Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.[OH-:16].[K+].[CH3:18]O>>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:16][CH3:18]
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Product: COc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone from the previous step and 17 L of methanol were added to a 50 L round bottomed flask equipped with a glycol cooling jacket and a mechanical stirrer. The resulting solution was cooled to 0° C. and 87% KOH (1172 g 18.17 moles) was added in small portions over approximately 1 h. The mixture exothermed to 40° C. Following the addition, the mixture was stirred an additional 3 h. at ambient temperature. The reaction mixture was partitioned with 12 L of ethyl acetate and 12 L of H2O. The aqueous layer was extracted with ethyl acetate (2×4 L). The combined organic layers were washed with brine (2×10 L) and dried (MgSO4). The organic solution was clarified by filtration and concentrated to give a dark semi-solid. The crude material was added equally to two 22 L flasks. The material was suspended in 12 L hexanes/ethyl ether (2:1 ratio). The washed material was vacuum filtered on a Buchner funnel and air dried overnight to give 3,406 g (77% over 2 steps) of 4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone as a dark tan solid suitable for further transformations. The product was purified by recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=118°-120° C.
Reaction SMILES: OCC([NH3+])(CO)CO.[CH:9]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](=O)[C:22]([OH:24])=[O:23])[CH:18]=2)[CH2:13]1)([CH3:11])[CH3:10]>>[CH:9]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]=2)[CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)C1Cc2ccc(C(=O)C(=O)O)cc2C1
Agent: [NH3+]C(CO)(CO)CO
Product: CC(C)C1Cc2ccc(CC(=O)O)cc2C1

Procedure:
A solution of 10 g of sodium hydroxide in 20 cc of water is added to a solution of 24.5 g of crude 2-isopropyl-α-oxo-5-indanacetic acid ethyl ester in 300 cc of ethanol, and the mixture is boiled at reflux for 11/2 hours. The solution is concentrated, diluted with water, and the neutral by-products are extracted with ether. The aqueous phase is then acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. 2-isopropyl-α-oxo-5-indanacetic acid is obtained as an oil and is used for the next reaction without purification. The (1,3-dihydroxy-2-hydroxymethyl-2-propyl)ammonium salt of 2-isopropyl-α-oxo-5-indanacetic acid has a M.P. of B 145°-147°.
Reaction SMILES: Cl[NH:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C.[CH3:16][NH:17][CH2:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])[OH:20].[OH-].[Na+].[CH:31]([OH:34])(C)C>O>[CH3:16][N:17]([CH2:18][CH:19]([OH:20])[CH:21]([OH:22])[CH:23]([OH:24])[CH:25]([OH:26])[CH2:27][OH:28])[C:31]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:34]
Reactant: CC(C)O
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCC(=O)NCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCNC(=O)N(C)CC(O)C(O)C(O)C(O)CO
Yield: 63 %

Procedure:
A mixture containing 7 g (30 mmol) of lauric N-chloramide dissolved in 200 ml of isopropanol, was reacted with a solution containing 5.85 g (30 mmol) of N-methyl-D-glucamine in 150 ml of isopropanol, 40 ml of water and 1.2 g (30 mmol) of sodium hydroxide at 50° C. for a period of 1 hour. The reaction mixture was processed in accordance with the procedures described in Example 12 to yield 7.38 g (63% yield) of N-methyl-N-(2,3,4,5,-6-pentahydroxy-n-hexyl)-N'-n-undecyl urea of the formula ##STR13## having a melting point of 109° C. and the following analysis:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[CH2:16]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[CH3:17]
Reactant: CC[O+](CC)CC
Reactant: COC(=O)c1cc(O)no1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(=O)OC)on1
Reaction time: 8 h
Yield: 86 %

