Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: C1CCNC1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCN1CCCC1
Temperature: 55 °C
Yield: 64.1 %

Procedure:
47 g pyrrolidine, 149.5 g 1-bromododecane and 83 g potassium carbonate were added to 560 mL acetone. The reaction mixture was heated at 55° C. for 24 hr, then filtered. Solvent was removed from the filtrate, yielding 92 g N-dodecylpyrrolidine. 80 g N-dodecylpyrrolidine and 52.6 g 1-bromo-3-chloropropane were dissolved in 133 mL methanol and the reaction mixture was heated at 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L diethylether with stirring and the mixture was allowed to stand for another 6 hr. The white precipitate thus formed was filtered and was dried at 40° C. under a vacuum for 24 hr yielding 85 g (3-chloropropyl)dodecylpyrrolidinium bromide as a white solid, Alkylation of crosslinked poly(diallylmethylamine) with (3-chloropropyl)dodecylpyrrolidinium bromide
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH:7][C:8](=[O:18])[C@@H:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6])[CH3:2].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH:7][C:8](=[O:18])[C@@H:9]([NH:17][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:6])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (S)-2-((S)-2-Amino-3-phenyl-propionylamino)-propionic acid ethyl ester.trifluoroacetate salt (10 g, 37.9 mmol) and DIPEA (19.5 mL, 113.6 mmol) in DCM (100 mL) was added benzoyl chloride (4.0 mL, 34.1 mmol) at −20° C. and stirred at −20° C. for 1 h. The reaction mixture was filtered to remove salts and the filtrate was washed with 10% citric acid solution (2×50 mL), 5% NaHCO3 solution (2×50 mL) and brine solution (50 mL) respectively, dried over Na2SO4, filtered and concentrated in vacuo to give a residue that was dissolved in CHCl3 (20 mL) and triturated with n-pentane. The precipitated solid was filtered and washed with a mixture of Et2O and n-pentane (50 mL, 1:1), then dried to obtain (S)-2-((S)-2-Benzoylamino-3-phenyl-propionylamino)-propionic acid ethyl ester (6.5 g, 47%) as a white solid. Rf: 0.8 (10% MeOH/CHCl3); 1H NMR (400 MHz, DMSO-d6): δ 8.60-8.55 (1H, m), 7.76 (2H, d, J=6.8 Hz), 7.52-7.35 (5H, m), 7.27 (2H, t, J=7.6 Hz), 7.18 (1H, t, J=7.6 Hz), 4.80-4.70 (1H, m), 4.30-4.22 (1H, m), 4.07 (2H, q), 3.11 (1H, dd, J=4, 14 Hz), 3.01-2.98 (1H, m), 1.34 (3H, d, J=7.2 Hz), 1.18 (3H, t, J=6.8 Hz); m/z 369 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]([F:31])([F:30])[F:29])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:17](NO)=[NH:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=[O:39].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>>[Cl:1][C:2]1[C:3]([C:28]([F:31])([F:30])[F:29])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:17]([NH2:18])=[O:39])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=N)NO)(c2ccc(Cl)cc2)CC1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=O)(c2ccc(Cl)cc2)CC1

Procedure:
To the crude material from Example 21 was added 5 mg of CSA and 1 mL of TMOF. The mixture was heated to 100C overnight and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid amide. MS (ES) M+H expected=463.0, found=463.1
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[CH2:1]([C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Diethyl prop-1-ylmalonate (70.23 g) was added dropwise to a stirred suspension of sodium hydride (8.35 g) in dimethylformamide (400 ml) under an atmosphere of nitrogen at 10° to 15° C. Following the addition, the mixture was allowed to stir at room temperature until effervescence ceased. The resulting clear solution was cooled again and ethyl bromoacetate (58.06 g) was added. The mixture was heated at 70° C. for 2 hours then allowed to cool, diluted with water, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated to give almost pure diethyl 2-prop-1-yl-2-ethoxycarbonylsuccinate (97.35 g, 97%) as a pale yellow liquid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.O>[Fe].C(OCC)(=O)C.CCCCCC>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1SC
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(N)ccc1SC
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Combine methyl 2-methylthio-5-nitrobenzoate (2.9 g, 12.7 mmol) and glacial acetic acid (100 mL). Heat to 90° C. Add iron powder (5 g) and water (20 mL) over about 10 minutes. After 30 minutes, the reaction mixture was filtered while still hot and diluted with water (500 mL). Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 20% ethyl acetate/hexane to give methyl 2-methylthio-5-aminobenzoate. Rf=0.51 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.NCC(N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(O)C)C1)=O.[NH2:41][C@@H:42]1[CH2:61][CH2:60][C@@:59]2([CH3:62])[C@@H:44]([CH2:45][CH2:46][C@@H:47]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:63])[C@H:48]3[CH2:49][CH2:50][C@@H:51]2[CH:52]([OH:54])[CH3:53])[CH2:43]1.[C:64]([NH:71][C@H:72]([C:74](O)=[O:75])[CH3:73])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:69][C:67]([CH3:70])([O:66][C:64]([NH:71][CH:72]([CH3:73])[C:74]([NH:41][C@@H:42]1[CH2:61][CH2:60][C@@:59]2([CH3:62])[C@@H:44]([CH2:45][CH2:46][C@@H:47]3[C@@H:58]2[CH2:57][CH2:56][C@@:55]2([CH3:63])[C@H:48]3[CH2:49][CH2:50][C@@H:51]2[C@@H:52]([OH:54])[CH3:53])[CH2:43]1)=[O:75])=[O:65])[CH3:68]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](NC(=O)CN)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)O)CC[C@@H]32)C1
Reaction time: 0.83 h

