Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[O:17][C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[O:17][C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 120 °C
Yield: 65.9 %

Procedure:
In 90 ml of dimethylformamide were dissolved 4.04 g (10.9 mmol) of Compound u and 7.1 g (109.2 mmol) of sodium azide and the solution was heated at 120° C. for 1.5 hours. The reaction mixture was allowed to stand for cooling and, then, the insolubles were filtered off. The filtrate was concentrated under reduced pressure. The residue was diluted with 120 ml of ethyl acetate and washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (chloroform-methanol=30:1) to give 2.28 g (65.9%) of 1-[5-(4-azidopiperidinomethyl)-2-furancarbonyl]piperidine (Compound v) as light yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C:12]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:15]2[O:16][C:17]([CH2:21][OH:22])([CH3:20])[CH2:18][CH2:19][C:14]=2[C:13]=1[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[OH:11][C:12]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:15]2[O:16][C:17]([CH:21]=[O:22])([CH3:20])[CH2:18][CH2:19][C:14]=2[C:13]=1[CH3:27]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C=O)O2
Temperature: -78 °C
Reaction time: 0.2 h
Yield: 71.1 %

Procedure:
A solution prepared by the sequential addition of oxalyl chloride (2.9 g, 23 mmol) and dimethyl sulfoxide (3.7 g, 47 mmol) to methylene chloride which had been cooled to -78° C. was allowed to stir for 12 minutes. A solution of 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanol (4.0 g, 18 mmol) in 50 mL methylene chloride was then added dropwise to the reaction mixture. After stirring for 40 min., triethylamine (7.3 g, 72.6 mmol) was added dropwise over 5 min. The reaction mixture was stirred at -78° C. for 15 min and then at ambient temperature for 30 min. The reaction mixture was diluted with methylene chloride (100 mL). The resulting solution was washed (water 100 mL, brine 100 mL, water 100 mL), dried (magnesium sulfate), and concentrated under reduced pressure to give a yellow oil. The oil was chromatographed (SiO2, 200 g, ethyl acetate-hexane, 1:9) to give 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl methanal as a white solid (3.0 g, 70% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](O)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17].C([O-])(O)=O.[Na+].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=O>CO.C(Cl)Cl.[Cl-]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:18]4[C:16]([S:17][C:30]([C:26]5[S:25][CH:29]=[CH:28][CH:27]=5)=[N:19]4)=[N:15][N:14]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)c1cccs1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: NNC(=S)NN
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1csc(-c2nn3c(Cc4ccc5c(c4)OCO5)nnc3s2)c1
Temperature: 170 °C

Procedure:
As shown in FIG. 2, 2-(benzo[d][1,3]dioxol-5-yl)acetic acid (1 mmol) and thiocarbonohydrazide (1.5 mmol) were heated at 170° C. for 15 min. The mixture was cooled and taken up in 5% MeOH/CH2Cl2 and saturated NaHCO3. The organics were washed with water, saturated NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting 5-((benzo[d][1,3]dioxol-5-yl)methyl)-4H-4-amino-3-mercapto-1,2,4-triazole (compound 1001) was used as is in the next reaction. Accordingly, a mixture of compound 1001 and thiopene-2-carbonyl chloride (0.176 g, 1.2 mmol) suspended in excess phoshoryl chloride (˜10 mL) was refluxed 5 hours. The excess phoshoryl chloride was removed under reduced pressure and the subsequent residue was mixed with crushed ice. The solids were filtered, washed with water, and dried in vacuo. Purification by reversed-phase HPLC produced pure 3-((benzo[d][1,3]dioxol-5-yl)methyl)-6-(thiophen-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (compound 2).
Reaction SMILES: [K].[C:2]([CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH2:25]>Cl>[C:5]([C:4]1[C:2]([NH2:3])=[N:25][N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:20])([F:22])[F:21])=[CH:16][C:15]=2[Cl:23])[C:10]=1[NH2:11])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)C(C#N)C#N
Agent: Cl
Agent: [K]
Product: CCOC(=O)c1c(N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 38.4 %

