by chromatography [SiO2; heptane:EtOAc (1:1) then (1:3)] to give the title compound (32 mg, 20%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CSc1ccc(Br)cc1)OC
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of 4-bromobenzenethiol (7.56 g; 40 mmol) in anhydrous acetone (50 mL) was added potassium carbonate (5.52 g, 40 mmol) and dropwise at room temperature 2-bromo-1,1-dimethoxy-ethane (4.7 mL, 40 mmol). After 24 h of stirring, the precipitate was filtered, the filtrate concentrated, the residue diluted with water and diethyl ether (150 mL), the organic layer washed successively with water (60 mL), NaOH 4N (30 mL) and water (60 mL), dried over Na2SO4 and concentrated to give 1-bromo4-(2,2-dimethoxy-ethylsulfanyl)-benzene (compound PRE12) (9.71 g; orange oil) (Yield=87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@H:8]2[C@@H:10]([C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)[O:9]2)=[O:5])[CH3:2].O1CCCC1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][C@@H:8]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:10]([OH:9])[C@H:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:12]=1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H]2O[C@H]2C1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](NCc2ccccc2)C1
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 5.08 g (20 mmol) (1S,5R,6S)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester in 20 ml tetrahydrofuran 1.03 g (4 mmol) magnesium bromide diethyl etherate was added at room temperature. The resulting suspension was treated with 4.40 ml (40 mmol) of benzylamine and heated to reflux under argon with stirring for 12 hours. The reaction mixture was evaporated in a rotary evaporator, the residue treated with 20 ml of ethyl acetate and extracted 6 times with 20 ml of 5N aqueous ammonium chloride solution. The organic phase was dried over 5 g of sodium sulfate, filtered and evaporated to yield 6.88 g of (3R,4S,5R)-5-benzylamino-3-(1-ethyl-propoxy)-4-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.00 g) in THF (120 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether, 42 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was heated from −78° C. to −40° C. over 1.5 hours while stirring, and then quenched with a saturated ammonium chloride solution at −40° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g). A solution of 4 N hydrochloric acid in ethyl acetate (90 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g) in ethyl acetate (90 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Sodium cyanoborohydride (3.29 g) and then acetic acid (4.27 mL) were added to a solution of the residue in methanol (150 mL) at 0° C., and the reaction solution was stirred at 0° C. for one hour and at room temperature for one hour. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with a heptane-diisopropyl ether system to obtain 2.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:52][O:53][C:54]1[CH:55]=[C:56]([CH:61]=[CH:62][CH:63]=1)[C:57](=[O:60])[CH2:58]Br.O>O1CCCC1>[CH3:52][O:53][C:54]1[CH:55]=[C:56]([C:57](=[O:60])[CH2:58][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[C:22]([C:45]6[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=6)=[N:23][N:24]([C:26]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])[CH:61]=[CH:62][CH:63]=1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)c1
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
50 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 5 mL tetrahydrofuran, then 0.07 mL of 1.0 M lithium bistrimethyl silyl amide was added thereto under ice-cooling, and the mixture was stirred for 0.5 hour. Under ice-cooling, a solution of 80 mg 3-methoxyphenacyl bromide in 2 mL tetrahydrofuran was added thereto and stirred for 1.5 hour. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 17 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([F:27])[C:7]([N+:24]([O-])=O)=[C:8]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:9]=2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:24][C:7]1[C:6]([F:27])=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:8]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C3CC3)cc(F)c2N)CC1
Yield: 100.2 %

Procedure:
1,1-Dimethylethyl 4-[(5-cyclopropyl-3-fluoro-2-nitrophenyl)amino]-1-piperidinecarboxylate (D26, 0.8 mmol, 300 mg) was dissolved in MeOH (15 ml) and it was reduced by THALIS H-CUBE apparatus (bought from Asynt) using a palladium cartridge. The process yielded 280 mgs of the title compound, complete conversion, M+-COOC(CH3)3=250.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:1])=[O:17]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a mixture of tert-butyl 2-(methylamino)ethylcarbamate (0.348 g, 2 mmol), 2-hydroxybenzoyl chloride (0.276 g, 2 mmol) and imidazole (0.136 g, 2 mmol) in ethyl acetate (8 mL) at 0° C. was slowly added a solution of DCC (0.412 g, 2 mmol) in ethyl acetate (2 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EtOAc/PE (20-50%) to afford tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 34%) as a colorless oil. 1HNMR (CDCl3): δ 7.5 (m, 2H, CH), 7.0 (d, 1H, CH), 6.8 (d, 1H, CH), 3.7 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.2 (m, 3H, CH3), 1.5 (s, 9H, CH3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]([CH2:23][CH2:24][CH2:25][N:26]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:27]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][N:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: ClC(c1ccccn1)c1ccccn1
Reactant: c1ccc(CNCCCNCc2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CN(CCCN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Yield: 64.9 %

Procedure:
A mixture of 1.7 g dipyridyl-methylchloride (14), 1 g N,N′-bis(pyrid-2-ylmethyl)-1,3-diamino-propane (15) and 0.5 g potassium carbonate in 20 ml acetonitrile was stirred and refluxed under argon for 48 h. TLC (silica/eluent CH2Cl2/MeOH(7N NH3) 90/10) indicated the reaction to be almost complete. The mixture was filtered and evaporated. The residue was chromatographed on silica using dichloromethane with increasing methanol concentration (up to 5%) to give 1.5 g pure product as a yellow/brown glassy gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C(O)C=2)=CC=1)C(OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:30])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2cccc(O)c2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(O)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from methyl 3-bromo-6-(3-hydroxyphenylthiomethyl)-2-methoxybenzoate (Intermediate 142).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[C:6]([F:9])=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Yield: 105 %

