Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18]1([CH2:24][C:25](OCC)=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Temperature: 25 °C
Yield: 191.4 %

Procedure:
Alternatively, the product can be prepared as follows: sodium (2.12 g) was dissolved in ethanol (145 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (10 g, 45 mmol), followed by ethyl phenylacetate (2.8 g) were added and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, stripped and then water, followed by 2 N HCl were added to the residue. The product was collected by filtration and recrystallized from ethyl acetate to afford 10.52 g (73%) of 1-cyclopentyl-3-ethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1.Cl>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:14][CH:15]=1)[C:9](=[O:10])[NH:3][NH:2][C:12]2=[O:11]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (2 ml, 33.0 mmol) was added to a suspension of 4-bromophthalic anhydride (7.5 g, 33.0 mmol) in ethanol (70 ml) and the resulting mixture was stirred at 90° C. for 24 hr. The volume of the reaction mixture was then reduced to half volume under reduced pressure and the residue was treated 0.5 N aq. HCl (20 mL). The title compound precipitated as a white solid and was collected by filtration (4.86 g, 61%); LRMS ESI+ (M+H)+ 241.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)[CH:24]=[CH:23][CH:22]=1)[CH3:19]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 7 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68 mg, 0.3 mmol) was converted, using 3-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the tide compound (8 mg, 7%) which was obtained as an off-white solid. MS: m/e=346.5 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][C:17]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCN1Cc1ccccc1
Yield: 92.4 %

Procedure:
To a solution of 35 mL of TFA in dichloromethane was added 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (10.39 g, 35.8 mmol) in portions. After 18 hours the solution was concentrated via rotary evaporator and H20 was added. The pH was adjusted to 12 with 4M NaOH. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-benzyl-piperazin-2-one (6.29 g, 92%) as an oil.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl:10][CH2:11][C:12](O)=[O:13].P(Cl)(Cl)(Cl)=O>>[CH:8]1[C:9]([C:12]([CH2:11][Cl:10])=[O:13])=[C:1]([OH:2])[C:3]([OH:4])=[C:5]([OH:6])[CH:7]=1
Reactant: O=C(O)CCl
Reactant: Oc1cccc(O)c1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCl)c1ccc(O)c(O)c1O

Procedure:
Pyrogallol is reacted with chloroacetic acid in the presence of phosphorus oxychloride to form ω-chloro-2,3,4-trihydroxyacetophenone,
Reaction SMILES: C(OC[N:9]1[C:17]2[C:16]([Cl:18])=[CH:15][C:14]([Cl:19])=[CH:13][C:12]=2[C:11]2[CH2:20][CH2:21][C:22]([C:28]([F:31])([F:30])[F:29])([O:23][Si](C)(C)C)[C:10]1=2)(=O)C(C)(C)C.[OH-].[K+]>C1COCC1.O>[Cl:18][C:16]1[C:17]2[NH:9][C:10]3[C:22]([C:28]([F:31])([F:29])[F:30])([OH:23])[CH2:21][CH2:20][C:11]=3[C:12]=2[CH:13]=[C:14]([Cl:19])[CH:15]=1
Reactant: CC(C)(C)C(=O)OCn1c2c(c3cc(Cl)cc(Cl)c31)CCC2(O[Si](C)(C)C)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 430 %

Procedure:
To (5,7-Dichloro-3-(trifluoromethyl)-3-(trimethylsilyloxy)-2,3-dihydrocyclopenta[b]indole-4(1H)-yl)methyl pivalate (0.32 g, 0.6 mmol) in THF (6.0 mL), cooled to 0° C., KOH (0.18 g, 3.2 mmol), in H2O (6.0 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 h, diluted with water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (3:17) as eluant] to afford the title compound as a white solid (0.80 g, 40%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.75 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1.5 Hz, 1H), 6.83 (s, 1H), 2.93-2.88 (m, 2H), 2.78-2.74 (m, 1H), 2.53-2.50 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][CH2:17][CH2:18][CH:19]([NH2:23])[C:20]([OH:22])=[O:21].CC#N>O>[C:20]([CH:19]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][CH2:17][CH3:16])([OH:22])=[O:21]
Reactant: CCCC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: O
Solvent: CC#N
Product: CCCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Yield: 15 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2-aminopentanoic acid to provide the title compound in 15% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH-20, 1, 0.3).
Reaction SMILES: [NH:1]([CH:8]1[CH2:17][CH:16]2[N:11]([CH2:12][CH2:13][C:14]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:15]=32)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:15]2[CH:16]3[N:11]([CH2:12][CH2:13][C:14]=2[CH:21]=1)[CH2:10][CH2:9][CH:8]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:33]([NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:17]3
Reactant: COc1cc2c(cc1OC)C1CC(Nc3ccccc3)CCN1CC2
Reactant: O=C=Nc1ccccc1
Product: COc1cc2c(cc1OC)C1CC(N(C(=O)Nc3ccccc3)c3ccccc3)CCN1CC2