Procedure:
Ethyl dicyanoacetate potassium salt (35.2 g) was added to a stirred suspension of 2,6-dichloro-4-trifluoromethylphenylhydrazine (49 g) in hydrochloric acid (0.9 M; 220 ml) and the mixture was stirred and boiled under reflux for 18 h, then cooled to precipitate a solid which was filtered off, triturated with diethyl ether (250 ml) and dried to give an off-white solid which was recrystallized from ethyl acetate-hexane to give 4-carboethoxy-3,5-diamino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (29.2 g), m.p. 196°-197° C., in the form of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[C:8]([C:12](OCC)=[O:13])=[CH:7][N:6]([CH3:17])[C:5]=2[S:4][C:3]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CO>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:12]([C:8]2[C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[C:3]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[S:4][C:5]=3[N:6]([CH3:17])[CH:7]=2)=[O:13])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)c(C)c2c1=O
Solvent: CO
Product: Cc1c(CN2CCOCC2)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 190 °C

Procedure:
A mixture of ethyl 3,7-dimethyl-2-(morpholin-4-ylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Preparation 28, 700 mg) and 4-chloro-benzylamine (1.25 mL) is heated to 190° C. under a nitrogen atmosphere for 1 h. The reaction mixture is allowed to cool briefly and methanol (10 mL) is added. After cooling to room temperature, the product is filtered and washed with methanol and diethyl ether to afford 634 mg of the title compound as a white solid. Physical characteristics. M.p. 222-224° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.67, 8.66, 7.41-7.33, 4.52, 3.92, 3.67, 3.59, 2.51, 2.47; MS (ESI+) m/z 446 (M+H)+. Anal. Found: C, 59.11; H, 5.47; N, 9.32; Cl, 7.96; S, 7.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[NH2:28][C:22]1[N:23]=[C:24]([NH:27][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH:25]=[CH:26][C:21]=1[C:19]1[O:18][N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridine-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and dichloromethane (1 mL) were added triethylamine (22 μL, 0.16 mmol) and methoxyacetyl chloride (15 mg, 0.14 mmol) at room temperature, which was stirred for 2 hours at the same temperature. The solids that precipitated in the reaction mixture were filtered out. Tetrahydrofuran was added to the solid thus obtained, and this mixture was filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.4 mg, 7%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1NC(=O)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0° C. was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70° C. overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H NMR (DMSO-d6) δ 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=O)[CH:3]=1.[NH3:14]>>[CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: N
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Product: Cc1cc(=O)[nH]c2c1C(=O)CCC2

Procedure:
4.46 g (0.025 mol) of 4-methyl-5,6,7,8-tetrahydro- cumarin-5-one are heated to 180° C. for 3 hours in 150 ml of saturated methanolic ammonia in a stirred autoclave. After cooling, the methanolic ammonia is distilled off using a rotary evaporator and the residue is recrystallised from ethanol using activated charcoal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4cc(F)ccc4F)sc3N)cnn2C)CCC1N
Yield: 33.6 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 326 (64.2 mg, 33.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.22-8.10 (m, 1H), 7.46 (d, J=9.7 Hz, 2H), 7.45-7.35 (m, 2H), 7.34-7.18 (m, 1H), 3.64 (s, 3H), 3.23 (d, J=12.0 Hz, 4H), 3.21-2.89 (m, 6H), 2.10-1.97 (m, 1H), 1.89-1.79 (m, 1H), 1.78-1.53 (m, 2H). LCMS (ES+) m/z 478 (M+1)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:42]2[N:43]=[CH:44]C=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC>CN(C)C=O.C(#N)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([N:43]([CH3:44])[CH3:42])=[O:19])=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cccc(C(=O)O)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3cccc(C(=O)N(C)C)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 59.3 %

