Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](OC)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:13][NH2:14].O>CO>[Cl:1][C:2]1[C:3]([NH:13][NH2:14])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NN
Reactant: COc1ncc(Cl)c(OC)n1
Solvent: CO
Solvent: O
Product: COc1ncc(Cl)c(NN)n1
Reaction time: 8 h

Procedure:
A solution containing 0.35 g (2.0 mmol) of 5-chloro-2,4-dimethoxypyrimidine and 0.35 g (7.0 mmol) of hydrazine hydrate in 2.9 g of methanol was heated at reflux with stirring for 8 hours. The mixture was then cooled causing a precipitate to form. Water was added until the precipitation appeared to be complete and the precipitate was then recovered by vacuum filtration and allowed to air dry overnight to obtain 0.23 g (66 percent of theory) of the title compound as a white solid. The product melted at 172°-173° C. after changing crystalline form from needles to cube-like shapes in a phenomenon that appeared to involve sublimation.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51](O)=[O:52])[CH2:17]2)=[CH:12][CH:11]=1)C>>[CH3:7][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[O:52])[CH2:17]2)=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: CCOc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N4CCNCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 102, piperazine is reacted with 3-[(2S,4R,5R)-4-(4-ethoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) to afford 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-1-piperazin-1-yl-propan-1-one which is subsequently deprotected according to general procedure A to afford the title compound.
Reaction SMILES: [Cl-:1].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Na+].[C:30]1([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CO.C(O)(=O)C>[ClH:1].[ClH:1].[C:36]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:37]=[CH:38][C:39]([CH:40]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:42][CH:43]=1
Reactant: [Cl-]
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)O
Product: C(=C1CCCN=C1c1cccnc1)c1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (128 mg, 0.51 mmol) was suspended in methanol (2 mL) and treated with N,N-diisopropylethylamine (165 mg, 1.27 mmol) in a reaction vessel. This gave a clear solution. A dual solution of 0.6 M acetic acid and 0.3 M sodium acetate in methanol (10 mL) was then added, followed by addition of 4-phenylbenzaldehyde (140 mg, 0.76 mmol). The reaction vessel was then sealed and the reaction heated to 80 ° C. overnight then cooled to room temperature. The reaction mixture was then concentrated under reduced pressure, treated with a saturated solution of NaHCO3(aq), and extracted three times with EtOAc. The EtOAc extracts were washed with brine, then combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 7:7:7:1:0.1 hexane:MtBE:CH2Cl2:MeOH:NH4OH eluant. One sample was recovered and dried under vacuum. This sample was then dissolved into MeOH and treated with two equivalents of 6 N HCl(aq), concentrated under reduced pressure and re-crystallized from isopropanol giving 80 mg (39%) of yellow needles. LC-MS: RT=5.72 min, [M+H]+ =325.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Yield: 84.8 %

Procedure:
2,5-Dimethylphenol (6.99 g, 57.20 mmol) and 4-chloro-3-nitrobenzonitrile (8.00 g, 43.96 mmol) were combined with K2CO3 (30.40 g, 220.00 mmol) in THF (100 mL). The reaction mixture was heated to reflux for 48 hrs and then the solid was filtered through a bed of Celite. After rinsing the residue with copious amounts of EtOAc, the filtrate was washed sequentially with NaHCO3, water, and brine, dried over anhydrous MgSO4, and filtrated. The filtrate was concentrated in vacuo to produce compound 30 as a white powder (10.00 g, 85.0% yield, 99.1% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.65 (d, J=2 Hz, 1H), 8.03 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.28 (d, J. 8 Hz, 1H), 7.09 (d, J=8 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J=9 Hz, 1H), 2.28 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[C:20]1([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][NH:27][CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:31][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: c1ccc(CNCCN2CCNCC2)cc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(N1CCN(CCNCc2ccccc2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 44.5 %

