Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.C(OC)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CCO
Product: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.5 %

Procedure:
(5-bromo-2-chlorophenyl)(4-methoxyphenyl)methanone (265 g, 0.81 mol) was dissolved in methylene chloride (515 mL) and acetonitrile (1030 mL). To the resulting mixture was added triethyl silane (352 mL, 2.22 mol). Then to the resulting mixture was added dropwise boron trifluoride-diethyl etherate (273 mL, 2.22 mol) at 0° C. under a nitrogen protection. After the completion of dropwise addition, the resulting mixture was stirred for 20 min, warmed up to room temperature and reacted for 2 hr. TLC indicated the completion of reaction. To the reaction mixture were added methyl tert-butyl ether (1.5 L) and a saturated sodium bicarbonate solution (1.5 L). The mixture was stirred for 30 mins. The organic phase was separated off, washed with a saturated sodium bicarbonate solution for four times and with a saturated sodium chloride solution for one time, dried over anhydrous sodium sulphate, and evaporated by rotation to produce an oily substance. To the oily substance was added ethanol. The resulting mixture was stirred at room temperature for 30 mins and in an ice bath for 30 mins. A great quantity of solid was separated out and filtered. The filter cake was dried to produce 226 g of a product in a yield of 89%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[OH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:13][CH:14]=1
Reactant: O=Cc1cc(I)ccc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 69.1 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (3.6 g, 14.4 mmol) (Aldrich) was reacted with methyl 4-hydroxybenzoate (2.62 g, 17.3 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(2-formyl-4-iodo-phenoxy)-benzoic acid methyl ester as a yellow oil (Yield 3.8 g, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH:37]=[CH2:38].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13](/[CH:38]=[CH:37]/[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(Br)cc(OCc3ccccc3)c2)=NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Reaction time: 48 h
Yield: 50.1 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)-5-bromophenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (500 mg), tert-butyl acrylate (586 mg), palladium acetate (10.27 mg), tris(2-methylphenyl)phosphine (41.8 mg), triethylamine (0.383 mL), and DMF (5 mL) was stirred at 100 C for 2 days under an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (272 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[O:13]CC(C)(C)N=2)=[C:7]([CH:19]2[O:24][CH2:23]CC[O:20]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.S(=O)(=O)(O)O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:12](=[O:13])[O:20][CH:19]2[O:24][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC1OC(=O)c2c(F)cc(C(C)(C)C)cc21
Yield: 87.9 %

Procedure:
A mixture of 101f (68.8 g, 205.4 mmol), methanol (1340 mL) and 50% aqueous sulfuric acid (881 mL) was stirred at reflux overnight. The reaction mixture was poured into 400 mL of water, extracted with DCM (3×1000 mL). The combined organic extracts were washed with 400 mL of brine, dried over Na2SO4, filtered and concentrated to dry to provide 101g (43 g) as a off-white solid which was used in the next step without further purification LCMS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@H:14]([O:16]C(C)(C)C)[CH2:13][C@H:12]1[C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:65]=[CH:64][C:39]5[NH:40][C:41]([C@@H:43]6[CH2:47][C@@H:46]([O:48]C(C)(C)C)[CH2:45][N:44]6[C:53](=[O:63])[C@@H:54]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:55]([CH3:57])[CH3:56])=[N:42][C:38]=5[CH:37]=4)=[CH:32][CH:31]=3)=[CH:29][C:23]=2[N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O>>[CH3:62][O:61][C:59](=[O:60])[NH:58][C@H:54]([C:53]([N:44]1[CH2:45][C@H:46]([OH:48])[CH2:47][C@H:43]1[C:41]1[NH:40][C:39]2[CH:64]=[CH:65][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:28]4[CH:27]=[CH:26][C:24]5[NH:25][C:21]([C@@H:12]6[CH2:13][C@@H:14]([OH:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:66])[CH:6]([CH3:8])[CH3:7])=[N:22][C:23]=5[CH:29]=4)=[CH:35][CH:34]=3)=[CH:37][C:38]=2[N:42]=1)=[O:63])[CH:55]([CH3:56])[CH3:57]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@H](OC(C)(C)C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc5[nH]c([C@@H]6C[C@@H](OC(C)(C)C)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5c4)cc3)ccc2[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1c1nc2cc(-c3ccc(-c4ccc5[nH]c([C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5c4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.2 %

