Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.I[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[CH2:27]([O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([C:37]#[C:38][Si](C)(C)C)[CH:34]=[N:33][CH:32]=1)[CH3:28]>O1CCCC1.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:27]([O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([C:37]#[C:38][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:34]=[N:33][CH:32]=1)[CH3:28]
Reactant: Fc1cccc(I)c1
Reactant: CCOC(=O)c1cncc(C#C[Si](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc(C#Cc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Add a 1 M solution of tetrabutylammonium fluoride (0.88 g, 3.38 mmol) in tetrahydrofuran to a mixture of 3-iodofluorobenzene (0.50 g, 2.25 mmol), 5-trimethylsilanylethynyl-nicotinic acid ethyl ester, (prepared as described in PREPARATION 16), (0.84 g, 3.38 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.03 g, 0.05 mmol) and copper (I) iodide (0.02 g, 0.09 mmol) at −78° C. Warm to room temperature, stir overnight and then dilute with ethyl acetate. Wash with an aqueous saturated solution of ammonium chloride, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 2.5:45:52.5 ethyl acetate:chloroform:hexanes, to give the title compound as a pale yellow solid (0.46 mg, 80%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:31]
Reactant: CCOC(C)=O
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCCC2)n1
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCCC2)n1

Procedure:
To a solution of 0.563 g (0.0017 mol) 5-bromo-3-cyclopentylmethoxy-2-pyrrolidin-1-yl-pyrazine in 4 mL methanol and 2 mL ethyl acetate was added 0.050 g PdCl2dppfCH2Cl2 and 0.48 mL (0.0035 mol) triethylamine and the mixture was stirred under an atmosphere of 70 bar carbon monoxide at 110° C. for 18 h in an autoclave. The solids were removed by filtration and the mother liquor was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with water (2×) dried over sodium sulfate, evaporated and the residue was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1 to yield 0.423 g of the title compound as slightly yellow orange crystals melting at 69-70° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:18])[CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([OH:28])=[O:27]>>[CH3:6][C:7]1([CH3:19])[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[C:14]([N+:26]([O-:28])=[O:27])[CH:15]=2)[NH:10][C:9](=[O:18])[CH2:8]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c1NC(=O)CC2(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc2c1NC(=O)CC2(C)C

Procedure:
A mixture of concentrated nitric acid (10 cm3, S.G.=1.42) and 98% w/w sulphuric acid (25 cm3) was added dropwise to a stirred solution of 3,4-dihydro-4,4,8-trimethyl-2-(1H)-quinolone (6 g) in 98% w/w sulphuric acid (25 cm3) cooled to -10°. The temperature was maintained at -10° for a further 30 minutes, the mixture poured onto ice (200 g), basified to pH 9 with saturated sodium carbonate solution and extracted with methanol:chloroform, 1:20 by volume (2×300 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give the title compound (6.46 g) which was characterised spectroscopically and used directly in Preparation 24 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[C:23]([OH:27])(=[O:26])[CH:24]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:24][C:23]([OH:27])=[O:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CC(=O)O
Product: CC1=C(CCON=CC(=O)O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[O:26]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:21][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]([CH3:20])([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCNCc2ccco2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
4.0 g of 1,1-dimethylethyl 2-[[4-(2-aminoethyl)phenyl]thio]-2-methyl-propanoate [(P. J. Brown et al., J. Med. Chem. 42, 3785-88 (1999)] are dissolved in 100 ml of methanol and treated with 2.6 g of furfural. 9.3 ml of glacial acetic acid are added and the mixture is boiled briefly (10 min). The mixture is then cooled to 0° C., and 4.25 g of sodium cyanoborohydride are added a little at a time. The mixture is then stirred at room temperature overnight. 1 N HCl is added until the mixture is acidic, and the mixture is stirred for 30 min. The mixture is concentrated slightly and made basic using sat. NaHCO3 solution. The mixture is then extracted twice with ethyl acetate and the extracts are washed (sat. NaCl solution) and dried and concentrated. Chromatographic purification (dichloromethane/methanol 15+1) gives 2.4 g of the title compound as a colourless oil.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]2[O:10][Si:11]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:12][Si:13]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:14][CH2:15][C@H:8]2[O:7][C@H:6]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[Cl:37])(=O)C>N.CO>[Cl:37][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[C:34]=1[N:35]=[CH:36][N:28]2[C@@H:6]1[O:7][C@H:8]2[C@@H:9]([O:10][Si:11]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[O:12][Si:13]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:17])[CH3:18])[O:14][CH2:15]2)[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Agent: N
Solvent: CO
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Yield: 94.2 %

Procedure:
(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-yl acetate (3.51 g, 6.14 mmol) (Kittaka, A.; Yamada, N.; Tanaka, H.; Nakamura, K. T.; Miyasaka, T. Nucleosides Nucleotides, 1996, 15, 1447-1457) was stirred in 7N NH3 in MeOH (2.33 mL) for 2.5 h. The mixture was then concentrated and the residue was purified by flash chromatography (20 to 50% EtOAc/hexanes) to give title compound as a light yellow foam (3.06 g, 92%).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCCCN(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(CCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCOC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
Ethyl 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoate (113 mg) is dissolved in a mixed solvent of ethanol (2 ml) and tetrahydrofuran (1 ml), and thereto is added 1M-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. The reaction solution is made weakly acidic with a 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→49:1) to give 6-{[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-hexanoic acid (111 mg). MS (m/z): 711 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C([O-])(O)=O.[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:3]2([O:2][CH3:1])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: COC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC1(c2ccc(F)cc2)CCC(=O)CC1
Yield: 94 %

