Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH:4](Cl)[C:5]([OH:7])=[O:6].[OH:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[C:12]([CH3:20])([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>O1CCOCC1.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:10]2[O:9][CH:4]([C:5]([OH:7])=[O:6])[O:19][C:12]([CH3:20])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:11]=2[CH:21]=1
Reactant: CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C

Procedure:
60 mg of dibenzo-18-couronne-6 were added at 150° C. to a mixture of 10 ml of dioxane and 1.35 g of sodium hydride as a 50% oil suspension and then a solution of 0.61 ml of dichloroacetic acid in 10 ml of dioxane was added thereto over 5 minutes followed by addition of solution of 1.25 g of 2-hydroxy-5-chloro-α-methyl-benzhydrol in 5 ml of dioxane over 10 minutes at 20° C. The mixture was heated for 6 hours at 80° C., cooled to 20° C. and 2 ml of methanol were added thereto. The mixture was poured into iced water and was extracted three times with ethyl acetate. The organic extracts were washed 5 times with 0.1 N sodium hydroxide and the combined aqueous phases were acidified to a pH of 1 with 2 N hydrochloric acid and extracted 3 times with methylene chloride. The organic extracts were dried and evaporated to dryness to obtain raw 6-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](=[S:9])[NH2:8])([O-:3])=[O:2].Cl[CH2:14][CH:15]=O.C(O)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[S:9][CH:14]=[CH:15][N:8]=2)[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=CCCl
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2nccs2)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A yellow suspension of 3-nitrobenzothioamide (2.0 g, 10.98 mmol), 2-chloroacetaldehyde (45% in H2O) (2.01 g, 11.53 mmol), and acetic acid (7.32 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature, poured into ice water, and rendered alkaline using 30 mL of 12 N NaOH solution. Ethyl acetate was then added, and the resulting emulsion was filtered through CELITE®. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded Intermediate 57A (2.107 g, 91% yield) as a brown solid. HPLC: Rt=3.331 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=207.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H, t, J=1.89 Hz), 8.34-8.41 (1H, m), 8.28-8.34 (1H, m), 8.00-8.05 (1H, m), 7.94 (1H, d, J=3.27 Hz), 7.80 (1H, t, J=8.06 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., and then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(4-chlorophenoxy)pheny]carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.B.O1CCCC1.O.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.3 %

Procedure:
To a stirred solution of 4-bromo-2-chlorobenzoic acid (4.27 g, 18.1 mmol) in tetrahydrofuran (39 mL) at 0° C. is added borane-tetrahydrofuran complex (1 M in THF) (36.3 mL, 36.3 mmol). The reaction mixture is stirred 16 h at room temperature. At 0° C., water is slowly added then NaHCO3 aq. sat. is also slowly added The resulting solution is extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hexanes/EtOAc 85:15 to 70:30) to provide the expected product (4-bromo-2-chlorophenyl)methanol (4.34 g, 108%). 1H NMR (300 MHz, CHLOROFORM-D): δ 7.53 (1H, d, J=1.8 Hz), 7.43 (1H, dd, J=8.2, 1.8 Hz), 7.38 (1H, d, J=8.2 Hz), 4.74 (2H, d, J=6.2 Hz), 1.90 (1H, t, J=6.3 Hz).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:21][CH3:22]>>[CH2:1]([NH:19][S:24]([NH:23][CH2:20][CH2:21][CH3:22])(=[O:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCCNS(=O)(=O)Cl
Product: CCCCCCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 31 %

Procedure:
The title compound was prepared following the method described in Example 6. The starting reactants are 0.54 g (2.0 mmol) of N-octadecylamine and 0.31 g (2.0 mmol) of N-propylsulfamoyl chloride. 0.06 g of a white solid were obtained. Yield 31%; m.p. 110-112° C.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OCC)=[O:18]>C(O)C>[C:13]1([C:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:18])[S:12][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cnccc2N1
Reactant: CCOC(=O)c1cccs1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccncc2C1C(=O)c1cccs1
Yield: 78.7 %