Procedure:
To a solution of compound from example 25 (15 mg, 0.015 mmol) is added TFA (0.3 mL) at 0° C. The reaction mixture is stirred 1 hour at rt, concentrated to dryness, and triturated with DCM (3×) to give title compound (16 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH2:2][C:3]3[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=3[C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=3)=[CH:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-4,5-difluorophenyl)picolinamido)propanoate (115 mg, 0.27 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (110 mg, 0.54 mmol), and K2CO3 (74 mg, 0.54 mmol) were diluted with DMF (0.3 mL) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([I:19])C(=O)C1>C(Cl)(Cl)Cl>[I:19][C:5]1[C:4]2[C:8](=[CH:9][N:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cncc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: COc1cncc2[nH]cc(I)c12
Reaction time: 18 h
Yield: 91.4 %

Procedure:
4-Methoxy-6-azaindole (662 mg, 4.47 mmol) was dissolved in CHCl3 (20 mL), NIS (1.06 g, 4.69 mmol) was added and the reaction mixture was stirred for 18 h. The precipitate was collected by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 10% aq sodium thiosulfate (50 mL), sat aq NaHCO3 (50 mL) and water (50 mL), dried (MgSO4), concentrated in vacuo and combined with the precipitate to give the title compound as a red solid (1.12 g, 91%). LCMS (ES+): 274.9 [MH]+. HPLC: Rf 3.98 min, 96% purity.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=[O:19])(=O)[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:22][N:21]=[C:1]([CH3:2])[C:4]=2[C:5](=[O:19])[CH2:6]1
Reactant: NN
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Solvent: CCO
Solvent: O
Product: COc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 782 %

Procedure:
A solution of 2-acetyl-5-(2-methoxyphenyl)cyclohexane-1,3-dione (0.10 g) and hydrazine hydrate (0.21 g) in ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.77 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:3]([C:1]#[N:2])([CH3:14])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
In a 100 mL 2-neck round-bottomed flask, tert-butyl 3-cyanoazetidine-1-carboxylate (1.5 g, 8.2 mmol) was dissolved in THF (30 mL). The colorless solution was cooled to −76° C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 9.0 mL, 9.0 mmol) was added dropwise over 25 min. The yellow solution was stirred at −76° C. for 30 min then iodomethane (0.78 mL, 12.5 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 30 min and then warmed to room temperature over 1 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ˜100 ml EtOAc (2×). The combined organic layers were washed with ˜10 mL water and ˜10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-30% EtOAc). All fractions containing product were combined and concentrated to afford 1.44 g (89%) of 3-cyano-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[S:12][CH3:13].Br.O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[S:12][CH3:13]
Reactant: COc1ccc(C(=O)O)cc1SC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1cc(C(=O)O)ccc1O

Procedure:
A suspension of 7c (0.5 g; 2.5 mmol) in glacial acetic acid/48% strength hydrobromic acid (1+1, 7 ml) was stirred under reflux for 6 h. The reaction mixture was cooled, added to H2O (20 ml) and adjusted to pH 2 using 10% strength Na2CO3 solution. The aqueous solution was extracted with diethyl ether (4×20 ml). The combined organic extract was washed with saturated NaCl solution (2×), dried over Na2SO4 and concentrated. On standing at room temperature, the off-brown oily residue (7d) crystallized out. The crystals were triturated with H2O, filtered off and dried.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N+:12]([O-])[CH:11]=[CH:10]2>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([Cl:3])=[N:12][CH:11]=[CH:10]2
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1nccc2cc(Br)ccc12
Yield: 47 %