Procedure:
A stirred suspension of 3.53 g (24.67 mmole) of a commercial sample of methyl 3-hydroxy-5-isoxazolecarboxylate in 50 ml of methylene chloride was treated dropwise with a solution of triethyloxonium tetrafluoroborate (5.62 g, 29.60 mmole) dissolved in 30 ml of methylene chloride at room temperature. After stirring overnight the solution was washed with water (2×30 ml), 5% sodium bicarbonate (2×30 ml) and water once again. The organic layer was dried (magnesium sulfate) and evaporated in vacuo to furnish the title compound (3.61 g, 86% yield) as a light yellow solid, m.p. 77°-9° C. 1H-NMR delta, 6.65 (1H, s), 3.93 (2H, q, J=7.4 Hz), 3.87 (3H, s) and 1.21 (3H, t, J=7.4 Hz); EIMS (m/z): 171 (M+, 48%), 156 (M+ -CH3, 4%), 143 (C5H5NO4 , 31%), 112 (C4H2NO3, 12%) and 69 (C3H3NO, base); ir (potassium bromide): 3105, 1744, 1611, 1441, 1241, 1106, 974 and 797 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=O.CC1C(C)=CC=CC=1NO.[CH3:22][N:23]([NH2:25])[CH3:24]>>[CH3:22][N:23]([CH3:24])[N:25]=[N+:9]([O-:11])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CN(C)N
Agent: Cc1cccc(NO)c1C
Product: Cc1cccc([N+]([O-])=NN(C)C)c1C

Procedure:
Similarly 12.1 g. of 2,3-dimethylnitrobenzene was hydrogenated to 2,3-dimethylphenylhydroxylamine, which was oxidized with ferric chloride to the nitroso compound. This compound was treated with unsymmetrical dimethylhydrazine to yield 3,3-dimethyl-1-(2,3-dimethylphenyl)triazene-1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32]>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:24][CH2:23][C:14]3[NH:15][C:16]4[CH:17]=[C:18]([C:37]5[CH:36]=[CH:35][CH:34]=[C:33]([CH:31]=[O:32])[CH:38]=5)[CH:19]=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4cc(Br)ccc4c3C2)nc1
Reactant: O=Cc1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4cc(-c5cccc(C=O)c5)ccc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.1 %

