Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH:17]([CH3:19])[CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH:17]([CH3:19])[CH3:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1CN(Cc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.5 g, 15.6 mmole) was added to the stirred solution of 1-benzyl-3-isopropylpiperid-4-one (3.3 g, 14.2 mmole) in methanol (25 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-4-hydroxy-3-isopropylpiperidine as oil. Yield 2.9 g (85%), C15H23NO, m/z 234 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([NH:19]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:39][CH3:40])[C:8]=2[N:9]=1.C([O-])(O)=O.[Na+]>Cl.CO>[CH3:1][O:2][C:3](=[O:41])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:39][CH3:40])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(-c3csc(N)n3)c2s1
Temperature: 25 °C

Procedure:
0.070 g of {4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-carbamic acid methyl ester (0.00012 Mol) were heated to reflux in 2 ml of 2.5 M HCl/MeOH for 4 hrs. After cooling to room temperature the pH was adjusted to 7 upon drop wise addition of sat. NaHCO3. A precipitate formed, which was filtered off, washed with ethyl acetate and dried. The title compound was obtained as a white solid (23%), F.p.: 293-296° C. (dec.).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:3]1>CO>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)C[C@H]1C1CCCC(F)(F)C1
Solvent: CO
Product: FC1(F)CCCC([C@@H]2C[C@H](c3ccccc3)CCN2)C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A mixture of compound 6 (130 mg, 0.31 mmol) and Pd (OH)2 (70 mg) in MeOH (20 mL) was stirred at 50° C. under H2 (50 psi) for 4 hours. The mixture was filtrated and the filtrate was concentrated to give 80 mg of (2S,4R)-2-(3,3-difluorocyclohexyl)-4-phenylpiperidine 7 in 92% yields.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12]
Reactant: Fc1cccc2c1CCN2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 4-fluoro-indoline (1 g, 7.30 mmol) and acetic anhydride (10 mL) was stirred at ambient temperature for 1 h. The resulting mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5×30 mL). The combined organic layers were washed with water (3×20 mL), sodium bicarbonate solution (3×20 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford 1-(4-fluoro-indolin-1-yl)ethanone (1 g, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[N:27][C:19]=3[CH3:18])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-methylsulfanyl-9H-β-carbolin-8-ylamine (Intermediate 28, 2.336 g, 8.86 mmol) and 2-methylnicotinic acid (3.219 g, 23.4 mmol) in 80 ml anhydrous pyridine. To the resulting reaction mixture at RT was added solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.080 g, 36.9 mmol) and the reaction mixture was heated to 100° C. (oil bath) for 2 days. The resulting mixture was cooled to RT and concentrated (rotavap) to afford a brown residue. The residue was redissolved in MeOH (50 ml), slowly added to a stirring mixture of 5:1 H2O/saturated aqueous sodium bicarbonate (600 mlL) and stirred at RT for ˜18 hr. The precipitated solid was collected via suction filtration, washed with Et2O (2×150 ml), and air-dried to afford 3.036 g of crude N-(6-chloro-7-methylsulfanyl-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as a brown solid. The crude material was purified via HPLC (yields=˜40-60%)
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([C:11](C#N)=[C:12]([C:15]#[N:16])[C:13]#[N:14])#[N:10]>O>[C:9]([C:11]1[C:12]([C:13]#[N:14])=[C:15]([NH2:16])[N:3]([C:4]([NH2:6])=[O:5])[N:2]=1)#[N:10]
Reactant: NNC(N)=O
Reactant: N#CC(C#N)=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1nn(C(N)=O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a mixture of semicarbazide hydrochloride (11.2 g, 0.1 mol), water (200 ml) and sodium hydroxide (4.0 g, 0.1 mol) cooled in an ice-bath was added dropwise tetracyanoethylene (12.8 g, 0.1 mol). The reaction mixture was warmed to room temperature, stirred for 1.5 hours and then allowed to stand for 24 hours. The white precipitate which formed during the course of the reaction was collected by filtration and washed with water to afford 15.6 g (89%) of 3-cyano-4-cyano-5-amino-1H-pyrazole-1carboxamide as a white solid, m.p. 225° C. (dec.) when dried at 85° C. in high vacuum.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].Br[CH:16]([CH2:21][CH2:22][CH2:23][Br:24])[C:17]([O:19][CH3:20])=[O:18]>>[Br:24][CH2:23][CH2:22][CH2:21][CH:16]([O:14][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]=1[N+:1]([O-:3])=[O:2])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(Br)CCCBr
Reactant: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Product: COC(=O)C(CCCBr)Oc1ccc2c(c1[N+](=O)[O-])CCCC2