Procedure:
A solution of 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (for a preparation see Example 174) (9.0 mg, 0.022 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (43.6 mg, 0.115 mmol) in N,N-dimethylformamide (DMF) (0.5 ml) was treated with N,N-diisopropylethylamine (DIPEA) (0.023 ml, 0.135 mmol) and dimethylamine (2.0M solution in THF, 0.112 ml, 0.224 mmol). The resulting mixture was stirred at room temperature for 55 min then was reduced in volume under a stream of nitrogen, diluted with acetonitrile and directly purified by MDAP to give 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-N,N-dimethylbenzamide (5.7 mg, 0.013 mmol, 59.3% yield) as a orange gum.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=1.[CH:16]1([CH2:22]O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[S:11][CH:12]=1
Reactant: OCC1CCCCC1
Reactant: O=C(O)c1cc(Br)cs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCC1CCCCC1)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of oxalyl chloride (1.4 mL, 16.1 mmol) in anhydrous CH2Cl2 (10 mL) was added dropwise to a solution of 4-bromothiophene-2-carboxylic acid (3.08 g, 14.9 mmol) and DMF (0.2 mL) in anhydrous CH2Cl2 (40 mL) over 30 mins. The reaction mixture was stirred at room temperature for 35 min then concentrated under reduced pressure. CH2Cl2 (30 mL) was added to the residue followed by cyclohexylmethanol (1.9 mL, 15.44 mmol) and Et3N (2.5 mL, 17.94 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between EtOAc and aqueous 25% NH4Cl. Organic layer was washed with brine, concentrated under reduced pressure and purified by flash chromatography (2%-20% EtOAc—hexanes gradient) to give cyclohexylmethyl 4-bromothiophene-2-carboxylate as a colorless oil which was directly used in the next step. Yield (3.61 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH2:19][CH3:20])=[CH:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=CC=1.B(F)(F)F.[CH3:33][CH2:34]OCC>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH2:33][CH3:34])([C:19]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:20]=3)[CH2:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC=C(CC)c1ccc2oc(C(=O)OCC)c(C)c2c1
Reactant: Cc1ccccc1O
Reactant: CCOCC
Agent: FB(F)F
Product: CCOC(=O)c1oc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2c1C
Yield: 90.8 %

Procedure:
5-(1-Ethyl-propenyl)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (3.20 g, 11.7 mmol) and o-cresol (1.91 g, 17.6 mmol) and BF3-Et2O (1.66 g, 11.7 mmol) are reacted analogous to Example 1D to give the title compound (4.04 g, 91%).
Reaction SMILES: [OH2:1].[O-2:2].[O-2:3].[O-2:4].[O-2].[O-2].[O-2].[Na+:8].[Na+].[Al+3].[Al+3].[Si+4:12]>[OH-].[Na+]>[Si:12]([O-:4])([O-:3])([O-:2])[O-:1].[Na+:8].[Na+:8].[Na+:8].[Na+:8]
Reactant: [Si+4]
Reactant: O
Reactant: [O-2]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
In another embodiment of the present invention for the production of zeolite X, zeolite A or combinations thereof, the present invention achieves its objectives by dissolving sand in a sodium hydroxide solution at a pressure of at least 100 psig heated to a temperature of at least 130° C. to produce a sodium silicate solution having a silica to sodium oxide molar ratio of between 2.4:1 and 2.8:1, activating the sodium silicate thus formed with alumina, forming a sodium aluminate solution, adding the sodium aluminate solution to the sodium silicate solution so that all of the sodium aluminate solution is added within 30 seconds to form a reaction mixture comprising a sodium silicate mother liquor and an amorphous sodium alumino silicate pigment having, in total, a certain composition, heating the mixture to a temperature of from 80° to 120° C., reacting the mixture at a temperature of from 80° to 120° C., then recovering the zeolite produced. Preferably the sodium silicate solution has a silica to sodium oxide molar ratio of about 2.4:1. The sodium silicate is activated with from 50 to 2000 ppm alumina at a temperature of from 15° to 100° C. for at least 10 minutes, preferably with from 400 to 600 ppm alumina at room temperature, most preferably with about 600 ppm alumina. Both the sodium silicate solution and the sodium aluminate solution are heated to a temperature of between 80° and 120° C., preferably 90° C., prior to the addition of the sodium aluminate to the sodium silicate. The reaction mixture is reacted at a temperature of from 80° to 120° C. until a zeolite is formed, preferably at a temperature of from 80° to 100° C., most preferably at a temperature of about 100° C. The sodium silicate mother liquor may be recycled as a source of sodium silicate solution.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:13].[CH2:17](Br)[C:18]#C.[I-:21].[K+].[CH3:23]O>O>[I-:21].[CH3:1][CH:2]([N+:14]([CH3:23])([CH3:15])[CH2:16][C:17]#[CH:18])[CH2:3][CH2:4][CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:13]
Reactant: CO
Reactant: CC1CCCC(C)(C)C1CCC(C)N(C)C
Reactant: C#CCBr
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C#CC[N+](C)(C)C(C)CCC1C(C)CCCC1(C)C