Procedure:
A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol, commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml), 4-fluorophenol (13.9 g, 124 mmol), and Cs2CO3 (56 g, 172 mmol) was stirred under N2 at 60-70° C. for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which was used in the next step without further purification. 1H NMR (DMSO-d6): δ7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:31])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:31])[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1C
Product: O=C(NC1CCCCC1)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 140 °C
Yield: 82 %

Procedure:
Cyclohexylamine (1.18 mL, 10.35 mmol) was added to a stirred solution of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (3) (1.68 g, 5.17 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase washed by water and brine, then dried over Na2SO4 and evaporated to yield 1.6 g (82%) of 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (7) as white solids. MP: 143° C.; 1H-NMR (DMSO-d6): δ 1.22-1.87 (m, 10H), 3.87 (m, 1H), 5.62 (s, 2H), 7.20-7.32 (m, 5H), 7.43 (dd, J=4.6, 8.0 Hz, 1H), 8.48 (dd, J=1.5, 7.5 Hz, 1H), 8.77 (dd, J=1.5, 7.5 Hz, 1H), 10.20 (s, 1H); EIMS: 378 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([CH:19]([F:21])[F:20])=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[CH3:22][O:23][P:24]([O:27]C)[O:25][CH3:26]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:3]([CH:19]([F:21])[F:20])[CH2:2][P:24](=[O:27])([O:25][CH3:26])[O:23][CH3:22])=[CH:6][CH:7]=1
Reactant: COP(OC)OC
Reactant: Fc1ccc(C(=C(CBr)C(F)F)c2ccc(F)cc2)cc1
Product: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)F)OC
Yield: 73.6 %

Procedure:
A solution of 2-bromomethyl-3,3-difluoro-1,1-bis(4-fluorophenyl)propene (0.5 g, 1.4 mmol) and trimethylphosphite (0.5 g, 4 mmol) was heated at relfux for 20 minutes. Excess trimethyl phosphite was removed in vacuo and the residue purified by chromatography on silica eluting with 40% ethyl acetate to give 0.4 g of the title compound as a viscous oil. MS(EI): m/e =388 for M+ of C18H17F4O3P.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A3) Rt 7.22 [M+H]+ 338.08. 1H NMR (Me-d3-OD) δ 2.64-2.74 (4H, m), 3.22-3.25 (4H, m), 7.33-7.45 (6H, m), 7.65 (2H, d), 8.37 (2H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li]CCCC.[C:14]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)(=[O:16])[CH3:15]>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)([OH:16])[CH3:15])=[N:3][CH:4]=1
Reactant: CC(=O)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (1.3 g, 7.50 mmol) in anhydrous THF (30 mL) was added n-BuLi (2.76 mL, 6.62 mmol) at −78° C. dropwise, and the mixture was stirred at −78° C. for 2 h, followed by the addition of benzyl 4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (1.5 g, 4.41 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. LCMS showed the reaction was completed. The solution was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to afford the title compound (0.4 g, 20%) as a white solid. MS (ES+) C23H24FN5O3 requires: 437. found: 438 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCOCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(N2CCN(CCOCCO)CC2)cc1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
A mixture of 54.3 grams (0.61 mol) of N-[2'-(2"-hydroxyethoxy)ethyl]piperazine, 50 grams (0.40 mol) of 4-fluorobenzaldehyde, 50 grams of anhydrous potassium carbonate, and 50 mL of DMSO was heated to 120° C. for four days under nitrogen. After cooling to room temperature, the solution was diluted with one liter of water. The aqueous solution was "processed" as follows. It was extracted with dichloromethane; the separated organic layers were combined and dried over anhydrous magnesium sulfate or sodium sulfate. The organic layer was separated, and solvent was removed on a rotary evaporator under reduced pressure (hereafter these steps will be referred to as "processed" and the product was dried under vacuum overnight to afford 75.3 grams (96%) of 4-[4'-(2"-(2'"-hydroxyethoxy)ethyl)piperazino]benzaldehyde (F).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)O>P(=O)(O)(O)O>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:14][C:16]=1[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Product: Oc1ccccc1N(c1ccccc1)c1ccccc1

Procedure:
Diphenylamine and 5 times the molar amount of resorcin were reacted at 200° C. for 20 hours in the presence of a phosphoric acid catalyst to obtain a hydroxytriphenylamine derivative. In the product was dissolved double the molar amount of phthalic anhydride by heating at 150° C. for 4 hours in the presence of a zinc chloride catalyst. After completion of the reaction, the reaction mixture was worked up in the same manner as in Synthesis Example 1 to obtain 3'-diphenylamino-6'-(N-p-isopropylphenylanilino)spiro[isobenzofuran-1(3H),9'-(9H)-xanthen]-3-one and 3-diphenylamino-7,12-dihydro-12,12-dimethyl-7-phenyl-spiro[14H-[1]benzopyrano[3,2-b]acridine-14,1'[13'H]-isobenzofuran]-3'-one.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N+:9]([O-])=[C:8]([CH3:13])[CH:7]=2)[CH2:3][CH2:2]1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:13][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:11]=[CH:10][N:9]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCC2CC2)cc[n+]1[O-]
Product: CC(=O)OCc1cc(OCC2CC2)ccn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-cyclopropylmethoxy-2-methylpyridine-N-oxide (3.8 g 0.021 mol) was dissolved in acetic anhydride (10 ml) and was added dropwise to acetic anhydride (20 ml) (warmed to 90° C.). After the addition the temperature was raised to 110° C. and the mixture was stirred at 110° C. for 1 h and then the solvent was distilled off and the crude product was used without purification. NMR data is given below.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2ccc(Cl)cc2)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (12.2 mg) with purity >90%. LCMS (pos) m/z 331.2.