Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:9][C:7]=3[CH:8]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
The product from Example 1B (2.03 kg, 7.71 mol) in acetonitrile (31.8 kg) was treated in succession with triethylamine (1.86 kg, 18.34 mol), 4-(dimethylamino)pyridine 0.10 kg, 0.87 mol), and p-toluenesulfonyl chloride (3.50 kg, 17.99 mol). After stirring at room temperature for about 5 hours, the reaction mixture was distilled to a minimum volume and treated with isopropyl alcohol (24.1 kg). The suspension was heated at about 30° C. for 1 hour, then cooled to about 5° C., filtered, and the filter cake was washed with isopropyl alcohol (5.20 kg). The solid was dried at 50° C. to provide 2.59 kg (80% yield) of the title compound. MS-DCI (M+NH4)+ m/z at 435; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.15 (t, 2H), 4.38 (t, 2H), 6.50 (s, 1H) 7.18-7.24 (m, 2H), 7.37-7.46 (m, 2H), 7.67-7.74 (m, 7H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.9, 67.2, 104.4, 110.3, 111.2, 118.7, 119.2, 123.0,127.5, 127.6, 129.0, 129.4, 132.2, 132.4, 133.9, 144.4, 145.7, 154.1, 154.5.
Reaction SMILES: [I:1][CH3:2].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:22])[O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:7][CH:6]=1>CCOC(C)=O>[I-:1].[CH2:30]([O:29][C:27]([C:26]1[CH:25]=[C:24]([NH:23][CH:11]([C:8]2[CH:9]=[N:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:12]([O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N+:16]([CH3:2])([CH2:17][CH2:18]3)[CH2:15]2)=[O:22])[CH:34]=[CH:33][CH:32]=1)=[O:28])[CH3:31]
Reactant: CI
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(C)CCC2CC3)c2ccc(OC)nc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Iodomethane (7.1 μl, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-methyl-1-azoniabicyclo[2.2.2]octane iodide (24.3 mg, 36.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20].Cl>C(O)C.CC(C)=O>[ClH:17].[CH3:18][N:19]([CH2:15][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14])[CH3:20]
Reactant: CNC
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: C=O
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(=O)C(CN(C)C)C2
Reaction time: 0.21 h
Yield: 53.8 %

Procedure:
5,6-Dimethoxy-1-indanone (5.0 g), paraformaldehyde (1.6 g) and dimethylamine hydrochloride (2.7 g) are suspended in 15 ml of absolute ethanol, treated with 0.43 ml of concentrated hydrochloric acid and the mixture refluxed for 7 hours. The resulting suspension is cooled, diluted with 100 ml of acetone, stirred for 10 to 15 minutes and the precipitate filtered off to yield 4.0 g of the title compound, melting point 178°-180° C.
Reaction SMILES: O1CCOCC1.O.C([O:14][C@H:15]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH2:18][NH:17][CH2:16]1)(=O)C(C)(C)C.O.[OH-].[Li+]>C(Cl)(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C@H:15]([OH:14])[CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)O[C@@H]1CNCC=C1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: O[C@@H]1CNCC=C1c1ccc(F)cc1
Yield: 46 %

Procedure:
To a 1,4-dioxane (11 mL)-water (6.5 mL) solution of the crude product of (S)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl pivalate synthesized in Reference Synthesis Example 137, lithium hydroxide monohydrate (1.54 g, 36.7 mmol) was added and the resultant mixture was stirred at 115° C. for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=32/1→13/7) to obtain the title compound (383 mg, two step yield 46%).
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]23[O:22][CH2:21][C:18]([CH2:23][CH2:24][CH3:25])([CH2:19][O:20]2)[CH2:17][O:16]3)[CH2:11][CH2:10]1.CCOCC>CCCCCC.O1CCCC1>[C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]23[O:16][CH2:17][C:18]([CH2:23][CH2:24][CH3:25])([CH2:19][O:20]2)[CH2:21][O:22]3)[CH2:13][CH2:14]1)#[CH:7]
Reactant: CCCC12COC(C3CCC(C=C(Br)Br)CC3)(OC1)OC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C#CC1CCC(C23OCC(CCC)(CO2)CO3)CC1

Procedure:
n-Butyllithium (1.6 ml of a 1.1M solution in hexane) was added at -70° C. to a solution of 1-[4-(2,2-dibromovinyl)cyclohexyl]-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane (0.25 g) in dry tetrahydrofuran (5 ml) under a stream of nitrogen. After warming to room temperature over 2 hours ether (~25 ml) was added. The ethereal solution was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography on alumina eluting with 3:7 dichloromethane:hexane saturated with ammonia. 1-(4-Ethynylcyclohexyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless oil (0.13 g).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=2)/[C:33]1=[O:58])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:58])[C:34]3([CH:42]([C:43]4[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=4)[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a toluene solution (50 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (18 mmol) was added E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-ylmethylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 6 mmol). Then the reaction mixture were heated at 130° C. for 2 h. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (170 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:49][C:18]2[N:19]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][C:35]=3[F:48])[C:20](=[O:32])[N:21]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:49][C:18]2[N:19]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][C:35]=3[F:48])[C:20](=[O:32])[N:21]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CCN3CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CCN3CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.63 g), sodium hydrogencarbonate (2.37 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-(2-morpholin-4-ylethyl)-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.22 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (50 mL), N,N′-carbonyldiimidazole (0.42 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless amorphous solid (0.77 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([I:11])[CH:3]=1.C(Cl)(=O)C([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)cc1I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)cc1I
Reaction time: 2 h

