Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:39]([C:41]1[N:42]=[C:43]([C:54]([O-])=[O:55])[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=1)#[N:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[C:12]([NH:13][C:54]([C:43]3[N:44]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:45]=[C:41]([C:39]#[N:40])[N:42]=3)=[O:55])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1cccnc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1cccnc1C1=CCCCC1
Yield: 69.1 %

Procedure:
A solution of 365 mg (2.10 mmol) of 2-cyclohex-1-enyl-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 1.46 g (3.14 mmol) of PyBroP, 704 mg (2.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 1.09 mL (6.28 mmol) of DIEA at RT for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 615 mg (69%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.86 (br s, 1H), 8.69 (dd, 1H, J=8.0, 1.6 Hz), 8.37-8.34 (m, 1H), 7.78 (s, 1H), 7.22-7.17 (m, 1H), 6.05 (sept, 1H, J=1.6 Hz), 5.93 (s, 2H), 3.68-3.63 (m, 2H), 2.45-2.39 (m, 2H), 2.37-2.30 (m, 2H), 1.91-1.77 (m, 4H), 1.00-0.95 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1([CH3:23])[CH:14]=[C:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH:10]1[C:18](=C)[CH2:19]CO.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:18](=[CH2:19])[CH:10]1[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([CH3:15])=[CH:14][C:9]1([CH3:23])[CH3:8])(=[O:7])[CH3:6]
Reactant: C=C(CCO)C1C(C)(C)C=C(C)CC1(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(CCOC(C)=O)C1C(C)(C)C=C(C)CC1(C)C

Procedure:
A solution of acetic anhydride (0.23 mL) in dichloromethane (2 mL) was reacted with a mixture of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol (0.56g, 0.0025 mol), triethylamine (0.41 mL), 4-dimethylaminopyridine (0.031g) and dichloromethane at 25° C. Work-up, chromatography and distillation gave 0.60g of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol acetate bp (kugelrohr bath 110°-120° C.), 0.5 mm (GLC purity: 88%). 1H-NMR (60 MHz, CDCl3) δ0.93 (6H, s), 1.00 and 1.03 (6H, 2s), 1.60 (3H, s), 2.00 (3H, s), 0.9-2.6 (5H, m), 4.20 (lH, t, J =7 Hz), 4.86-5.07 (3H, m); IR (film) vmax 2960, 1735, 1635, 1440, 1370, 1350 cm-1 ; MS (m/e) 264, 249, 221, 204, 189, 108, 96.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: FC(F)(F)c1ccc(S)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (2.2 g), 2-mercapto-5-trifluoromethylpyridine (1.9 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 4.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (3.2 g, yield: 100%). mp: 165°-170° C. (dec.) IR (Nujol): 3175, 1695, 1640, 1600, 1565, 1330 cm-1
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.C=O.[C:37]([BH3-])#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:13][C:14]([NH:16][CH2:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[N:24]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH3:37])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NC[C@@H]2CCCC[C@H]2NCCCc2ccc(F)cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CCCc1ccc(F)cc1)[C@@H]1CCCC[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea (98 mg), the product of Step g of Example 31, in 4 mL of CH2Cl2 was added a solution of formaldehyde in THF (excess), and the mixture was stirred for 15 minutes. Then excess amount of sodium cyanoborohydride was added, and the mixture was continued to stir for 5 hrs at room temperature. After quenching the reaction with saturated Na2CO3, it was extracted with CH2Cl2. The extract was washed with water, dried over MgSO4 and evaporated to give an oily residue. It was purified by column chromatography (silica gel, 0.6:5.494 cNH4OH/CH3OH/CH2Cl2) to give pure N-[3-(1-methyl-tetrazol-5-yl)phenyl]-N′-[(1S,2R)-2-[N-methyl-3-(4-fluorophenyl)propylamino]-cyclohexylmethyl]urea.
Reaction SMILES: [C:1]([CH:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)([O:3]CC)=[O:2].ClC1C=CC=C([C:38](OO)=[O:39])C=1.Cl[CH2:43]Cl>>[C:1]([CH:6]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]4=[O:29])=[CH:15][C:14]=3[F:30])[CH2:11][CH2:12]2)[CH2:43]1)([O:3][O:39][CH3:38])=[O:2]
Reactant: ClCCl
Reactant: CCOC(=O)C=C1CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COOC(=O)C1CC12CCN(c1ccc(N3C[C@H](CNC(C)=O)OC3=O)cc1F)CC2
Yield: 37 %