Procedure:
The title compound of Example 2 (0.72 g, 2.45 mmol) was combined with N-(phenylmethyl)-1-piperazineethanamine (0.75 g, 3.40 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic separation, 0.52 g of the white solid title product was obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].Cl[C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:16]([O:18][CH3:19])=[O:17])([O-:5])=[O:4]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.3 g, 12.5 mmol) in DMF (5 mL) was treated with 4-nitro 1H-indazole (1.33 g, 10 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. The mixture was treated with methyl chloroformate (0.9 mL) and stirred at room temperature for 3 hours. The mixture was treated with water and filtered to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 4.1 9 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+:23]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.ClCCl>[N+:1]([CH:4]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:23][C:7](=[O:9])[CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=Cc1ccccc1
Reactant: [NH4+]
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: O=C1CCC([N+](=O)[O-])C(c2ccccc2)N1
Temperature: 5 °C

Procedure:
A solution of methyl 4-nitrobutyrate (23 g) and benzaldehyde (16 ml) in acetic add (39 ml) containing ammonium acetate (12.12 g) was heated at reflux under nitrogen for 2 h. The reaction mixture was cooled to 5° C., whereby a pale-yellow solid crystallised. This was isolated by filtration, then dissolved in dichloromethane, washed cautiously with saturated aqueous sodium bicarbonate solution (2×), then dried (MgSO4) and concentrated to leave a yellow solid. Recrystallisation from ethyl acetate provided 5-nitro-2-oxo-6-phenylpiperidine (12.5 g) as a crystalline, white solid. 1H NMR (CDCl3) d 7.46-7.26 (m), 6.0 (br s), 5.24 (dd, J=1.4, 7.0 Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m).
Reaction SMILES: [NH2:1][CH:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[C:3]1=[N:14][C:15]1[CH:20]=[CH:19][C:18](C#N)=[CH:17][CH:16]=1.CC(OC(/[N:29]=N/C(OC(C)C)=O)=O)C.[CH2:37]([CH2:40]OC)OC>>[CH3:12][N:5]1[C:4](=[O:13])[C:3]2[NH:14][C:15]([C:20]3[CH:19]=[CH:18][C:17]([C:16]#[N:29])=[CH:40][CH:37]=3)=[N:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCCN1C(=O)N(C)C(=O)C(=Nc2ccc(C#N)cc2)C1N
Reactant: COCCOC
Product: CCCn1c(=O)n(C)c(=O)c2[nH]c(-c3ccc(C#N)cc3)nc21

Procedure:
6-Amino-3-methyl-5-(4-cyanophenyl)imino-1-n-propyluracil (5.00 g, 17.4 mmol) is dissolved in 75 ml of glyme and 4.2 ml (21.4 mmol) of diisopropylazodicarboxylate is added. The solution is then brought to reflux. The solution is refluxed 30 minutes and then filtered hot. The filter cake is washed with glyme (3×20 ml) and ether (3×30 ml) and airdried to give 1-methyl-8-(4-cyanophenyl)-3-n-propylxanthine.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][CH2:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.C(N(CC)CC)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[NH:11]1[CH2:12][CH:9]([CH2:8][NH:7][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:10]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CNC1)C1CC1
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (315 mg, 3.0 mmol) was added into a solution of tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (372 mg, 2.0 mmol) and triethylamine (1 mL) in CH2Cl2 (20 mL) at r.t. After 2 h, the reaction mixture was condensed. The residue was dissolved in CH2Cl2 (10 mL) and treated with TFA (10 mL) at r.t for 1 hr. Evaporation of solvents provided the desired product as its TFA salt, which was used in Step A directly.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([OH:50])=O)=[CH:44][C:43]=2[CH3:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH3:52][N:53]1[C:62]2[NH:61][C:60]3[CH:63]=[CH:64][CH:65]=[CH:66][C:59]=3[NH:58][CH2:57][C:56]=2[CH:55]=[N:54]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:58]3[CH2:57][C:56]4[CH:55]=[N:54][N:53]([CH3:52])[C:62]=4[NH:61][C:60]4[CH:63]=[CH:64][CH:65]=[CH:66][C:59]3=4)=[O:50])=[CH:44][C:43]=2[CH3:51])[CH2:36][CH2:37]1)=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: Cc1cc(C(=O)O)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 40 %

