Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:12]C.[CH3:14]N(C)C=O>CC(C)=O>[I-:12].[CH3:14][N+:1]1[C:10]2[CH:9]=[CH:8][NH:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]ccc2ncccc12
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc2c(=O)[nH]ccc21
Product: [I-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of 5.85 g (40 mmol) of 1,6-naphthyridin-5(6H)-one (3), 10 mL of iodomethane, and 50 mL of anhydrous N,N-dimethylformamide is stirred at 25° C. for 19 hours. The suspension is treated with an additional 4 mL of iodomethane, stirred for 24 hours more, and poured slowly into 100 mL of stirring acetone. The solids are collected by filtration, washed with acetone, and dried to leave 10.54 g of pure product, mp 240°-244° C. The filtrate is concentrated in vacuo to give a solid residue that is triturated with 2-propanol and further processed to give 0.78 g of a second crop, mp 235°-240° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][PH:23]([O-])([O-:27])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@:10]([NH:9][C@H:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:23]([CH3:22])(=[O:27])[O:24][CH2:25][CH3:26])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, 23-a, (16 g, 43.83 mmol), ethyl methylphosphite (9.47 g, 87.67 mmol) and Et3N (13.3 g, 132 mmol) in THF (200 ml) was added PdCl2(dppf) (1.6 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1 l/1) to provide the crude product, 23-b, (9.5 g, 55%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:37])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C@H:25]([OH:28])[CH2:26][Cl:27])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:12]([O:16][C:17](=[O:37])[C@@H:18]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:24][C@H:25]([OH:28])[CH2:26][Cl:27])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCl)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93.1 %

Procedure:
A solution of benzyl chloroformate (1.21 g, 7.09 mmol) in chloroform (10 mL) was added over a period of 15 min to an ice-cold solution of 12a (2.16 g, 5.46 mmol) in chloroform (40 mL) under an Ar atmosphere. After dropwise addition of triethylamine (1.11 g, 11.0 mmol) in chloroform (10 mL), the reaction mixture was stirred for 4.5 hours at rt. The reaction mixture was extracted with 1 N HCl (60 mL) and water (60 mL), dried, and concentrated. The residue was purified by flash chromatography (33% ethyl acetate/hexane) to give 13a (2.69 g, 93%) as a colorless oil: 1H NMR 61.30-1.83 (m, 6H), 1.44 (s, 9H), 1.45 (s, 9H), 3.20-3.64 (m, 6H), 3.93 (dd, 1H, J=8.2; 5.5), 4.00 (m, 1H), 5.12 (s, 2H), 7.26-7.40 (m, 5H); 13C NMR δ 24.1, 28.3, 28.8, 32.5, 49.4, 51.4, 52.2, 55.7, 68.4, 71.0, 80.4, 82.5, 129.0, 129.1, 129.6, 138.0, 157.5-158.4 (br), 158.1, 173.7; HRMS m/z calcd for C26H42ClN2O7 529.2681, found 529.2694. Anal. calcd. for C26H41ClN2O7: C 59.03, H 7.81, N 5.29. Found: C 59.09, H 7.78, N 5.21. [α]23D−21.8° (c 1.00, CH3OH).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:35])=[O:2])=[O:30])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)OC(=O)N[C@@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 43 in methanol (5 ml) is added 2M aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (40 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15].[C:21](Cl)(Cl)=[S:22]>O.C(Cl)(Cl)Cl>[CH:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:8][C:7]=1[N:6]=[C:21]=[S:22])([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1N=C=S
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium bicarbonate (16.8 g, 199.5 mmol) in water (400 mL) was added to 3-amino-4-isopropoxy-benzenesulfonamide (15.3 g, 66.5 mmol, example 2, step d) in a mixture of chloroform (200 mL) and water (200 mL). Thiophosgene (6.37 mL, 83.1 mmol) was then added. The biphasic solution was stirred at room temperature for 1.5 h. The phases were separated and the aqueous phase was extracted with CH2Cl2. The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated, yielding the crude title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(S)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.369 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 93.5%, 425.0449 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.P(Br)(Br)[Br:18].O>ClCCl>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: COCCOCCOc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: COCCOCCOc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
To a solution of {4-[2-(2-methoxyethoxy)ethoxy]phenyl}methanol (Step 2, 500 mg, 2.21 mmol) in 10 mL dichloromethane was added dropwise phosphorous tribromide (210 μL, 2.21 mmol) at 0° C. After the addition was completed, stirring of the reaction mixture was continued for 1 h at the same temperature. Then, water was added with caution, and it was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to yield a crude product which was purified by MPLC (silica, cyclohexane/ethyl acetate 10:1) affording the title compound in pure form (530 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H), 6.88 (d, 2H), 4.50 (s, 2H), 4.13 (t, 2H), 3.85 (t, 2H), 3.71 (t, 2H), 3.58 (t, 2H), 3.40 (s, 3H); DCI(NH3)-MS m/z 306/308 (M+NH4)+; HPLC RT (Method I) 3.20 min.