Procedure:
In a manner similar to that of Reference Example 5, 5,6,7,8-tetrahydro-1-nitro-2-naphthol was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2(5,6,7,8-tetrahydro-1-nitro-2-naphthyloxy)valerate, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperazine to obtain methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(5,6,7,8-tetrahydro-1-nitro-2-naphthyloxy)valerate as an oily product. The overall yield was 65.1%. NMR(CDCl3)δ: 1.55-2.17(8H,m), 2,41(2H,5,J=7.2 Hz), 2.52-2.81(8H,m), 2.96-3.14(4H,m), 3.72(3H,s), 4.67(1H,t,J=6 Hz), 6.55-7.11 (6H,m)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18](=[O:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C:18]([OH:29])=[O:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SC3CCCC3)n2)c(Cl)c1
Yield: 57.4 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (46 mg, 0.20 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (45 mg, 71%).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CC1C=CC=CC=1C.ClCCl.CO>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:23][N:24]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cnc(-c2ccccc2)nc1
Reactant: NNC(=O)c1cccnc1
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1C
Product: c1ccc(-c2ncc(-c3n[nH]c(-c4cccnc4)n3)cn2)cc1
Yield: 9.7 %

Procedure:
2-Phenyl-pyrimidine-5-carbonitrile (Biofine International, 0.20 g, 1.10 mmol) and nicotinic hydrazide (Aldrich, 0.151 g, 1.10 mmol) were dissolved in o-xylene (5 mL) and heated to 200° C. under nitrogen atmosphere for seven hours as the o-xylene slowly boiled off. The remaining crude solid was dissolved in a minimal amount of 98:2 v/v dichloromethane-methanol and purified by flash silica column chromatography. Elution through a 40-g Analogix® flash silica cartridge with 100% dichloromethane to 5% methanol in dichloromethane afforded the title compound as a yellow solid (32 mg, 10% yield); Rf 0.27 with 95:5 v/v dichloromethane-methanol; melting point 322-333° C.; 1H-NMR (400 MHz; CDCl3) δ 9.53 (s, 2H), 9.32 (d, 1H), 8.76-8.75 (m, 1H), 8.53-8.46 (m, 3H), 7.64-7.60 (m, 4H); MS (ESI+) m/z 301.1 (M+1); H-PGDS FPBA IC50: 1 μM.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([OH:20])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([O:20][CH3:24])[C:17](=[O:21])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(OCc3ccccc3)cc2)CN1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CI
Product: CON1CC(c2ccc(OCc3ccccc3)cc2)CC1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture containing 0.7 g 4-(4-benzyloxyphenyl)1-hydroxy2-pyrrolidone (Example 2), 5.0 ml methyl iodide and 2.0 g potassium carbonate in 5.0 ml N-methylpyrrolidone was stirred for 2 h at 50° C. 20 ml 1N sodium hydroxide solution was then added and the solution was extracted with a mixture of 20 ml cyclohexane and 10 ml of ether. The extract was washed with water and concentrated in vacuo whereupon the product crystallized. yield 0.31 g (41%), mp 92°-97° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([N:13]([CH3:15])[CH3:14])[CH2:8]2.B(Br)(Br)Br.N>C(Cl)Cl>[CH3:14][N:13]([CH3:15])[CH:7]1[CH2:6][CH2:5][C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1
Reactant: COc1cccc2c1CCC(N(C)C)C2
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: CN(C)C1CCc2c(O)cccc2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 33.9 %

Procedure:
N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N,N-dimethylamine (8.86 g, 43.156 mmol) was dissolved in CH2Cl2 (200 mL), cooled to 0° C. and BBr3 (1.0 M in CH2Cl2, 51.8 mL, 51.788 mmol) was added over a period of 20 min. The reaction mixture was allowed to reach r.t. while stirring overnight (ca. 14 h). The mixture was cooled again to 0° C., NH3 aq. (25%, 50 mL) was added slowly and the mixture was stirred at 0° C. for 15 min. The salts were filtered off, layers were separated and the aqueous phase was extracted with CH2Cl2 (4×40 mL). All organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (6.99 g) was purified by flash chromatography on silica gel (30:70:2-100:0:2 AcOEt/Hexane/Et3N and 30:70:2 AcOEt/Hexane/Et3N-90:10:2 AcOEt/MeOH/Et3N) affording 2.80 g of the title compound (Rf=0.3 (AcOEt/Hexane/Et3N 10:10:2), off-white solid, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH:11][C:12]1[CH:19]=CC=C[C:13]=1C#N>>[NH2:8][C:7]1[C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:10][C:13]=1[C:12](=[O:11])[CH3:19]
Reactant: N#Cc1ccccc1O
Reactant: N#Cc1cc(Cl)ccc1O
Product: CC(=O)c1oc2ccc(Cl)cc2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 5-chloro-2-hydroxy-benzonitrile (5A) in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])OC)[S:3][CH3:4].C(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.C[O-].[Na+]>CCOCC.CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:21](=[O:22])[N:1]=[C:2]([S:3][CH3:4])[NH:5][C:6]2=[O:9])=[CH:16][CH:15]=1
Reactant: COC(=O)N=C(N)SC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CSc1nc(=O)n(-c2ccc(Cl)cc2)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of 148 parts of said methyl N-(1-amino-1-methylthiomethylene)carbamate in 2,000 parts methylene chloride is added 154 parts of 4-chlorophenyl isocyanate. The reaction is stirred overnight. Then to it is added 54 parts of sodium methoxide in 540 parts of methanol. The reaction mixture is then refluxed for one hour. The reaction mass is cooled, and 2,000 parts of ether are added. The solid collected by filtration is dissolved in water and the solution neutralized with hydrochloric acid. The new solid thus formed is collected, dried, and recrystallized from ethanol/H2O to give 140 parts of 3-(4-chlorophenyl)-6-methylthio-s-triazine-2,4-(1H,3H)-dione melting at 292°-295° C.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[NH:42])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:43]=[C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][CH2:24][OH:23])[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)[N:42]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)Nc1ccc(N2CCN(CCCCO)CC2)cc1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Product: OCCCCN1CCN(c2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccccc3F)C4)cc2)CC1