Procedure:
To a solution of methyl-2-(7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (0.360 g, 0.93 mmol) in THF:H20 (4:1) were added Cs2CO3 (2.42 g, 7.44 mmol) and 3-formylphenylboronic acid (0.27 g, 1.86 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (0.268 g, 0.23 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 ml) and water (15 mL). The organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{7-[3-(formyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.15 g, 39.13%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.O.Cl.Cl.[CH3:30][N:31]1[C:35]([CH:36]=O)=[N:34][C:33]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[N:32]1.C(N(CC)CC)C.Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[C:13]([CH2:36][C:35]3[N:31]([CH3:30])[N:32]=[C:33]([C:38]4[CH:43]=[N:42][CH:41]=[CH:40][N:39]=4)[N:34]=3)=[C:12]([OH:17])[CH2:11]2)[CH:7]=1
Reactant: Cn1nc(-c2cnccn2)nc1C=O
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(-c4cnccn4)nn3C)C(=O)O2)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A solution of 6-[2-(5-chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.300 g, 0.78 mmol, from step 6 below) in hot isopropanol (5 mL) was treated with (CH3)2NHBH3 (48 mg, 0.815 mmol, 1.04 equiv), then with a solution of 2-methyl-5-pyrazin-2-yl-2H-[1,2,4]triazole-3-carbaldehyde dihydrochloride monohydrate (229 mg, 0.819 mmol, 1.05 equiv, from step 3 below) in isopropanol (3 mL) containing triethylamine (0.230 mL, 2 equiv). The reaction mixture was stirred at room temperature, resulting in complete conversion after 1 h. The mixture was acidified with 1 M aqueous HCl to a pH of 2, stirred for 10 min, and concentrated in vacuo to afford a resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×15 mL). The extract was dried over Na2SO4, filtered, and concentrated, affording the crude product (410 mg). This material was recrystallized from hot methylene chloride/ether, then the resulting solid triturated with acetone containing petroleum ether, filtered, and dried, affording the title product (107 mg, 24%). 1H NMR (300 MHz, DMSO-d6): δ 1.26–1.75 (m, 8H), 1.78–2.13 (m, 2H), 2.37 (m, 1H), 2.45–2.50 (m, 2H, overlap with DMSO-d5), 2.65 (d, J=17.9 Hz, 1 H), 2.73 (d, J=17.9 Hz, 1 H), 3.73 (s, m overlap, 5H), 3.80 (s, 3H), 3.95 (s, 3H), 6.63 (s, 1H), 7.05 (s, 1 H), 8.6 (m, overlap, 2H), 8.93 (s, 1H), 11.07 (br s, 1H). LC-MS (APCI) calcd for C28H32ClN5O5: 553.21, found (M+H+): 554.4 m/z.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][CH2+:40]1SC)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([N:39]1[C:43](=[O:44])[C:42](=[C:45]2[N:49]([CH3:50])[C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[S:46]2)[S:41][C:40]1=[N:16][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])=[O:19])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C(=O)NCCN(C)C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(=O)NCCN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate N-(2-dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29])[CH:25]=1)[C:19]([O:21]C)=[O:20].[Li+].[OH-].Cl>C1COCC1.CO>[NH2:8][C:9]1([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([N:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29])[CH:25]=1)[C:19]([OH:21])=[O:20]
Reactant: CCCN(c1cc(COC2OCCC2(N)Cc2ccccc2)cc(C(=O)OC)c1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCN(c1cc(COC2OCCC2(N)Cc2ccccc2)cc(C(=O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 3-{[(3-amino-3-benzyltetrahydrofuran-2-yl)oxy]methyl}-5-[(methylsulfonyl)(propyl)amino]benzoate TFA salt (40 mg, 0.07 mmol) in THF (0.5 mL) and MeOH (0.5 mL) is 1N LiOH (0.6 mL, 0.6 mmol) and the reaction mixture is stirred at RT for 3 h. 1N HCl (0.4 mL, 0.4 mmol) is added and the reaction mixture is concentrated in vacuo to give 3-{[(3-amino-3-benzyltetrahydrofuran-2-yl)oxy]methyl}-5-[(methylsulfonyl)(propyl)amino]benzoic acid as a white solid, used as is in the following coupling.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([OH:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.CCN(CC)CC>[C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([O:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate from Preparation 6 (1.5 g, 5.7 mmol) in CHCl3 (20 ml) and Et3N (1 ml) is treated with benzoyl chloride (1.0 g, 7.1 mmol). The resulting solution is stirred at room temperature for 4.5 hours. The reaction mixture is concentrated and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The organic phases are combined, dried (MgSO4) and concentrated. The residue is purified by silica gel chromatography (50% EtOAc/Heptane). An oil of methyl α-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2-propenyl)benzeneacetate is obtained (2.1 g, quantitative).
Reaction SMILES: [I:1][C:2]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C1(N2CCC3C=C(I)C(OC4N=CC(C(NC)=O)=CC=4)=CC=3CC2)CCC1>>[CH:21]1([N:8]2[CH2:7][CH2:6][C:5]3[CH:11]=[C:12]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:2]([I:1])=[CH:3][C:4]=3[CH2:10][CH2:9]2)[CH2:24][CH2:23][CH2:22]1
Reactant: Ic1cc2c(cc1OCc1ccccc1)CCNCC2
Reactant: O=C1CCC1
Agent: CNC(=O)c1ccc(Oc2cc3c(cc2I)CCN(C2CCC2)CC3)nc1
Product: Ic1cc2c(cc1OCc1ccccc1)CCN(C1CCC1)CC2

Procedure:
Example 226 (E226) was prepared from 7-iodo-8-[(phenylmethyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (D45) and cyclobutanone using the method described for Example 225 (E225); MS (ES+) m/e 434 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[S:15](Cl)(=[O:17])=[O:16])(=[O:3])[CH3:2].[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][S:15]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:5]2[NH:4][C:1](=[O:3])[CH3:2])(=[O:17])=[O:16]
Reactant: CN
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCO
Product: CNS(=O)(=O)c1cccc2c(NC(C)=O)cccc12