Reaction SMILES: IC.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:13][C:12]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension of indole-6-carboxylic acid (1.68 g, 10.5 mmol) and potassium carbonate (2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirred at room temperature for 19 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 176 (MH)+.
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1NC(=O)C[P:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[OH:17])C.[CH3:26][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[NH:38][C:39](=[O:47])[CH2:40]P(=O)([O-])OCC)[CH3:28].[CH3:48][CH:49](O)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>>[CH3:37][CH:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH:27]([CH3:26])[CH3:28])[C:30]=1[NH:38][C:39](=[O:47])[CH2:40][C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[PH:16](=[O:18])[O:17][CH:60]([CH3:61])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH3:48])[CH3:36]
Reactant: CCOP(=O)([O-])CC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CP(=O)(O)c1ccccc1
Reactant: CCCCCCCCCCCCC(C)O
Product: CCCCCCCCCCCCC(C)O[PH](=O)c1ccccc1CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
In a process analogous to Example 7, using (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenylphosphinic acid in place of 25 (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, ethyl ester and 2-tetradecanol in place of 1-nonanol, the title compound is obtained as a light yellow oil; IR (film) 3232, 2962, 2925, 2855, 1684, 1522, 1467, 1217, 987, 968 cm-1 ; 1H NMR (250 MHz, CDCl3) (mixture of diastereomers) 8.47 (br s, 1 H), 7.88 (dd, J=13 and 8 Hz, 2 H), 7.64 7.45 (m, 3 H), 7.30-7.10 (m, 3 H), 4.55-4.30 (m, 1H), 3.40-3.11 (m, 2 H), 3.35-2.60 (m, 2 H), 1.95-0.90 (m, 28 H), 1.16 (d, J=7 Hz, 12 H), 0.88 (t, J=7 Hz, 3 H); Mass spectrum, m/e (relative intensity) 556 (9), 555 (9), 388 (15), 360 (92), 342 (11), 201 (100), 177 (36), 157 (40), 141 (21), 111 (17), 97 (29).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:16]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:16])=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccc(N2CCNCC2)cc1
Yield: 19.5 %

Procedure:
To 8.0 g (0.04 mol) of 4-(1-piperazinyl)benzonitrile was added, with stirring, 50.0 mL (0.87 mol) of 93% sulfuric acid over a 15 min period. The mixture was stirred overnight and the resulting suspended amide was collected by filtration, rinsed with water, and allowed to air dry. The solid was recrystallized from absolute ethanol to give 1.6 g (20%) of white solid, mp 240°-243° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][CH3:12])=[CH:4][N+:3]=1[O-].P(Br)(Br)Br.O.CO>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:11][CH3:12])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]
Agent: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CNc1cnc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Bromo-5-(methylamino)-4-nitropyridine 1-oxide (10.0 g, 40.4 mmol) in 200 mL dichloromethane was mixed with phosphorous tribromide (10 mL, 106 mmol) in 50 mL dichloromethane at 10° C. and stirred for 10 minutes at ambient temperature. Water and methanol were added and the mixture was extracted with dichloromethane. The organic layers were washed with Na2CO3 (aq.) dried over MgSO4. The residue was triturated with ethanol, filtered and dried at 50° C. i. vac.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH2:10]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: SCc1ccccc1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1ccc(SCc2ccccc2)cc1