Procedure:
PyBroP (224 mg, 0.48 mmol) and DMAP (39 mg, 0.32 mmol) were added to a solution of 4-[3-(4-carboxy-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.3 (120 mg, 0.32 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (70 mg, 0.35 mmol) in dichloromethane (5 ml) and DIEA (0.111 ml, 0.64 mmol). The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to yield the title compound (71 mg, 40%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5]([NH2:7])=[O:6])[CH3:2].[Cl:12]O>C(OCC)(=O)C>[Cl:12][NH:7][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6]
Reactant: OCl
Reactant: CCCCC(CC)CC(N)=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)CC(=O)NCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
2-ethylhexyl carboxamide (35.75 g, 250 mmol) was suspended in 300 ml of ethyl acetate and cooled to 1°. Hypochlorous acid (43.3 g of 30.6% solution, 252 m mol) was added dropwise over 13 minutes with stirring. After 10 minutes, the cooling bath was removed and stirring continued for 1 hour while the mixture warmed to room temperature. The ethyl acetate layer was then separated and dried (MgSO4) and the solvent was removed on the rotary evaporator and, finally, on the vacuum pump to give 44 g (98%) of colorless liquid N-chloro-2-ethylhexyl carboxamide.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.CCOCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1.O>[C:2]1([B:28]([OH:33])[OH:29])[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-Bromopyrene (2.00 g, 7.12 mmol) was dissolved in anhydrous THF (150 ml) and anhydrous ether (150 ml). The light yellow solution was cooled to −78° C. in nitrogen. n-Butyllithium (4.9 ml, 7.83 mmol) was slowly dripped into the solution. At this time, the solution became murky. This mixture was kept at −78° C. for ten minutes, 0° C. for ten minutes, and then −78° C. for thirty minutes. Then, triisopropyl borate (4.93 ml, 21.36 mmol) was slowly dripped into the solution, and the mixture was kept at −78° C. for thirty minutes. Finally, the mixture underwent reaction at room temperature for 1.5 days. Next, water was added into the reaction mixture, and the resulting mixture was stirred vigorously for one hour. The water layer and the organic layer were separated, the water layer was then extracted by ethyl ether (2×25 ml), and the organic layer was water washed (2×50 ml). The combined organic solution was contact with MgSO4 to remove water, then filtered, and concentrated on a rotary evaporator to obtain a pyreneboronic acid solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 183 %

Procedure:
A mixture of 5-methoxyindole (1 g, 6.79 mmol), potassium carbonate (0.5 g), N,N-dimethylformamide (10 mL) and dimethyl carbonate (1.7 mL, 20 mmol) was stirred and heated to reflux (˜130° C.). The progress of the reaction was monitored by HPLC. Within 5 h, the starting indole had been consumed and after the mixture was cooled to ˜3° C., it was treated with ice cold water (30 mL). The formed precipitate was filtered off, then was washed in turn with water (2×30 mL) and hexanes (30 mL). The colorless product was dried under vacuum at 25° C. for 48 h to afford 5-methoxy-1-methylindole (1.067 g, 97.4% yield).
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:23][C:24]=1[CH:25]=[CH:26][C:27]1[S:28]C=[CH:30][CH:31]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH:22]=[CH:23][C:24]=1[CH:25]=[CH:26][C:27]1[S:28][C:1]([C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[C:9]#[N:10])=[CH:30][CH:31]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=C(C#N)C#N)s2)c(OCc2ccccc2)c1
Temperature: 40 °C
Yield: 31.7 %

Procedure:
In 3 ml of N,N-dimethylformamide, 0.13 g (1.01 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 0.4 g (0.95 mmol) of [3-benzyloxy-4-[2-(thiophene-2-yl)vinyl]phenyl]dibutyl amine was dissolved in 1 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 40 minutes and further stirred with heating at 40° C. overnight. After the reaction mixture was poured into 100 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with ethanol to give 157 mg of a black crystal having a mp of 125-130° C. (yield: 31.7%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18](=[O:26])[C@H:19]([CH3:25])[NH:20][C:21](=O)[CH:22]=[CH2:23])[CH3:16].[OH-].[K+]>C(Cl)(Cl)Cl>[CH2:15]([O:17][C:18]1[O:26][C:21]([CH:22]=[CH2:23])=[N:20][C:19]=1[CH3:25])[CH3:16]
Reactant: C=CC(=O)N[C@@H](C)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=Cc1nc(C)c(OCC)o1