Procedure:
Pellets of sodium metal (1.15 g, 50 mmol) were added to dry ethanol (30 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-azaoxindole (1.40 mg, 10.4 mmol) was added followed by ethyl 2-thiophenecarboxylate (2.7 mL, 20.1 mmol). The mixture was heated under nitrogen at reflux for 1 hour. At this point, the volume of the mixture was reduced 50% by distillation of ethanol at atmospheric pressure. The mixture was cooled and poured into ice/water. The resulting solution was filtered to remove a small amount of insoluble material which was washed well with water. Upon acidification of the filtrate to pH 7 with 6N HCl solution, the product precipitated. This was collected by filtration, washed with water and dried in the air to yield the title compound as a yellow/brown solid (2.0 g, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.75 mmol 3-(4-trifluoromethyl-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml dioxane at 0° C. was added dropwise 9.20 mmol trifluoroacetic acid, and the reaction mixture was then stirred at RT for 3 h. The reaction mixture was then concentrated in vacuo, and the residue resuspended in ethyl acetate and washed with 1 M aqueous hydrochloric acid. The aqueous phase was separated and then made basic by addition of 1 M aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white amorphous solid (yield 69%). MS (m/e): 232.1 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:34])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Br
Yield: 86 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.51 g, 1.16 mmol) was reacted with NBS (0.21 g, 1.16 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.52 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:7]2[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][C@@H:6]2[CH3:8])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H](C)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 68 h
Yield: 42 %

Procedure:
To a stirred solution of (3R,5R)-benzyl 3,5-dimethylpiperazine-1-carboxylate (500 mg, 2.02 mmol) in anhydrous dichloromethane (8 mL) was added diisopropylethylamine (1.4 mL, (8.08 mmol) followed by 4-tert-butylbenzene-1-sulfonyl chloride (940 mg, 4.04 mmol). The reaction mixture was stirred for 68 hours. Reaction was complete as determined by TLC. After solvent evaporation the crude product was purified by flash column chromatography to afford benzyl (3S,5S)-4-[(4-tert-butylphenyl)sulfonyl]-3,5-dimethylpiperazine-1-carboxylate in 42% yield (377 mg) as light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].C1C=CC=CC=1.[CH:24]([NH:26][NH2:27])=O>CCO.N1C=CC=CC=1>[N:26]1[N:27]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:16][CH:17]=2)[NH:2][CH:24]=1
Reactant: NNC=O
Reactant: N#Cc1ccc(CCNC(=O)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(NCCc1ccc(-c2nnc[nH]2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
(N-(4-cyanophenethyl)-2,2,2-trifluoroacetamide (0.61 g, 2.52 mmol) was azeotroped with benzene and was dissolved in 10 mL of anhydrous EtOH. To this solution dry HCl was bubbled though for 90 min at 0 C. The solvent was evaporated to dryness under high vacuum to give a yellow solid. This yellow solid and formohydrazide (151 mg, 2.52 mmol) was dissolved in 10 mL of dry pyridine and the resulting solution was refluxed for 2 h. After cooling to RT, pyridine was evaporated and the residue was treated with 5% HCl, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/DCM=1:1 to Dcm/MeOH=10:1) afforded N-(4-(4H-1,2,4-triazol-3-yl)phenethyl)-2,2,2-trifluoroacetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a stirred suspension of 2-chloro-5-(chloromethyl)pyridine (2.0 g, 12 mmol) in acetonitrile (40 mL) was added potassium carbonate (1.5 mL, 25 mmol) followed by tert-butyl 1-piperazinecarboxylate (2.3 g, 12 mmol). The resulting mixture was stirred at room temperature for 20 h. Upon workup, the mixture was poured into ice and 2 N NaOH aqueous solution and extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 339 (3.17 g, 82% yield) as a thick colorless liquid. 1H NMR 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.32 (1 H, d, J=2.0 Hz), 7.66 (1 H, d, J=7.4 Hz), 7.30 (1 H, d, J=8.2 Hz), 3.50 (2 H, s), 3.37-3.47 (4 H, m), 2.38 (4 H, br. s.), 1.46 (9 H, s). LCMS-ESI (POS), M/Z, M+1: Found 312.1.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][C:4]=1[N:21]=[CH:22][N:23]([CH3:25])C)#N.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>C(O)(=O)C>[NH2:26][C:27]1[S:28][C:29]([C:25]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:21]=[CH:22][N:23]=2)=[CH:30][N:31]=1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCN1CCOCC1
Reactant: Nc1nccs1
Solvent: CC(=O)O
Product: COc1cc2c(-c3cnc(N)s3)ncnc2cc1OCCCN1CCOCC1
Yield: 69.7 %