Procedure:
1.14 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added with stirring under an inert atmosphere at 0° to 5° C. to a solution of 1.92 g of (20S) 3α-amino-5α-pregnan-20-ol, 2.27 g of tert.-butyloxycarbonyl-L-alaine (BOC-L-Alanine), 60 ml of chloroform and 12 ml of pyridine and the mixture was stirred for 75 minutes after which another 1.15 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added thereto. The mixture was stirred at 0° to 5° C. for 50 minutes and was evaporated to dryness. The residue was taken up in aqueous sodium bicarbonate solution and the solution was extracted with ethyl acetate. The organic phase was washed with aqueous saturated sodium chloride and then with aqueous N hydrochloric acid and then with aqueous saturated sodium chloride solution, dried and evaporated to dryness. The residue was crystallized from isopropyl ether and was vacuum filtered. The product was rinsed with isopropyl ether and dried at 60° C. under reduced pressure to obtain 2-[1,1-dimethylethoxycarbonylamino]-N-[(20S)-5α-pregnan-20-ol-3α-yl]-propanamide melting at 171° C.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=443.03.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23](=[O:25])[NH2:24])=[C:17]([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH:38]=4)=[CH:29][CH:28]=3)[N:16]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[N:16]=[C:17]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH:38]=3)=[CH:29][CH:28]=2)[C:18]([C:23]([NH2:24])=[O:25])=[N:19][C:20]=1[CH2:21][CH3:22]
Reactant: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(N)=O)c(Oc2ccc(C3=CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a mixture of tert-butyl[3-({5-carbamoyl-3-ethyl-6-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazin-2-yl}oxy)phenyl]carbamate (150 mg) and dichloromethane (3 mL) was added trifluoroacetic acid (421 μL), followed by stirring at room temperature for 2 hours. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and then the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol=1:0-95:5) to obtain 5-(3-aminophenoxy)-6-ethyl-3-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazine-2-carboxamide (56 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]1[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=1)OC1C=CC=CC=1)#[N:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:25]([NH:24][C:22]#[N:23])=[N:33][CH2:34][CH2:35][S:36][CH2:37][C:38]2[N:39]=[C:40]([NH:43][C:44]([NH2:46])=[NH:45])[S:41][CH:42]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (2.6 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.98 g (2.6 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=585 ([M+H]+, 6), 230 (100); IR (KBr): 2164 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 160° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1([C:9]([F:12])([F:11])[F:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C([NH2:20])C1C=CC=CC=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl.CCO.[Pd]>[NH2:20][CH:5]1[CH2:6][CH2:7][C:2]([C:9]([F:12])([F:11])[F:10])([OH:1])[CH2:3][CH2:4]1
Reactant: O=C1CCC(O)(C(F)(F)F)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CC(=O)O
Product: NC1CCC(O)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 82.2 %