Procedure:
A catalytic amount of DMF (approximately 3 drops) was added to a stirred mixture of 4-chloro-2-iodobenzoic acid (24.47 g, 86.63 mmol) and oxalyl chloride (11.34 mL, 129.9 mmol) in DCM (100 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and then concentrated in vacuo to give 4-chloro-2-iodobenzoyl chloride as a yellow oil that solidified upon standing (26.07 g).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:6]2[NH:7][C:8](=[O:26])[CH:9]([NH:18]C(=O)OC(C)(C)C)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][CH:9]1[C:8](=[O:26])[NH:7][C:6]2[C:27]([O:29][CH3:30])=[CH:28][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10]1
Reactant: COc1cc(C#N)cc2c1NC(=O)C(NC(=O)OC(C)(C)C)N=C2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)cc2c1NC(=O)C(N)N=C2c1ccccc1
Reaction time: 8 h

Procedure:
tert-Butyl 7-cyano-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (0.441 g, 1.086 mmol) was dissolved in DCM (4 ml) and TFA (1 ml, 12.98 mmol) and stirred at room temperature for 1.5 h. TFA (1 ml, 12.98 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, then dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted twice more, then the organic layers were dried with Na2SO4 and evaporated. The residue was purified silica gel chromatography (DCM/MeOH). The fractions containing product were evaporated, then the material was triturated with EtOAc to give 3-amino-9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepine-7-carbonitrile (Intermediate B-19). 1H NMR (400 MHz, chloroform-d) δ 7.54-7.45 (m, 3H), 7.42-7.37 (m, 2H), 7.26 (d, J=1.8 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 4.46 (s, 1H), 4.01 (s, 3H), 2.45 (br. s., 2H).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16]COC)[C:9]=2[CH:8]=1)=[O:6])[C:2]#[CH:3]>C([O-])(=O)C.[Hg+]>[OH:16][C:15]1[C:9]2[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:3])=[CH:1][N:4]=3)[S:11][C:10]=2[CH:12]=[CH:13][CH:14]=1
Reactant: C#CCNC(=O)c1cc2c(OCOC)cccc2s1
Agent: CC(=O)[O-]
Agent: [Hg+]
Product: Cc1cnc(-c2cc3c(O)cccc3s2)o1
Yield: 47.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using N-propargyl-4-(methoxymethyloxy)benzo(b)thiophene-2-carboxamide (6.00 g) and mercury acetate (765 mg), the title compound (2.41 g) was obtained as yellow crystals, melting point 188-189° C.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3](C(O)=O)=[N:2]1.C(=O)(O)[O-].[Na+].[I-:17].[Na+].II>ClC(Cl)C.O.ClCCl>[I:17][C:3]1[C:4]2[CH2:8][CH2:7][CH2:6][C:5]=2[NH:1][N:2]=1
Reactant: [I-]
Reactant: O=C(O)c1n[nH]c2c1CCC2
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Ic1n[nH]c2c1CCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.4 %

Procedure:
To a mixture of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid (0.5 g, 3.29 mmol), and sodium bicarbonate (911 mg, 422 μL, 10.8 mmol) in dichloroethane (5 mL) and water (5 mL) were added in one portion sodium iodide (1.28 g, 8.54 mmol) and iodine (1.08 g, 4.27 mmol) and the mixture heated at to 100° C. (oil bath temperature) with vigorous stirring for 24 h. After cooling to 25° C. the mixture was diluted with dichloromethane then washed with 10% Na2S2O3 and saturated NaHCO3. The organic phases were combined, dried (MgSO4) and concentrated to a yellow solid which was dissolved in dichloromethane, cyclohexane added to promote solid formation and allowed to stand. The solid was separated by filtration and dried to give 3-iodo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (580 mg, 2.48 mmol, 75%) as needles. MS (M+H)+=234.9; 1H NMR (CDCl3) δ: 2.71-2.99 (m, 31H), 2.39-2.66 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8].CCN(CC)CC.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)c1sc(CO)cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1sc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reaction time: 14 h