Procedure:
By a procedure analogous to that of Example 1, 2-anilino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (U.S. Pat. No. 3,634,431) is reacted with phenyl isocyanate to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C@H:7]2[N:9]([CH3:10])[CH:3]1[CH2:4][C:5](=[O:11])[CH2:6]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:10][N:9]1[CH:3]2[CH:2]([O:1][C:19](=[O:21])[CH3:20])[CH2:8][C@@H:7]1[CH2:6][C:5](=[O:11])[CH2:4]2
Reactant: CC(=O)OC(C)=O
Reactant: CN1C2CC(=O)C[C@H]1CC2O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1C[C@@H]2CC(=O)CC1N2C
Reaction time: 12 h

Procedure:
To an ice bath cooled, stirred solution of (R)-6-hydroxy-8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (4.08 mmol, 0.634 g), triethylamine (20.4 mmol, 2.86 mL), and DMAP (0.245 mmol, 0.03 g) in dry DCM (3.5 mL) was added acetic anhydride (6.12 mmol, 0.58 mL). The reaction mixture was allowed to come to room temperature and was stirred for 12 hours. The reaction was evaporated and the resulting residue was purified on a 12 g SiO2 cartridge using 0-3% (2N NH3 in MeOH) in DCM to give acetic acid (R)-8-methyl-3-oxo-8-aza-bicyclo[3.2.1]oct-6-yl ester.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[C:36]([NH:44][NH2:45])(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:36]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)=[N:44][N:45]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NNC(=O)c1cccnc1
Solvent: Cc1ccc(C)cc1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3cccnc3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 34.1 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and nicotinic acid hydrazide (84 mg, 0.308 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in cyclohexane) to give the title compound (33 mg, 25%). LCMS (Method D): RT=1.364 min, M+1=573. 1H NMR (500 MHz, CDCl3): 9.00 (1H, d), 8.87 (1H, dd), 8.10 (1H, dt), 7.56 (1H, dd), 7.36-7.27 (5H, m), 7.24-7.17 (3H, m), 6.99-6.93 (2H, m), 5.67 (2H, s), 2.56-2.39 (4H, m), 2.13-2.01 (1H, m), 1.88-1.75 (1H, m), 1.49-1.26 (9H, bs).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[C:32]1([Mg]Br)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:40]1([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[C:41]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Br[Mg]c1cccc2ccccc12
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc4ccccc34)sc2c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperdinyl)ethoxy]phenyl]methanone (1.58 g, 3.6 mmol) (see U.S. Pat. No. 5,420,349) in tetrahydrofuran (THF, 12 mL) was cooled to 0° C. and treated with a 0.65M THF solution of 1-naphthylmagnesium bromide (20.0 mL, 13 mmol) (prepared from 1-bromonaphthalene, catalytic iodine, and magnesium turnings in THF). The mixture was allowed to warm to ambient temperature and when the starting material was consumed, the reaction was quenched with water and extracted with ethyl acetate (a small amount of methanol was added to improve solubility). The organic layer was washed with water (2×), and brine (2×), dried (sodium sulfate), and concentrated. The residue was purified via chromatography (silica gel, 0-10% methanol in methylene chloride) to provide 1.08 g (58%) of the title compound as a yellow foam: 1H NMR (300 MHz, CDCl3) δ1.46 (m, 2H), 1.60 (m, 4H), 2.47 (m, 4H), 2.68 (t, J=5.9 Hz, 2H), 3.92 (s, 3H), 3.96 (t, J=5.9 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 7.06 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.27-7.50 (m, 5H), 7.54 (d, J=8.8 Hz, 2H), 7.67-7.75 (m, 2H), 7.79 (d, J=8.9 Hz, 1H), 8.06-8.09 (m, 1H); MS (FD) m/e 521 (M+).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:6]=[CH:7][S:8](Cl)(=[O:10])=[O:9]>CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:6]=[CH:7][S:8]([NH2:1])(=[O:10])=[O:9]
Reactant: N
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 97 %