Yield: 89.4 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoanisole (234 mg, 1.0 mmol), benzylmercaptan (117 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 4-benzylsulfanylanisole (206 mg, 90% yield) as colorless solid. Column chromatographic solvent (hexane/ethyl acetate=50/1). Melting point; 48-50° C. Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.14-7.24 (m, 7 H), 6.76 (dt, 2 H, J=8.7 Hz, 2.1 Hz), 3.97 (s, 2 H),3.76 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 159.3, 138.3, 134.3, 129.1, 128.5, 127.2, 126.2, 114.6, 55.6, 41.6. IR (neat, cm−1) 3043, 3012, 2982, 2861. MS (EI) m/z (relative intensity) 230 (30), 91 (100). Anal Cald for C14H14OS, Cald. C: 73.01, H: 6.13; Found C: 72.86, H: 5.93.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.S(Cl)([Cl:20])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([Cl:20])=[O:17])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-phenylpicolinic acid (3.00 g, 11.2 mmol) in toluene (40 mL) was added thionyl chloride (1.22 mL, 16.8 mmol) and dimethylformamide (0.04 mL, 0.6 mmol). Reaction mixture was heated at 80° C. for 3 h. HPLC analysis of an aliquot treated with methanol and dimethylaminopyridine indicated complete conversion of the starting material. Reaction was allowed to cool to room temperature and then concentrated under reduced pressure to provide a white solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-phenylpicolinoyl chloride was isolated as a white solid (2.84 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.83-7.75 (m, 2H), 7.55-7.47 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 168.80, 158.88, 146.42, 145.21, 136.79, 134.40, 129.98, 129.61, 128.31, 124.74, LRMS Calcd. C12H6Cl3NO: 284.95. Found: m/z=285 (M+), 250 (M+-Cl), 222, 187, 152, MP. 106-111° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.Cl[CH2:8][CH2:9][CH2:10][OH:11]>[OH-].[Na+]>[OH:11][CH2:10][CH2:9][CH2:8][N:3]1[C:2]([NH2:1])=[N:6][N:5]=[N:4]1.[OH:11][CH2:10][CH2:9][CH2:8][N:4]1[N:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nnn[nH]1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nnn(CCCO)n1
Product: Nc1nnnn1CCCO

Procedure:
5-Aminotetrazole (2.1 g.) and 3-chloropropanol (2.1 ml.) were added to aqueous sodium hydroxide (1 g. in 20 ml.) and the mixture heated at 90° for 18 hours. The resulting solution was evaporated and the residue extracted with hot EtOH. The EtOH extracts were evaporated and the residue extracted with EtOAc to give a colourless oil which was a mixture of isomers. These were separated on a column of silica gel using EtOAc/MeOH/aqueous ammonia (s.g. 0.880) 6:1:1 v/v/v as eluant to give 1-(3-hydroxypropyl)-5-aminotetrazole as a white solid (0.2 g.) and 2-(3-hydroxypropyl)-5-aminotetrazole as a gum (1.0 g.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].O>ClCCl>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=2)[CH2:3]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC1CNCC(C)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N2CC(C)CC(C)C2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3,5-Dimethylpiperidine (0.73 g) and triethylamine (2.25 ml) were dissolved in dichloromethane (20 ml). A solution of 3-methylbenzoylchloride (1.00 g) in dichloromethane (10 ml) was added dropwise at the freezing point. After stirring for 30 minutes at 0° C., the reaction solution was poured into water (100 ml) and extracted with chloroform (50 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent: n-hexane/ethyl acetate=4:1) to obtain the subject compound (NCR-1 cis form:trans form=9:1) (0.95 g, yield 63%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz, δ; ppm) 0.76-1.86 (10H, m), 2.15-2.23 (0.9H, m), 2.36 (3H, s), 2.44-2.49 (0.9H, m), 3.08 (0.1H, m), 3.20 (0.1H, m), 3.32-3.34 (0.1H, m), 3.63-3.65 (0.9H, m), 7.14 (1H, d, J=7.3 Hz), 7.19 (1H, d, J=7.3 Hz), 7.20 (1H, s), 7.26 (1H, t, J=7.6 Hz); MS (EI) m/z: 231 (M+).