Procedure:
A solution of [1-methyl-3-(2,6,6-trimethylcyclohexyl)propyl]dimethylamine (3.0 g) and propargylbromide (3.0 g) in methanol (20 cc) was refluxed for 1 hour, and thereto was added a solution of potassium iodide (4.5 g) in water (15 cc). After shaking the mixture, water (50 cc) was added thereto, and the aqueous solution was extracted with chloroform, The chloroform layer was washed with water, dried and concentrated to dryness. The residue was recrystallized from a mixed solvent of ethanol and ether to give colorless crystals (4.5 g) of [1-methyl-3-(2,6,6-trimethylcyclohexyl)propyl]dimethylpropargylammonium iodide, m.p. 165°-167° C.
Reaction SMILES: [CH:1]1([C@H:4]([OH:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12]C(C)(C)C)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:35](OC(ON1C(=O)CCC1=O)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[CH:1]1([C@H:4]([OH:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O)C1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To 21D (88 mg, 0.229 mmol) in EtOAc (2 mL) was added 4.0 M HCl in dioxane (1.5 mL, 6.00 mmol). The mixture was stirred rt for 1 h, concentrated. The residue was dissolved in DMF (10 ml). N-(benzyloxycarbonyloxy) succinimide (62.8 mg, 0.252 mmol) was added, followed by N,N-diisopropylethylamine (0.120 mL, 0.687 mmol). The mixture was stirred rt for 16 h, then was quenched with water, extracted with EtOAc (3×30 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc in hexane) to give 21E (99 mg, 103% yield). MS (ESI) m/z: 419.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][C:30](=O)[CH3:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+:37]>C(O)C>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH:11]1[C:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:30]([CH3:31])[NH:37][C:13]([CH3:14])=[C:12]1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(=O)C(=Cc1ccccc1OCc1ccccc1)[N+](=O)[O-]
Reactant: CC(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(c2ccccc2OCc2ccccc2)C([N+](=O)[O-])=C(C)N1
Yield: 4.8 %

Procedure:
3 g (10 mmol) of 2-benzyloxybenzylidenenitroacetone in 15 ml of ethanol are heated under reflux with 1.34 g (10 mmol) of phenylacetone and 770 mg (10 mmol) of ammonium acetate for 1.5 hours. The mixture is cooled and concentrated. The residue from evaporation is taken up in ethyl acetate, and the solution is washed with water, dried and concentrated. The resulting residue from evaporation is purified through a column of volume 150 ml, stationary phase silica gel and mobile phase toluene/ethyl acetate 10:1. The pure fractions are combined, concentrated and crystallized using ether. 0.2 g of yellow crystals, of melting point 189° C., is obtained.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:26]([CH:29]([CH3:31])[CH3:30])=[C:27]=[O:28]>ClCCl.CCOC(C)=O>[CH:29]([NH:26][C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)N=C=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of benzyl piperazine-1-carboxylate (1, 5.0 g, 23 mmol) and diisopropylethylamine (5.86 g, 45.4 mmol) in dichloromethane (50 mL) was added 2-isocyanatopropane (4.83 g, 56.8 mmol) and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with to 0-20% CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (3.94 g, 57%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.45-7.25 (m, 5H), 5.14 (s, 2H), 4.19 (d, J=6.7 Hz, 1H), 4.05-3.90 (m, 1H), 3.60-3.45 (m, 4H), 3.44-3.25 (m, 4H), 1.20-1.10 (m, 6H); Multimode MS m/z 306 [M+H]+.