Procedure:
The title compound was prepared by reacting (S)-N-[3-{4-[4-carboethoxymethylidenepiperidin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-ylmethyl]-acetamide (0.3 mmol) and m-chloroperbenzoic acid (0.31 mmol) in dichloromethane at a temperature 0° C. for 14 hours in 37% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:24])[C:12]3[CH:19]=[C:18]([C:20]#[C:21][CH2:22][OH:23])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.C(O)C>C(O)C.[Pd]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:24])[C:12]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][OH:23])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Yield: 40 %

Procedure:
A solution of N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 24) (0.520 g) in 1/1 CH2Cl2/ethanol (160 mL) is hydrogenated over 10% Pd/C (0.156 g) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale yellow solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid (this material contains a small amount of partially reduced product). This material is dissolved in ethanol (100 mL) and hydrogenated over 10% Pd/C (0.156 g) at 35 psi for 1 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting off-white solid is recrystallized from ethanol to yield 0.211 g (40%) of the desired product as an off-white solid.
Reaction SMILES: [N+](C1C=CC(CBr)=CC=1)([O-])=O.S([O-])([O-])=O.[Na+].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:19].[N+:24]([C:27]1[CH:37]=[CH:36][C:30]([CH2:31][S:32]([O-])(=[O:34])=[O:33])=[CH:29][CH:28]=1)([O-:26])=[O:25].[Na+]>O>[N+:24]([C:27]1[CH:37]=[CH:36][C:30]([CH2:31][S:32]([Cl:19])(=[O:34])=[O:33])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Agent: O=S([O-])[O-]
Agent: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 4-nitrobenzyl bromide (100.0 g, 0.46 mol), sodium sulphite (84.8 g, 0.67 mol) and water (316 ml) was heated at 90° C. for 5 h. The solution was cooled and the resultant solid filtered and washed with diethyl ether. The product was dried under vacuum at 60° C. (95 g, 86%). Phosphorus pentachloride (78 g, 0.375 mol) was added to sodium 4-nitrobenzylsulphonate (60 g, 0.25 mol) and the mixture heated at 90° C. for 2 h. The mixture was cooled and volatile material removed under vacuum. The residue was dissolved in dichloromethane (500 ml) and water (150 ml). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give 4-nitrobenzyl sulphonyl chloride (48.9 g, 83%) which was pure by 1H NMR. Methylamine gas was bubbled through a solution of 4-nitrobenzyl sulphonyl chloride (37.9 g, 0.16 mol), in dichloromethane (325 ml), until uptake had ceased (0.5 h). The resulting solid was filtered, washed with H2O and dried under vacuum to give the title-sulphonamide (32.5 g, 88%), δ (250 MHz, D6 -DMSO) 2.61 (3H, s, Me), 4.55 (2H, s, CH2), 7.06 (1H, s, NH), 7.66 (2H, d, J=8.7Hz, Ar--H), 8.25 (2H, d, J=8.7Hz, Ar--H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.N.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[NH2:23][C:16]1/[C:21](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:20]=[CH:19][C:18](=[NH:22])[CH:17]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1cccc(N)c1
Agent: N
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1c(/N=C2\C=CC(=N)C=C2N)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Yield: 29.3 %