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and 1-(4-(4-(4-hydroxybutyl)piperazin-1-yl)phenyl)guanidine as described in general procedure 1. LCMS m/e 524 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:33][CH2:34]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (133 mg, 0.469 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC(NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was slurried with hot MeCN (5 mL), cooled to ambient temperature, filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (70.3 mg, 0.152 mmol, 35.4% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.33-1.57 (m, 3H) 1.64 (d, J=12.13 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=12.13 Hz, 1H) 2.26 (s, 3H) 2.52-2.70 (m, 5H) 2.87 (br. s., 4H) 3.19-3.29 (m, 2H) 3.37-3.43 (m, 2H) 3.84 (dd, J=11.49, 2.65 Hz, 1H) 4.50 (d, J=12.88 Hz, 1H) 6.98 (d, J=1.52 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.62 (d, J=8.59 Hz, 1H) 7.65 (dd, J=9.35, 1.26 Hz, 2H) 8.26 (t, J=5.43 Hz, 1H) 10.49 (s, 1H); [M+H] calc'd for C26H34N6O2, 463; found, 463.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=C)=[O:14].CSC.C(Cl)Cl.C[OH:40]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=[O:40])=[O:14]
Reactant: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Reactant: CO
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride/methanol (10:1, 220 mL). Cool to -78° C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78° C. to remove excess ozone. Treat with methyl sulfide (60 mL, 0.82 mol) and allow to warm no room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g).
Reaction SMILES: [CH2:1]=[CH2:2].CO.[P].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:6]=[CH2:7].[CH2:1]([C:9]1[CH:10]=[CH:11][C:6]([CH3:12])=[CH:7][CH:8]=1)[CH3:2]
Reactant: Cc1ccccc1
Agent: C=C
Agent: [P]
Solvent: CO
Product: CCc1ccc(C)cc1

Procedure:
FIG. 2 compares ethylene selectivity vs. methanol conversion over a phosphorus-loaded ZSM-5, D/r2=0.5×10−6 s−1, 1 alpha catalyst using 12:1 molar methanol:aromatic feedstock, showing similar results for ethylene selectivity between toluene and para-ethyltoluene as aromatic feedstock.
Reaction SMILES: [C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1([C:4]2[C:14]3[CH2:13][CH2:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[C:9](=[O:19])[C:8]=3[CH:7]=[CH:6][CH:5]=2)[O:22][CH2:21][CH2:20][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc2c1CCc1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1

Procedure:
7.4 g. of 1-acetyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, 9.5 g. of ethylene glycol, 30 ml. of toluene and 60 mg. of p-toluenesulfonic acid are heated in a water separator at reflux for 8 hours. Thereafter, the mixture is concentrated under reduced pressure, taken up in ethyl acetate, washed with sodium carbonate solution and water, dried and evaporated, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is obtained as yellow crystals having a melting point of 144°-145°C. (from ethyl acetate/petroleum ether).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1[C:13]([CH2:12][O:11][C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)=[CH:17][O:16][N:15]=1
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccccn2)cn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 68.3 %

Procedure:
As described for example 17a, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid methyl ester (432 mg, 1.4 mmol), instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, was converted to the title compound (285 mg, 71%) which was obtained as a white solid. MS: m/e=297.1 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].C(OCC)(=O)C>ClCCl>[CH3:22][N:23]([CH3:28])[S:24]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 412 mg (2.06 mmol) of tert-butyl 4-piperidinyl-carbamate in 20 mL of dichloromethane were added 430 μL (3.09 mmol) of triethylamine and 265 μL (2.47 mmol) of dimethylsulfamoyl chloride and the mixture was stirred for 2 hours at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 536 mg (85%) of the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[N:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:3][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:9]([CH3:21])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C(=O)OC)c(O)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)c(Cl)nc1C
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (4.11 mL) was added to a mixture of dimethyl 2-hydroxy-6-methylpyridine-3,5-dicarboxylate (4.96 g) and acetonitrile (30 mL), and the resultant mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and then, a saturated aqueous solution of sodium bicarbonate was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.97 g).