Procedure:
A solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol methyl ether in acetone (200 ml) was stirred for 96 hr with p-toluenesulfonic acid (0.1 g) and the solution diluted with saturated NaHCO3 solution. The mixture was concentrated in vacuo and the residue suspended in water. The mixture was extracted with ether and the ether extracts dried and concentrated in vacuo. The residue was crystallized from hexane to give 4-(4-fluoro-phenyl)-4-methoxycyclohexanone (94%, mp: 57°-59° C.).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[CH3:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:33]=1B(O)O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:21]([O:20][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([C:33]4[CH:32]=[CH:31][N:30]=[CH:29][C:28]=4[O:27][CH3:26])=[CH:3][N:4]=3)[N:7]=2)[CH2:12][CH2:13]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cnccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3ncc(Br)n3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COc1cnccc1-c1cnc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)nn12
Temperature: 85 °C

Procedure:
To a mixture of tert-butyl 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-1,4-diazepane-1-carboxylate (329.9 mg, 0.8 mmol), (3-methoxy pyridin-4-yl)boronic acid monohydrate [1072952-50-1] (153.6 mg, 1.0 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (384.1 mg, 1.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (69.2 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 6 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to afford a brown solid which was purified by preparative RP-HPLC to provide 4-[3-(3-methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as 79.5 mg of off white powder, mp. 115-116° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.01 (s, 4H) 1.20 (s, 4H) 1.91 (s, 2H) 2.51 (dt, J=3.60, 1.86 Hz, 2H) 3.27-3.35 (m, 4H) 3.57 (br. s., 1H) 3.64 (s, 1H) 3.70 (br. s., 2H) 3.81 (d, J=16.67 Hz, 2H) 4.02 (s, 3H) 7.19 (d, J=9.85 Hz, 1H) 7.93 (s, 1H) 8.11 (d, J=8.59 Hz, 1H) 8.32 (d, J=5.05 Hz, 1H) 8.49-8.54 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 13.89, 22.03, 24.66, 24.75, 27.49, 27.74, 31.20, 44.27, 44.96, 45.60, 47.99, 48.26, 48.39, 56.31, 78.25, 78.41, 109.66, 109.87, 119.88, 120.03, 120.27, 124.50, 126.00, 126.08, 134.46, 135.39, 135.52, 136.92, 141.96, 150.98, 152.56, 152.65, 154.01, 154.34. LRMS (ESI) m/z 425.2 [(M+H)]+, calc'd for C22H28N6O3: 424.51.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][CH:11]=1.O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:16](=[O:17])[C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
4-Aminobenzonitrile (1.10 g) was dissolved in chloroform (30 ml). After having been cooled to 0° C., the reaction solution was added with 4-dimethylaminopyridine (1.70 g) and p-toluic acid chloride (1.95 g). The reaction solution was warmed back to room temperature and stirred overnight. The reaction solution was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then purified by recrystallization (hexane/ethanol), thereby obtaining the subject compound (1.26 g) as a white solid.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42]([OH:44])=O)=[CH:35][CH:34]=1.N.CO>CN(C=O)C.ClCCl.O>[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42]([NH2:2])=[O:44])=[CH:37][CH:38]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
HATU (0.23 g, 0.60 mmol) and (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.20 g, 0.46 mmol) in DMF (15 mL) were stirred at RT for 10 min, then a solution of ammonia in MeOH (3 mL, 21 mmol) was added. The solution was stirred at RT for 16 h, then water (50 mL) and dichloromethane (50 mL) were added and the organic layer was separated, washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from 50% ethyl acetate/hexanes to 100% ethyl acetate to give the title compound as a white powder (0.095 g, 48%). 1H NMR (400 MHz, DMSO) δ 8.01 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 7.46 (s, 1H), 6.82 (d, J=8.2 Hz, 2H), 6.78 (s, 1H), 6.51 (d, J=8.3 Hz, 2H), 6.20 (t, J=5.8 Hz, 1H), 4.38 (d, J=5.6 Hz, 2H), 2.42 (s, 3H), 2.04-1.99 (m, 1H), 1.63-1.59 (m, 1H), 1.18-1.14 (m, 1H), 1.01-0.97 (m, 1H). ES-MS m/z 433.2 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:21][S:22][CH3:23])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[C:9]([C:15]([O:17]CC)=[O:16])[O:10]2.[OH-].[Na+].Cl>CC(C)=O>[OH:1][CH:2]([CH2:21][S:22][CH3:23])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[O:10]2
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)CSC)cccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CSCC(O)COc1cccc2oc(C(=O)O)cc(=O)c12
Temperature: 50 °C
Yield: 89.8 %