Procedure:
1.10 g of 5-acetylaminonaphthalene-1-sulfonyl chloride is dissolved in 8 mL of ethanol and 8 mL of methylamine solution in ethanol are added dropwise. Then the resulting mixture is stirred at reflux temperature for 3.5 hours and the solvent is distilled off in vacuo. The residue is purified by chromatography. Yield: 0.50 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].CCN(CC)CC.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[CH:21][C:20](Br)=[CH:19][N:18]=1)=[O:16].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[CH:21][C:20]([C:5]#[C:4][CH2:3][O:2][CH3:1])=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1ncc(Br)cc1N
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COCC#Cc1cnc(C(=O)OC)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of 3-methoxy-propyne (421 mg, 6 mmol), bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol), copper(I) iodide (23 mg, 0.12 mmol) and NEt3 (1.17 ml, 8.4 mmol) in THF (10 ml) under Argon was added 3-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (277 mg, 1.2 mmol) and the mixture was heated to 80° C. for 5 h. At 0° C. water (12 ml) was added and the mixture was extracted with EtOAc, the combined organic layers were washed with half-saturated aq. sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as orange solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:15]=[CH:14][O:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[C:1]1([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2ccoc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of phenylboronic acid (15 g, 123.02 mmol) in dioxane (150.0 mL) and water (3.0 mL) was added 3-bromofuran (16.3 g, 110.91 mmol), K3PO4 (43 g, 202.57 mmol) and Pd(PPh3)4 (6.0 g, 5.19 mmol) with stirring for 2 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 3-phenylfuran as a white solid (15 g, 85%).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[C:10](O)([C:21]3[C:30]([OH:31])=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[C:9]2=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:34]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]([C:21]3[C:30]([OH:31])=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[C:9]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: COc1cc(OC)c2c(c1)N(C(c1ccccc1)c1ccccc1)C(=O)C2c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one was obtained (92%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.35-7.25 (m, 8H), 7.21-7.14 (m, 2H), 6.87 (s, 1H), 6.61 (s, 1H), 6.27 (s, 1H), 6.17 (d, J=1.8 Hz, 1H), 5.68 (d, J=1.8 Hz, 1H), 5.02 (s, 1H), 4.24-4.10 (m, 4H), 3.73 (s, 3H), 3.48 (s, 3H), 3.47 (s, 1H).
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>C1(C)C=CC=CC=1>[OH:24][CH2:23][CH2:25][N:26]1[C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:1][CH:15]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCCCCCCC(S)C(=O)O
Reactant: NCCO
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCO)C1=O
Reaction time: 1 h
Yield: 72.6 %

Procedure:
2-Mercaptoundecanoic acid (7 g, 32.1 mmol), nicotinaldehyde (3.03 ml, 32.1 mmol), and ethanolamine (1.93 ml, 32.1 mmol) were added to toluene, (100 ml). and subjected to azeotropic dehydration for 1 hour. The product mixture was cooled and evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography, giving 3-(2-hydroxy-ethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (8.17 g, 73% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][CH:16]=[CH:17][C:11]=2[N:10]([CH3:18])[C:9]1=[O:19])(=[O:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:11]=2[N:10]([CH3:18])[C:9]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]ccc2n(C)c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2c(ccn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 60.3 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (52 mg, 0.2 mmol) in DMF (3 mL) was added 1-chloro-4-(chloromethyl)benzene (64 mg, 0.4 mmol) and K2CO3 (82 mg, 0.6 mmol). The reaction was heated at 85° C. for 2 h, cooled to RT then diluted with EA (30 mL) and water (20 mL). The organic layer was washed with aq. 1N LiCl solution (3×10 mL), dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (47 mg, 59% yield) as a solid. LCMS: MH+ 390 and TR=1.399 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(CO)ccnc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CCl)ccnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(2-Chloro-3-methyl-pyridin-4-yl)-methanol (12-4, impure, 0.200 g) was dissolved in 5 mL anhydrous DCM under N2. Anhydrous DMF (0.098 mL, 1.3 mmol) and POCl3 (0.118 mL, 1.27 mmol) were added and the reaction was stirred at RT for 17 h. The reaction was quenched with sat NaHCO3 (aq) and extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered and concentrated to provide 2-chloro-4-chloromethyl-3-methyl-pyridine still contaminated with a major by-product. 2-Chloro-4-chloromethyl-3-methyl-pyridine (impure, 0.215 g) was stirred in 3 mL DMSO. 1-Acetylpiperazine (0.626 g, 4.88 mmol was added and the reaction was stirred at RT overnight. The solution was purified by directly loading onto a preparative reverse phase column to afford an oil which slowly crystallizes. TFA salt: 1H NMR (CD3OD) δ8.30 (d, 1H, J=5.0 Hz), 7.53 (d, 1H, J=5.0 Hz), 4.48 (s, 2H), 3.84 (bs, 4H), 3.39-3.30 (m, 4H), 2.14 (s, 3H).