Procedure:
N′-(2-cyano-4-methoxy-5-(3-morpholinopropoxy)phenyl)-N,N-dimethylimidoformamide (692 mg, 2 mmol) was reacted with amino-1,3-thiazole (240 mg, 2.4 mmol) in acetic acid (6.9 ml) at reflux for 4 hours. The mixture was concentrated, the residue dissolved in AcOEt, washed with aqueous sodium bicarbonate, the organic phase was dried, concentrated, the residual oil triturated in ether to give a solid (560 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]=O)[C@@H:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@@H:17]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:38]([NH:45][CH2:22][C@@H:19]1[C@@H:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@H:17]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:16]([O:15][C@@H:13]([C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:4]=2)[CH3:14])[CH2:21][CH2:20]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1[C@@H](CNCc2ccccc2)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Yield: 97 %

Procedure:
A solution of aldehyde obtained from Step C (0.45 g, 0.84 mmol), benzyl amine (0.093 mL, 0.85 mmol), sodium triacetoxy borohydride (0.55 g, 2.6 mmol) in 30 mL dichloromethane was stirred at room temperature for 12 hr. The reaction mixture was washed with 2 N aq. NaOH, brine, dried over MgSO4, filtered and the solvent was removed under vacuum to give the title compound (0.51 g) which was used without further purification. MS: (MH)+ 626.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5]2.CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8]2
Reactant: BrBr
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (1.27 g, 3.85 mmol) in HOAc (25 mL) at 0° C. was added KOAc (0.453 g, 4.62 mmol). The reaction was stirred at this temperature for 10 min., and then a solution of Br2 (0.218 mL, 4.24 mmol) in HOAc (5 mL) was added dropwise to it over a period of ˜10 min. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was then diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc:petroleum ether gradient) to afford the product (0.782 g, 50%) as a solid (inseparable mixture of mono- and di-bromo-substituted analogs which were separated in the next step); monobrominated compound: mass spectrum [(−) ESI], m/z 406/408 (M−H)− and dibrominated analog: mass spectrum [(−) ESI], m/z 486 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16](Br)[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NCCN(C)C)c1nc2sc(Br)cc2c(=O)n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(NCCN(C)C)c1nc2sccc2c(=O)n1Cc1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 3-benzyl-6-bromo-2-(1-{[2-(dimethylamino)ethyl]-amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (2-8, 17 mg, 0.38 mmol, 1 equiv) and 10% Pd/C in ethyl acetate (5 mL) was hydrogenated at 1 atm. for 3 h. The mixture was filtered and the filtrate concentrated to provide 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (3-1) as a pale yellow gum. MS(M+1)=371.1.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:28]1C=CC=CC=1)([C:22]1C=CC=CC=1)[O:6][CH2:7][CH:8]([NH:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]([OH:12])[CH2:10]C)([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH3:1][C:2]([Si:5]([CH3:22])([CH3:28])[O:6][CH2:7][C@H:8]([NH:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:9](=[O:12])[CH3:10])([CH3:3])[CH3:4]
Reactant: CCCCCCC(=O)NC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(O)CC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)C(C)=O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