Procedure:
20 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one and 20 mmol of meta-phenylene diamine was dissolved in 30 g of an ice/water mixture and the pH was adjusted to 10 using 20 ml of 20% aqueous ammonia. While stirring, a solution of 24 mmol of ammonium persulfate in 10 ml of water was added dropwise over 30 minutes. The mixture was stirred at 0° C. for 1 h 30 min and the solid formed was separated by filtration and washed with water and acetone and dried in a desiccator under vacuum for 12 hours, which resulted in 1.8 g of expected product, or a yield of 30%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]([CH3:23])[C:14](=[O:22])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][CH2:8][S:7][C:6]=2[CH:24]=1.I.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](SC)=[NH:32]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:23][N:13]([CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:24]=[C:2]([NH:1][C:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)=[NH:32])[CH:3]=[CH:4][C:5]1=2)[C:14](=[O:22])[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1CCSc2cc(N)ccc21)C(=O)Oc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a stirred solution of phenyl 2-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(methyl)carbamate (80 mg, 0.233 mmol) in ethanol (5 mL) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (133 mg, 0.466 mmol). The mixture was then stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and then extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in ethyl acetate, yielding the desired product (72 mg, 68%). 1H NMR (DMSO-d6) δ 7.74-7.69 (m, 1H), 7.58-7.56 (m, 1H), 7.42-7.34 (m, 2H), 7.25-7.17 (m, 1H), 7.14-7.05 (m, 3H), 6.83-6.80 (m, 1H), 6.53-6.44 (m, 2H), 6.36 (brs, 2H), 3.63-3.55 (m, 4H), 3.49-3.45 (m, 2H), 3.11, 2.98 (2s, 3H), 3.06-3.01 (m, 2H); MS-EI: (m/z, %) 452 (M+, 97), 288 (100).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(OCC)(=O)C>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Br)cccc1Br
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: BrCCOc1c(Br)cccc1Br
Yield: 55.9 %

Procedure:
1,2-Dibromoethane (5.0 ml, 58 mmol) was added to a solution of sodium hydroxide (2.5 g, 63 mmol) and 2,6-dibromophenol (14.5 g, 57.6 mmol) in 45 ml of water. The mixture was stirred under reflux for 20 hours and then extracted with ether. The combined organic layers was dried over Na2SO4, filtered and concentrated to give colorless oil. Silica gel chromatography using a gradient of ethyl acetate in hexanes to afforded 1,3-dibromo-2-(2-bromo-ethoxy)-benzene (11.55 g, 57% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:18])=[C:15]([CH2:16][OH:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:17][CH2:16][C:15]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:2]=3[Cl:1])[C:12]=2[O:13][C:14]=1[CH3:18])(=[O:26])[CH3:25]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 83.5 %

Procedure:
A mixture of 7-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzo[b]furan (123 mg), acetic anhydride (43 mg) and pyridine (48 mg) in dichloromethane (5 ml) was refluxed for 2 hours. The reaction mixture was washed with 1N-hydrochloric acid, brine and aqueous saturated sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-acetoxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (115 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH2:12]([Si](C)(C)C)[C:13]#[CH:14].N1CCCCC1.CN(C=O)C>CCOC(C)=O.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>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]2[CH:12]=[C:13]([CH3:14])[O:8][C:7]=12
Reactant: OCc1cc(I)c(O)c(Cl)n1
Reactant: C#CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1cc2cc(CO)nc(Cl)c2o1
Temperature: 45 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (4.6 g, 16 mmol), propargyl trimethylsilane (2 g, 17.8 mmol), bis(triphenylphosphine)palladium dichloride (156 mg, 0.21 mmol), cuprous iodide (122 mg, 0.64 mmol), and piperidine (3.52 mL, 26.6 mmol) are added to 25 mL DMF in a dry flask under N2. The mixture is warmed to 45° C. for 7 h, is stirred overnight at rt, and is diluted with 150 mL EtOAc. The mixture is washed with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to an amber oil. The crude material is chromatographed over 40 g silica gel (230-400 mesh) eluting with 35% EtOAc/hexane to afford (7-chloro-2-methylfuro[2,3-c]pyridin-5-yl)methanol (C24) (44% yield). MS (CI) for C9H8ClNO2, m/z: 198 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:9].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>[Pd].C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:10]([CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH3:9])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1
Reactant: CC(c1ccccc1Br)N(c1cccnc1)c1cccnc1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)N3CCCC3)cc2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(c1ccccc1-c1ccc(S(=O)(=O)N2CCCC2)cc1)N(c1cccnc1)c1cccnc1
Temperature: 160 °C