Procedure:
To a solution of 3.4 g of ethyl 5-(2-hydroxy-3-methylthiopropoxy)chromone-2-carboxylate in 20 ml of acetone there is added 11 ml of N sodium hydroxide and the mixture is heated at 50° C. for 10 minutes. After evaporating the solvent under reduced pressure, 30 ml of water are added, the resulting mixture is extracted with diethyl ether, filtered on charcoal and the limpid solution thus obtained is acidified with hydrochloric acid. The product which precipitates is filtered, washed with water and dried. Thus, 2.8 g of 5-(2-hydroxy-3-methylthiopropoxy)chromone-2-carboxylic acid is obtained as dihydrate (CM 57202); m.p. 76°-79° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[NH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:9]([CH3:10])=[O:11]
Reactant: Nc1ccccc1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1O
Temperature: 60 °C

Procedure:
10.9 g of o-aminophenol and 100 ml of acetic acid were placed in a 300 ml round-bottom flask, followed by addition of 10.2 g acetic anhydride under ice-water cooling. The mixture was heated at 60° C. for one hour to complete the reaction, resulting in formation of 2-acetaminophenol. 23.4 g gaseous chlorine was then passed into the reaction mixture at a temperature of 80°-90° C. and the resulting reaction solution was cooled and evaporated under reduced pressure to leave 24.9 g of yellow crystals of 2-acetamino-4,5,6-trichlorophenol which melted with decomposition at 200° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH2:14].C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:14][CH2:13][C:12]([F:11])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCC(F)(F)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Temperature: 85 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.66 g, 3.69 mmol), 2,2-difluoro-2-phenyl-ethylamine (0.58 g, 3.69 mmol), and NaHCO3 (0.93 g, 11.1 mmol) in 95% EtOH (10 mL) is heated to reflux. After stirred at 85° C. for 5 h. The mixture is diluted with water, filtered, washed (water), and dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine as a solid (0.58 g). LCMS: RT=3.17 minutes, MS: 300 (M+H). 1H NMR (300 MHz, CDCl3) □7.57-7.45 (5H, m), 6.1 (1H, s), 5.2 (1H, s), 4.2-4 (2H, m), 3.92 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=2)[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:15]1.C(N(CC)CC)C>CO.CCOC(C)=O.[Pd]>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([N:14]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:26]=3)[C:16]3([CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:15]2)[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC3(CCOCC3)c3ccc(N4CCOCC4)cc32)c1C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2c(N2CC3(CCOCC3)c3ccc(N4CCOCC4)cc32)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(6-chloro-2,3-dimethylquinolin-4-yl)-6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.027 g, 0.058 mmol), triethylamine (0.008 mL, 0.058 mmol), and 10% Pd/C (0.02 g, 0.0188 mmol) in MeOH-EtOAc (2:1, 3 mL) was stirred under hydrogen at rt. After 3 h, the mixture was filtered through a Celite™ pad and the pad was washed with MeOH and EtOAc to give a tan solid. The tan solid was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 1-(2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 7.97 (1H, d, J=8.3 Hz), 7.71 (1H, d, J=8.1 Hz), 7.62-7.68 (1H, m), 7.42-7.49 (1H, m), 7.08 (1H, d, J=8.3 Hz), 6.23 (1H, dd, J=8.2, 2.1 Hz), 5.41 (1H, d, J=2.2 Hz), 3.77-3.96 (4H, m), 3.52-3.59 (4H, m), 3.41-3.51 (2H, m), 2.81 (4H, dd, J=5.4, 2.9 Hz), 2.68 (3H, s), 2.22 (3H, s), 1.91-2.03 (2H, m), 1.78-1.85 (1H, m), 1.65-1.72 (1H, m); Mass Spectrum (ESI) m/e=430.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.O>CC(C)=O>[NH:11]1[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])=[CH:14][CH:13]=[N:12]1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc[nH]n1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Ethoxycarbonyl isothiocyanate (3.16 g, 24.07 mmol) was added to 3-aminopyrazole (Aldrich) (2.0 g, 24.07 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature for 1 hour. Then cold water (100 mL) was added to the reaction mixture. The solid precipitate was collected through filtration, washed with water (50 mL), and then air dried to give 4.64 g (90%) of ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]([CH3:24])/[CH:23]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH:11]([OH:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(F)c(C(O)c2ccccc2)c1

Procedure:
A round-bottomed flask was charged with 1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}ethanone (140 mg) and dimethylformamide dimethylacetal (4 mL). The mixture was heated to reflux for 18 h then concentrated to dryness. The residue was taken up in minimal methylene chloride then added to rapidly stirring diethyl ether to induce a solid. The solids were collected on filter and washed with diethyl ether to provide (2E)-3-(dimethylamino)-1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}-2-propen-1-one as a white powder (60 mg). 8.09 (dd, 1H), 7.82 (m, 1H), 7.69 (d, 1H), 7.31 (m, 4H), 7.21 (m, 1H), 7.14 (dd, 1H), 6.06 (d, 1H), 5.94 (d, 1H), 5.75 (d, 1H), 3.14 (s, 3H), 2.88 (s, 3H).