Procedure:
Phosphorus oxychloride (0.60 mL, 6.44 mmol) was added in one portion to a stirred solution of 6-bromoisoquinoline N-oxide (409 mg, 1.83 mmol) in CH2Cl2 (10 mL) and the mixture was heated at reflux for 6 hours. Excess solvents were evaporated in vacuo, the residue suspended in water (10 mL) and basified with 0.880 ammonia. This mixture was extracted with CH2Cl2 (2×25 mL) and the combined organics were dried over MgSO4 and evaporated in vacuo to leave the crude product. Purification by column chromatography upon silica gel using hexanes-EtOAc (90:10) as eluant gave 6-bromo-1-chloroisoquinoline (215 mg, 0.86 mmol) as a cream-coloured solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[N:13]=1)(=O)C>CO>[OH:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]#[N:20])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: CC(=O)OCc1nc(C#N)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(C#N)nc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.4 %

Procedure:
Potassium carbonate (65 mg) was added to a solution of (6-cyano-3-methyl-2-pyridinyl)methyl acetate (2.89 g) in methanol (20 ml) and the mixture stirred under argon at ambient temperature for 2.5 hours. It was concentrated in vacuo to ca. ½ volume and water (40 ml) added. The mixture was neutralized with 5% acetic acid (1.2 ml) and extracted with dichloromethane (40 ml then 2×20 ml). The combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by Biotage chromatography eluting with 2:1 hexane:ethyl acetate to afford the title compound (1.45 g, 64%) as a pale buff solid. LC/MS [MH+]=149, RT=1.46 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Product: Cc1ccc(-c2ccccc2Oc2ccccc2[N+](=O)[O-])cc1

Procedure:
Prepared from 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) and 1-fluoro-2-nitrobenzene by the procedure described in Example 27, Step A. 1H NMR (200 MHz,CDCl3): δ 2.30 (s,3H), 6.74 (dd;2,8 Hz;1H), 6.9-7.5 (m,10H), 7.84 (dd;2,8 Hz;1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:37][CH2:36][CH2:35][NH:34][CH2:33][C:30]4[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: NCCNCc1ccncc1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCNCc3ccncc3)nc21
Yield: 25 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1317 g (0.871 mmol) of N-(4-picolyl)ethylenediamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.0307 g (25%) of the title compound: HPLC=87% pure.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16]Br)=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:20]([CH3:29])[CH:19]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:22]([CH3:24])[CH:23]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CCNCC
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(CBr)c(C)c23)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(C)c(OC(C)=O)c(C)c3)c2c1C
Yield: 94.9 %

Procedure:
Acetic acid 4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (1.21 g, 2.27 mmol) was treated with diethylamine (0.71 mL, 6.82 mmol), potassium carbonate (0.94 g, 6.82 mmol), and N,N-dimethylformamide (12.1 mL). After 1 h at room temperature the reaction mixture was poured in water (250 mL), filtered, and rinsed well with water. Air drying gave the title compound as a yellow solid (1.13 g, 94.5%): NMR (DMSO-d6): δ8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47 (d, 2 H), 7.13 (s, 2H), 3.73 (s, 2H), 2.58-2.52 (q, 4H), 2.40 (s, 3H), 2.16 (s, 6H), 1.61 (s, 3H), 1.02 (t, 6H); MS(EI): [M+], 1 bromine isotope pattern, 523/525; Anal. Calc. for C28H30BrNO2S: C, 64.12; H, 5.77; N, 2.67. Found: C, 63.30, H, 5.67; N, 2.55.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([N:29]=[C:30]=[S:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(N=C=S)cc1OC
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.0 mmol), 3,4-dimethoxyphenyl isothiocyanate (0.787 g, 4.0 mmol), and ethyl acetate (25 mL) was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The reaction mixture was diluted with ethyl acetate (˜100 mL), heated to 80° C. briefly, then allowed to stand 5 days at room temperature. The precipitate was filtered off to afford the product (0.552 g); m.p. 170-171° C.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[NH:7]1.O.[OH-].[Na+].Cl>CO>[CH2:5]1[CH:6]2[N:7]([C:8](=[O:11])[CH2:9][CH2:10]2)[C:3](=[O:12])[CH2:4]1
Reactant: COC(=O)CCC1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CCC2CCC(=O)N12