Procedure:
Ammonia is bubbled through a solution of 3,4-dichlorostyrylsulfonyl chloride (27.2 g., 0.1 mole) in 250 ml. of ether for a period of 30 min. at about 20° C. The solvent is evaporated and the residue stirred with water, collected and dried at 100° C. under vacuum affords 24.6 g. (97% yield) of 3,4-dichlorostyrylsulfonamide, m.p. 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:41](O)(=[O:44])[CH:42]=[CH2:43].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:41](=[O:44])[CH:42]=[CH2:43])=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 17 %

Procedure:
288 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.07 ml of acrylic acid, 0.17 ml of pyridine and 0.29 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (52 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>CC(C)=O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:16]
Reactant: CCOC(CBr)OCC
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirring mixture of 20.0 gm (0.138 mol) 3-chlorothiophenol and 21.0 gm (0.15 mol) potassium carbonate in 220 mL acetone were added dropwise 1.1 equivalents of bromoacetaldehyde diethyl acetal. After stirring for 17 hours at ambient temperature, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was partitioned between diethyl ether and water. The organic phase was separated, washed with saturated sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to give 35.1 gm (97%) of the desired. compound as a rust colored oil.
Reaction SMILES: COC(C)(C)C.[C:7]([O:12][CH:13]([O:17][C:18]([CH3:20])=[S:19])[CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:8][CH2:9][CH3:10]>O>[C:7]([O:12][C@@H:13]([O:17][C:18]([CH3:20])=[S:19])[CH2:14][CH2:15][CH3:16])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)OC(CCC)OC(C)=S
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(=O)O[C@H](CCC)OC(C)=S
Reaction time: 120 h
Yield: 10 %

Procedure:
A mixture of 33 mL methyl-tert-butyl ether (MTBE) and 0.33 mL water was stirred until a clear solution was obtained (ca. 5 hrs). To this solution was added methylthiocarbonyloxybutyl butanoate (2e) (2.0 g) and PLE/MPEG (60 mg/1 g; 12.65 g). The resulting suspension was stirred at room temperature. The reaction was monitored by 1H-NMR using a chiral solvating agent. After ca. 5 days, the reaction was quenched by filtration through a pad of CELITE® 545. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). Evaporation of the solvent afforded 0.20 g (20% yield) of the title compound (16). The enantiomeric excess as determined by chiral HPLC was 90% e.e.
Reaction SMILES: O1CCCC1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1.[F:16][CH2:17][CH2:18][OH:19]>O>[F:16][CH2:17][CH2:18][O:19][C:12]1[N:11]=[N:10][C:9]([Cl:8])=[CH:14][CH:13]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FCCOc1ccc(Cl)nn1
Reaction time: 0.02 h
Yield: 83.1 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) containing sodium hydride (NaH 60%, 121 mg, 3.02 mmol) was slowly added anhydrous tetrahydrofuran (2 mL) having 3,6-dichloropyridazine (107, 300 mg, 2.01 mmol) dissolved therein at 0° C., and added dropwise 2-fluoroethanol (194 mg, 3.02 mmol). The reaction mixture was stirred for one minutes and water was carefully added. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-(2-fluoroethoxy)-6-chloropyridazine (108b, 295 mg, 83%) as a white solid.
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH2:8]2.[CH3:14][CH2:15][O-].[Na+].Cl>CS(C)=O>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[CH:7][CH:8]2[CH2:10][CH:9]1[C:5]2[C:6](=[C:15]([CH3:14])[CH:11]=[CH:12][C:4]=2[CH3:3])[CH:7]=[CH:8]1
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: CC[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C)c2c1C=CC2CC1C=Cc2c(C)ccc(C)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Paraformaldehyde (2.08 g, 69.4 mmol) was added to a mixture of 4,7-dimethylindene (25.0 g, 174 mmol) and EtONa (5.9 g, 87 mmol) in DMSO (200 mL) at 25° C. After stirring at room temperature for 12 hours, the reaction mixture was heated at 65° C. for 8 hours. It was then cooled to room temperature and a solution of HCl (1 M, 400 mL) was added. The mixture was extracted with CH2Cl2 (400 mL); the organic phases were combined, washed with a saturated solution of NaCl and then with water, dried with MgSO4, filtered and finally concentrated to yield a brown viscous liquid. GC analysis showed only the final product and the starting material, no fulvene derivative being detectable. Precipitation occurred when the brown liquid was added into pentane (100 mL). Bis(4,7-dimethylindenyl)methane was obtained as a yellow solid after filtering and washing with pentane and EtOH, with a yield of 33% (6.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][CH:7]=[N:8][C:9](=O)[C:10]=2[N:11]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2ccc(Cl)nc12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2ncnc(Cl)c2n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (150 mg, 0.83 mmol) in POCl3 (2.0 mL) was added DIPEA (0.22 mL, 1.24 mmol) at room temperature. After stirring for 1 hour at 110° C., the reaction mixture was cooled to room temperature. The reaction mixture was concentrated in vacuo, and then diluted with water and extracted with dichlormethane. The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=10:1) to give 4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 73%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.87 (1H, d, J=8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 9.14 (1H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH:17]1(B(O)O)[CH2:19][CH2:18]1>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: OB(O)C1CC1
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c(C2CC2)nc1C(=O)O