Procedure:
A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q; 3.4 g, 14 mmol) in CH2Cl2 (4.0 mL) was treated with NEt3 (2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), and t-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture was stirred for 14 hours, then diluted with Et9O and washed with H2O. The organic layer was dried (MgSO4) and the solvent evaporated to provide the crude product, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([O:8][P:9]2([O:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-])=O)=[CH:50][CH:49]=3)[N:14]=[P:13]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[P:11]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC=CC=1.[H][H]>[Pt]=O.C1CCCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][P:9]2([O:47][C:48]3[CH:49]=[CH:50][C:51]([NH2:54])=[CH:52][CH:53]=3)[N:14]=[P:13]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=3)([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[N:12]=[P:11]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:10]=2)=[CH:57][CH:58]=1
Reactant: O=[N+]([O-])c1ccc(OP2(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccc([N+](=O)[O-])cc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCCCC1
Solvent: Nc1ccccc1
Product: Nc1ccc(OP2(Oc3ccc(N)cc3)=NP(Oc3ccc(N)cc3)(Oc3ccc(N)cc3)=NP(c3ccccc3)(c3ccccc3)=N2)cc1
Yield: 78 %

Procedure:
2,2,4,4-Tetra(p-nitrophenoxy)-6,6-diphenylcyclotriphosphazene (16.01 g, 0.021 moles), platinum oxide catalyst (0.09 g, 0.0004 moles), and 50 mls aniline are added to a 500 ml Fischer-Porter reaction vessel. The reaction is heated to 50° C. at 50-60 psi of hydrogen pressure for 65 hours. The reaction mixture is then cooled and concentrated to about 25 mls under vacuum. The concentrate is poured into 250 mls cyclohexane, and a brown coagulate forms. The solvent is decanted off and the residue is poured into hot cyclohexane and allowed to cool until stirring becomes difficult. The solvent is decanted off and the residue chilled for about 20 minutes. Recrystallization from o-dichlorobenzene yields a pale brown precipitate, which is boiled in cyclohexane for two hours. A solid is recovered (10.8 g, 78% yield). 31P NMR (THF), δ21.3(triplet), 10.1(doublet).
Reaction SMILES: [C:1](Br)(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].C(=O)=O.CC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:8]=[C:7]1[NH:9][C:2]([C:1]([NH:12][CH:13]([CH:14]([CH3:15])[CH2:16][CH3:17])[C:18]([OH:20])=[O:19])=[O:10])=[CH:3][C:4](=[O:5])[NH:6]1
Reactant: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCC(C)C(NC(=O)c1cc(=O)[nH]c(=O)[nH]1)C(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the orotoyl bromide solution, 9.84 g (75 mmol) of Isoleucine is suspended, with stirring, in 100 mL of dry DCM. To this suspension a catalytic amount (˜0.1 mmol) of DMAP is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of about −15° C. When the target temperature is reached the drop wise addition of orotoyl bromide is commenced. Addition of orotoyl bromide continues, with constant cooling and stirring, until all of the orotoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant agitation. The solution is then filtered to remove any remaining Isoleucine and the volatile DCM is removed from the filtrate under reduced pressure, the remainder is then purified by flash chromatography (ethyl acetate/hexanes; 1/5), yielding 2-(2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamido)-3-methylpentanoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1)#[CH:2].C([Li])CCC.CCCCCC.[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29]>CCOCC>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH:12]=[CH:11][C:10]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a cold solution (-78° C.) of 2-ethynyl,5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalene (900 mgs, 4.3 mmols) in ether (20 ml) was added n-butyllithium in hexane (5.6 mmols). The mixture was stirred for 45 mins, and ethylchloroformate (1.3 g, 12 mmols) was added via syringe. Stirring was continued for 45 mins then the mixture was warmed gradually to -10° C. and quenched by adding sodium bicarbonate (NaHCO3) solution (10 ml). Diethyl ether (100 ml) was added, the organic phase washed with water (10 ml), brine (10 ml), and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue over silicagel (5% ethylacetate in hexane) gave the title compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6](=[O:13])[CH2:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:4].Cl[CH:15](OCC)[CH2:16]Cl>O.C(OCC)C>[CH2:3]([O:5][C:6]([C:7]1[CH:16]=[CH:15][O:12][C:8]=1[CH:9]([CH3:10])[CH3:11])=[O:13])[CH3:4]
Reactant: CCOC(Cl)CCl
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccoc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:13]([O:18][CH:19]([O:21][C:22](OC1CC(=O)NC1=O)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]>O.C(#N)C.C(OC)(C)(C)C>[C:13]([O:18][CH:19]([O:21][C:22]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
To a solution of gabapentin (6.8 g, 0.04 mole) in water (40 mL) is added a solution of [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (10 g, 0.036 mol) in acetonitrile (40 mL) over a period of 30 minutes. The reaction is stirred at ambient temperature for 3 hours. The reaction mixture is diluted with methyl tert-butyl ether (200 mL), washed with water (2×100 mL) and brine (50 mL). The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid (12 g, quantitative).