A mixture of (10c), (2.30 g, 6.94 mmol) and pyridinium dichromate (10.62 g, 28.2 mmol) in 20 mL of N,N-dimethylformamide is stirred under argon for 18 h. The reaction mixture is diluted with 100 mL of water and extracted with ethyl acetate (3×40 mL). The organic layer is separated, washed with water and brine, dried and evaporated to give 1.87 g of a residual brown liquid. The liquid is purified by chromatography using 1:6 ethyl acetate/hexane to give 997 mg of the desired product as an oil. NMR δ0.83 (s, 9H), 1.61 (m, 2H), 2.22 (t, 2H), 2.23 (s, 3H), 3.82 (dd, 1H), 4.09 (dd, 1H), 4.57 (m, 1H), 6.42 (brd, 1H); MS (FAB) m/z 330 (M+H calc'd for C17H36NO3Si 330).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:10](=[O:20])[NH:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C>[OH-].[Na+]>[CH2:13]([O:12][NH:11][C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:21])=[O:3])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(CC(C)C)C(=O)NOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CC(C(=O)O)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Intermediate (3b) (7.5 g, 25.5 mmol, 1.0 eq) was dissolved into 80 mL of 1N NaOH solution and stirred at room temperature overnight. The solution was then washed with 80 mL EtOAc, acidified to pH 1 with 6N HCl and extracted 2×100 mL EtOAc. The organic was dried over MgSO4 and concentrated to yield intermediate (3c) (6.6 g). 1H NMR (DMSO) δ (ppm): 1.0 (m, 6H), 1.4-1.8 (m, 3H), 1.3 (t, 3H), 1.5-1.7 (m, 1H), 3.2 (t, 1H), 4.9 (s, 2H), 7.4-7.6 (m, 5H) 11.4 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[N:6][C:5]=1[Cl:12].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:14])=[N:6][C:5]=1[Cl:12]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
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: [K+]
Solvent: O
Product: COC(=O)c1cc(F)c(C)nc1Cl
Temperature: 110 °C
Yield: 45.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinic acid methyl ester (1.00 g 4.46 mmol), trimethylboroxin (0.620 mL, 4.40 mmol), tetrakis(triphenylphosphine)palladium (0.500 g, 0.433 mmol) and potassium carbonate (1.50 g, 12.0 mmol) is heated at 110° C. overnight. The mixture is cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phase is washed with water followed by brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography using a gradient of 0-30% EtOAc/heptane to provide 0.410 g (45.1%) of 2-chloro-5-fluoro-6-methyl-nicotinic acid methyl ester as a solid.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2OS(C(F)(F)F)(=O)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[CH2:6][CH:1]3[CH2:5][CH:4]([CH:3]=[CH:2]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc(CC2CC=CC2)c(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C1C=CC(C2)C1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
Trifluoro-methanesulfonic acid 2-cyclopent-3-enylmethyl-5-methoxy-phenyl ester (2.00 g, 5.95 mmol) was dissolved in DMF (10 mL) under a N2 atmosphere and treated with triethylamine (0.91 g, 8.92 mmol) and 1,3-bis(diphenylphosphino)propane (0.37 g, 0.89 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles), and then treated with palladium acetate (93 mg, 0.42 mmol). After stirring for 20 min. the mixture was warmed to 100° C. for 18 hours, cooled and poured into brine (30 mL). The resulting mixture was extracted with EtOAc (4×10 mL) and the combined organic layer was washed with sat. aq. NaHCO3 soln. (10 mL), H2O (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated to an oil. The oil was chromatographed on Silica gel (2% CH2C2/hexanes) to provide product as an oil (1.05 g, 95%). (TLC 10% EtOAc/hexanes Rf 0.52). 1H NMR (CDCl3) δ 6.94 (d, J=8.0 Hz, 1H), 6.68 (dd, J=8.0, 2.8 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 6.23 (dd, J=5.5, 2.8 Hz, 1H), 5.79 (dd, J=5.5, 2.6 Hz, 1H), 3.77 (s, 3H), 3.28 (m, 1H), 2.96-2.89 (m, 2H), 2.49 (d, J=15.5 Hz, 1H), 2.19 (m, 1H), 1.85 (d, J=10.5 Hz, 1H). 13C NMR (CDCl3) 156.94, 144.07, 138.95, 131.24, 131.21, 126.34, 111.73, 111.45, 55.22, 45.10, 40.18, 38.47, 29.49. GCMS m/e 186 (M+).