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5](S(C)(=O)=O)=[C:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]=12)#[N:2].[CH2:19]([Mg]Cl)[CH:20]([CH3:22])[CH3:21]>C1COCC1>[C:1]([C:3]1[S:4][C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]=12)#[N:2]
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C#N)c2C1
Reactant: CC(C)C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)Cc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a stirred solution of 1-cyano-6,6-dimethyl-3-methanesulphonyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (1.5 g, 5.3 mmol) in THF (15 mL) at −10° C. was added isobutylmagnesium chloride. After 1 h the cooling bath was removed and the mixture stirred at room temperature for 2 h. After this time the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol: EtOAc (6:1), to give the title compound (526 mg, 38%) as an orange oil. 1HNMR (360 MHz, CDCl3) δ 0.97 (6H, d, J=6.6 Hz), 1.08 (6H, s), 1.94-2.02 (1H, m), 2,42 (2H, s), 2.85 (2H, s), 3.16 (2H, d, J=7.1 Hz).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl[C:25]1[C:34]2C(=CC=CC=2)N=C(CCl)[N:26]=1.C[O:38]C1C=CC(NC)=CC=1.Cl>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:3][NH:26][C:25](=[O:38])[CH3:34])[N:13]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: ClCc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(OC)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CNC(C)=O)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride: A suspension of 4-chloro-2-chloromethyl-quinazoline (7.383 g, 35.0 mmol) and (4-methoxy-phenyl)-methyl-amine (4.837 g, 35.3 mmol) in i-PrOH (50 mL) was treated with HCl (12 M, 1.5 mL, 18 mmol) and stirred at rt for 2 h. The resulting solid was collected by vacuum filtration, yielding 10.367 g (85%) of the title compound. 1H NMR (DMSO-d6) δ 7.80-7.94 (m, 2H), 7.40-7.80 (m, 2H), 7.26-7.34 (m, 1H), 7.07-7.15 (m, 2H), 6.83 (br d, 1H), 4.94 (s, 2H), 3.83 (s, 3H), 3.72 (s, 3H); LC-MS (ESI+; 314 ([M+H]+)).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[Mg].[C:9]1([C:15]2([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.CCCCCCC.CCOCC>[CH3:24][C:23]([OH:25])([CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6])[CH2:22][CH2:21][CH2:20][C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(=O)CCCC1(c2ccccc2)OCCO1
Reactant: CC(C)=CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCCCCCC
Solvent: CCOCC
Product: CC(C)=CCCC(C)(O)CCCC1(c2ccccc2)OCCO1
Reaction time: 0.75 h
Yield: 37.8 %

Procedure:
A Grignard reagent of 3.50 g (0.021 mol) of 5-bromo-2-methyl-2-pentene in 13 ml of ether and 0.62 g (0.026 mol) of magnesium turnings in 14 ml of ether was added slowly at −25° under N2 to a stirred solution of 5.54 g (0.024 mol) of 5-(2-phenyl-1,3-dioxolan-2-yl)-2-pentanone obtained under b) in 20 ml of ether. During the introduction, the temperature was left rising up to −5° C. and the reaction mixture left stirring for 45 min. Then a saturated solution of NH4Cl was added and the formation of a white precipitate was observed. Extraction with ether (2×), washing with water (3×), drying (Na2SO4) and concentrating gave 6.24 g of the crude product. Column chromatography (SiO2, heptane/ether 7:3) gave 2.53 g (38%) of a yellow oil.