Procedure:
A microwave vial was charged with amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (0.5 g, 1.754 mmol), cyclopropylboronic acid (0.753 g, 8.77 mmol), and 1,1′Bis(diphenylphosphosphino)ferrocene palladium dichloride (0.143 g, 0.175 mmol). The mixture was taken up as a solution in THF (6 ml) and flushed with N2, sealed and heated using microwave radiation at 150° C. for 20 minutes. The reaction mixture was filtered through Celite® (filter material) and washed through with EtOAc (20 ml). The filtrate was partitioned between EtOAc (30 ml) and water (50 ml). The phases were separated and the organic portion was washed with brine (30 ml), dried over MgSO4, filtered and concentrated under vacuum.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[S:3].I[CH3:35]>CO>[NH:1]=[C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:18])=[O:19])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[S:3][CH3:35]
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(N)=S)c2)c1)c1ccccc1
Reactant: CI
Solvent: CO
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=N)SC)c2)c1)c1ccccc1

Procedure:
2.42 g of Ethyl 3-[({3′-[(aminocarbothioyl)amino][1,1′-biphenyl]-3-yl}sulfonyl)-amino]-3-phenylpropanoate 14.1.1 were dissolved in 80 ml methanol and 0.89 g Iodomethan were added. After reflux for 2 h, the reaction mixture was concentrated and crystalized from ether to obtain 3.1 g.
Reaction SMILES: [Na].C[O:3][C:4](=O)[CH2:5][C:6]1=[N:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9](=[O:21])/[C:10]/1=[C:11](/[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)\[CH3:12].Cl>CC(O)C>[CH2:22]([N:8]1[C:9](=[O:21])[C:10]2=[C:11]([CH3:12])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:4](=[O:3])[CH:5]=[C:6]2[NH:7]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CC1=NN(Cc2ccccc2)C(=O)/C1=C(\C)NCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: Cc1c2c(=O)n(Cc3ccccc3)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 97 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.017 g, 0.713 mmol, 1 equiv) in i-PrOH (16 ml), was treated with methyl[(4E)-1-benzyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (0.270 g, 0.713 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.12 ml of a 20% aqueous HCl solution. 15 ml of i-PrOH were removed in vacuo and 10 ml of H20 were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×3 ml), then with cyclohexane and dried in vacuo. 0.240 g of pure product 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 97%. 1H NMR (500 MHz, DMSO-d6, ppm) 2.78 (s, 3H), 4.81 (s, 2H), 5.37 (s, 2H), 5.59 (s, 1H), 7.31-7.26 (m, 5H), 7.36 (m, 2H), 7.76 (td, J 7.6, 1.9 Hz, 1H), 8.46 (dt, J 4.2, 1.6 Hz, 1H), 10.34 (s, 1H); MS (ESI+)=347.2.