Procedure:
In 0.5-2 mL microwave vial with stirbar was placed crude product N-(1-(2-bromophenyl)ethyl)-N-(pyridin-3-yl)pyridin-3-amine (3-2) (0.030 g, 0.08 mmol), 1-[4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]pyrrolidine (0.040 g, 0.12 mmol), Pd (dppf) Cl2 dichloromethane adduct (0.013 g, 0.0 16 mmol), Cs2CO3 (1 M aq. solution, 0.5 mL, 0.5 mmol) and THF (0.5 mL). The vial was sealed and heated in microwave to 160° C. for 10 min. The organic phase was filtered through packed celite, concentrated and dried. Reverse phase chromatography yielded a TFA salt Analytical LCMS: single peak (214 nm), 2.426 min. 1H NMR (300 MH, CDCl3): δ 9.00 (s, 1 H), 8.65 (s, 1 H), 8.35 (d, J=5.1 Hz, 1 H), 8.17-8.25 (m, 2 H), 7.75-7.82 (m, 4 H), 7.56-7.7.67 (m, 4 H), 7.45-7.47 (m, 2 H), 7.28-7.31 (m, 1 H), 6.20 (q, J=6-6 Hz, 1 H), 3.19-3.24 (m, 4 H), 2.07 (d, J=6.6 Hz, 3 H), 1.76-1.80 (m, 4 H). m/e (m+1): 485.1.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[C:11]([Si](C)(C)C)=[C:10]([OH:16])[C:9]([CH3:17])=[C:8]([CH3:18])[C:6]=1[OH:7].CO.[NH3:23].C(O[CH2:28][CH3:29])(=O)C>>[CH3:3][C:4]1[NH:23][C:28]([CH3:29])=[C:11]2[C:5]=1[C:6](=[O:7])[C:8]([CH3:18])=[C:9]([CH3:17])[C:10]2=[O:16]
Reactant: N
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c(O)c([Si](C)(C)C)c(C#C[Si](C)(C)C)c1O
Solvent: CO
Product: CC1=C(C)C(=O)c2c(C)[nH]c(C)c2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
General procedure A was followed using 2 (39.6 mg, 0.12 mmol), 2 mL of methanol saturated with ammonia (large excess). The mixture was stirred at room temperature for 12 h. Column chromatography (20% ethyl acetate in petroleum ether) gave yellow product in 88% yield (21.4 mg). Melting point: Turns black after 290° C. and becomes totally black until 360° C. without melting.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=1.O=P(Cl)(Cl)[Cl:27].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:27][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Temperature: 120 °C
Yield: 58 %

Procedure:
4-(4-(2-(Methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl)pyrimidin-2-ylamino)benzonitrile (34) (700 mg, 2.081 mmol) was dissolved in POCl3 (1940 μl, 20.81 mmol), then the reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to rt, then was slowly poured into an ice-cooled saturated Na2CO3 solution while stifling vigorously. The reaction mixture was then adjusted to pH 7 with additional Na2CO3 solution. DCM was added to the mixture and the aqueous layer was extracted twice with DCM. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo to obtain the desired product as a bright yellow solid (428 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3 H) 7.39 (d, J=5.05 Hz, 1 H) 7.74 (m, 2 H) 8.00 (m, J=9.09 Hz, 2 H) 8.69-8.80 (m, 1 H) 8.93 (s, 1 H) 10.42 (s, 1 H). MS (ES+): m/z=355.3 (100) [MH+]. HPLC: tR=1.57 minutes over 3 minutes. Purity: 91% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24](O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To 40 ml of tetrahydrofuran were dissolved 1.8 g of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate, 1.74 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.92 g of triphenylphosphine. At room temperature, 1.94 g of diethyl azodicarboxylate was added to the above solution, and the resulting mixture was stirred for 18 hours. After distilling off the solvent, the residue thus obtained was dissolved in ethyl acetate, and the solution was washed with water, and then dried. Thereafter, the solvent was distilled-off, and the resulting residue was purified by silica gel column chromatography using a toluene/chloroform mixture as an eluant, thereby obtaining 2.53 g of the title compound as a viscous yellow oil.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11].C(N(CC)CC)C.O>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.CN(C=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:8])[CH2:11][CH2:10][C:12](=[O:13])[CH3:14]
Reactant: C=CC(C)=O
Reactant: Cc1ccccc1C=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCC(=O)c1ccccc1C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
25 g (208 mmol) of o-tolualdehyde, 14.58 g (208 mmol) of methyl vinyl ketone, 21.05 g (208 mmol) of triethylamine, 5.4 g (21.4 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide were dissolved in this order in 100 ml of DMF and stirred at 80° C. for 12 hours. The reaction mixture was subsequently admixed with 400 ml of water and extracted twice with methylene chloride. The combined methylene chloride phases were washed with 10% strength sulfuric acid and saturated sodium hydrogencarbonate solution and dried over sodium sulfate. After taking off the solvent on a rotary evaporator, the product was purified by fractional distillation.