Procedure:
A solution of 136 g of gamma-nitropimelic acid dimethyl ester in 500 ml of methanol is hydrogenated at approximately 3780 psi using 15 g of Raney Nickel as catalyst. The resulting slurry is filtered to remove the catalyst and the filtrate is concentrated at reduced pressure to yield crude 5-oxo-2-pyrrolidinepropanoic acid methyl ester. The 5-oxo-2-pyrrolidinepropanoic acid methyl ester is dissolved in 100 ml of methanol and 100 ml of water and is treated with 94 g of 50% sodium hydroxide solution. The reaction mixture is stirred and is heated to 98° C. with distillation of methanol. The solution is cooled, neutralized with 151 ml of concentrated hydrochloric acid and concentrated at reduced pressure. The residue containing 5-oxo-2-pyrrolidinepropanoic acid is heated at 98°-100° C. for 24 hours with 200 ml of acetic anhydride. The sodium chloride is removed by filtration after the acetic anhydride reaction. The filtrate is then concentrated at reduced pressure and 200 ml of toluene is added and concentration is repeated. The dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione crystallizes and is isolated by filtration. The product is best purified by sublimation at 100° C. and 0.1 mm Hg or by recrystallization from ethanol to give melting point of 179°-182° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:24])[CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[OH:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:25])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:23]2
Reactant: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccc(O)cc2CN1C1CCNCC1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)-6-hydroxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 60 mg (81%) of the desired material. LC/MS: tR=0.75 min, 248.22 (MH)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[Li]CCCC.CCCCCC.COB(OC)OC.FC(F)(F)S(O[C:31]1[C:40]2[C:35](=[CH:36][C:37]([CH3:41])=[CH:38][CH:39]=2)[O:34][C:33](=[O:42])[CH:32]=1)(=O)=O>CCOCC.C1COCC1.CCOC(C)=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.O>[O:4]1[CH:5]=[CH:6][C:2]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([CH3:41])=[CH:38][CH:39]=3)[O:34][C:33](=[O:42])[CH:32]=2)=[CH:3]1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc2c1
Reactant: Brc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromofuran (1.9 g, 12.7 mmol) in dry Et2O (30 mL) at -70° C. was added BuLi in hexane (1.9M, 6.7 mL, 12.7 mmol) and the resulting mixture was stirred for 20 min. Trimethylborate (Aldrich) (1.4 mL, 12.7 mmol) was added dropwise and the mixture stirred for 20 min. A solution of the triflate from Step 4 in THF: H2O (24 mL, 6 mL) containing (Ph3P)4Pd (1.1 g, 0.97 mmol) was added and the reaction was heated to reflux for 16 h. The reaction mixture was cooled to r.t. and EtOAc was added and the organic phase washed with H2O (3×), brine, dried over MgSO4 and evaporated to give a white solid. A swish in EtOAc gave, after filtration, 1.8 g (82%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9]C)=O)[S:5][CH:6]=1.O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:7]([NH:12][NH2:13])=[O:9])[S:5][CH:6]=1
Reactant: COC(=O)c1nc(C)cs1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1csc(C(=O)NN)n1
Reaction time: 1.5 h

Procedure:
To a solution of methyl 4-methyl-2-thiazole carboxylate (step a, 2.1 g) in methanol (20 ml) was added hydrazine hydrate (3.2 ml) dropwise over 30 mins. The reaction mixture was stirred for 1.5 hours and the precipitate filtered off to yield the title compound as a white solid (1.6 g). 1H NMR (250 MHz, DMSO) δ 2.64 (3H, s), 4.82 (2H, bs), 7.79 (1H, s), 10.25 (1H, bs).