Procedure:
To a suspension of 1.0 mole of phosphorus pentoxide in 300 ml. of dry chloroform is added dropwise with stirring a solution of 0.5 mole of N-acryloylalanine ethyl ester. The reaction mixture is heated at gentle reflux for 5 hours and then cooled. To the cooled mixture is added with rapid stirring 750 ml. of 20% aqueous potassium hydroxide. After stirring at room temperature for 1 hour, the chloroform layer is separated and the aqueous layer extracted with 2×200 ml. of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo to yield 5-ethoxy-4-methyl-2-vinyloxazole.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Si:17]([O:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CCCC(O)CC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Yield: 81.6 %

Procedure:
A solution of ethyl 3-hydroxyhexanoate 1 (2.0 g, 12.5 mmol), imidazole (1.09 g, 18.7 mmol), and tert-butyldimethylsilyl chloride (2.26 g, 15.0 mmol) in DMF (25 mL) was stirred at 23° C. After 16 h the reaction was diluted with Et2O and then washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 100% hex followed by 19:1 hex/EtOAc) afforded 2.8 g (82%) of silyl ether 2 (see Scheme 1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(OC(C)C)(=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (Intermediate A) (20 g, 87.0 mmol) in isopropyl acetate (240 mL) was added to a stirred solution of sodium carbonate (11.3 g, 106 mmol) in water (80 mL). After 10 min phenyl chloroformate (12.1 mL, 96 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (160 mL), the layers were separated and the organics were washed with water (2×80 mL), brine (80 mL), dried (MgSO4) and concentrated in vacuo. The resulting yellow solid was suspended in 10% ether/iso-hexane (320 mL) and stirred until a uniform suspension was obtained. The solid was collected by filtration and washed with iso-hexane to yield the subtitle compound phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate as a white powder (27.3 g, 88%); Rt 2.65 min (Method 1); m/z 350 (M+H)+ (ES+); 1H NMR δ:1.29 (9H, s), 2.37 (3H, s), 6.35 (1H, s), 7.10-7.23 (3H, overlapping m), 7.33-7.46 (6H, overlapping m), 9.99 (1H, s).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[C:3]=1[CH3:12].O.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[S:6][C:2]([C:14]#[N:15])=[C:3]([CH3:12])[C:4]=2[CH:10]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1c(C#N)sc2ccc(Cl)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-5-chloro-3-methylbenzo(b)thiophene (1.00 g, 3.82 mmol), zinc cyanide (247 mg, 2.10 mmol), and Pd(PPh3)4 (440 mg, 0.38 mmol) in DMF (15 mL) was heated to 80° C. for 16 hours, added to water (50 mL), and extracted with 30% ethyl acetate/hexanes (3×100 mL). The combined extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: BrC1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12]1(C)C=CC=CC=1.[Si]([CH:23]=[N+:24]=[N-])(C)(C)C>CO>[NH2:24][C:23]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Solvent: CO
Product: COC(=O)c1cc(N)cc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-bromo-5-fluorobenzoic acid (6.12 g, 33.1 mmol) was dissolved in MeOH (10 mL) and cooled in ice-water bath and toluene (50 mL) and then TMS-diazomethane (19.84 mL, 39.7 mmol) was added dropwise. Reaction mixture was allowed to return to room temperature for 1 h and concentrated in vacuo and the residue dissolved in DCM/Ether and filtered through a short plug of silica and the filtrate evaporated in vacuo to afford the desired product which was then dissolved in MeOH (60 mL) and Pd/C 10 wt % 3.3 g was added and the mixture evacuated and stirred under 1 atm of hydrogen overnight and LCMS indicated desired product next morning. The reaction mixture was filtered through Celite and the filtrate was concnetrated in vacuo and the residue azeotroped with toluene twice and taken to the next step as such (99%). LCMS (m/z): 211.1 (MH+), 0.55 min.