Procedure:
4-hydroxy-4-(trifluoromethyl)cyclohexanone (570 mg, 3.13 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of benzylamine (0.38 ml, 3.44 mmol), NaBH(OAc)3 (1.06 g, 5.01 mmol), and acetic acid (0.18 ml, 3.13 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, and then filtered, concentrated under reduced pressure, and dried under vacuum. The residue thus obtained was dissolved in EtOH (20 ml), followed by addition of Pd (10 wt % on activated carbon, 80 mg), and then the resulting mixture was stirred at room temperature under hydrogen stream for 15 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 471 mg of yellow solid (82%).
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1>O.[Cu]>[Br:10][C:11]1[CH:16]=[C:15]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[N:13][CH:12]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccccc1
Agent: [Cu]
Agent: [Na]
Solvent: O
Product: Brc1cncc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
Under a nitrogen atmosphere, small pieces of sodium (1.48 g, 64.4 mmol) were added to benzyl alcohol (17.11 g, 158 mmol), and the mixture was stirred and heated at 70° C. for 18 h. To the stirring, viscous mixture was added 3,5-dibromopyridine (5.00 g, 21.1 mmol), copper powder (0.255 g, 4.0 mmol) and benzyl alcohol (15 mL). The mixture was further heated at 100° C. for 48 h. The reaction mixture was allowed to cool to ambient temperature, diluted with water (50 mL), and extracted with ethyl ether (5×50 mL). The combined ether layers were dried (Na2SO4), filtered, and concentrated. Distillation at 68-72° C. and 2.6 mm Hg removed excess benzyl alcohol. The remaining yellowish, brown residue was purified by vacuum distillation at 0.05 mm Hg to yield 3.17 g (38.0%) of a white, crystalline solid, mp 64-66° C.
Reaction SMILES: [N:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccccn1)C(c1ccccc1)N1CCOCC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccn1)C(c1ccccc1)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-Morpholin-4-yl-2-phenyl-1-pyridin-2-yl-ethanone (15 mg, 0.053 mmol) was dissolved in 3 mL of dry THF and cooled to −78° C. Phenylmagnesium bromide (159 μL, 1.0 M solution in TBH, 0.159 mmol) was added dropwise and the mixture was allowed to stir for 15 minutes. The reaction was quenched with 1 mL of aqueous NaHCO3(sat) and warmed to ambient temperature. The mixture was poured into NaHCO3 (sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The appropriate fractions were poured into NaHCO3(sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C:4]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>COCCOC>[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C:4]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=[S:35])[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:3]=1
Reactant: CC1(c2cc(NC(=O)c3ccc(Cl)cc3)ccc2F)COCC(N)=N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC1(c2cc(NC(=S)c3ccc(Cl)cc3)ccc2F)COCC(N)=N1
Temperature: 70 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A solution of (RS)-N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide (0.056 g, 0.2 mmol) in 1,2-dimethoxyethane (2 ml) was treated with Lawesson's reagent (0.083 g, 0.2 mmol). After heating to 70° C. the dispersion turned into solution; the temperature was kept during 16 hours. Another 0.5 eq of Lawesson's reagent were added to complete the reaction and heating was continued at 80° C. After 2 days the reaction was still incomplete. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on an Isolute flash NH2 column using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. There were obtained 0.006 g (10% of theory) of (RS)-N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide (27) as a yellow solid. Mass (calculated) C18H17ClFN3OS [377.87]; (found) [M+H]+=378.
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>C1COCC1>[O:28]=[C:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20]
Reactant: O=C1CCCN1CCl
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCN1CCCC1=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 8.5 %

Procedure:
Heated at 50° C. a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.0 g, 6.86 mmol) in anhydrous THF (100 mL) was oil bath for 20 min. Add to it a solution of N-(chloromethyl)-2-pyrrolidinone (1.10 g, 8.23 mmol) in anhydrous THF (5 mL) dropwise. After 3 hrs, cool the reaction to ambient temperature. Add water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic layers and wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 10-gram silicagel cartridge, eluting with ethyl acetate and then 5% methanol in ethyl acetate. Combine product containing fractions and concentrate to give the title compound as an off-yellow solid (205 mg): MS 313(M+H), TLC (silica gel, MeOH/EtOAc 1:1). Rf=0.33, 1H NMR (DMSO-d6) δ 11.78 (1H, s), 8.47 (1H, s), 8.09 (2H, d, J=6.2 Hz), 7.49 (3H, m), 7.09 (1H, m), 6.59 (2H), 5.76 (residual CH2Cl2), 5.44 (2H, s), 3.37 (2H, m), 2.22 (2H, m), 1.87 (2H, m).
Reaction SMILES: [SH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.COS(C1C=CC(C)=CC=1)(=O)=O.C1(N=C=NCCN2CCOCC2)CCCCC1.Cl.[CH3:51][O:52][C:53](=[O:56])[CH2:54][NH2:55]>CN(C=O)C.C(N1CCOCC1)C.C(OCC)(=O)C.CCCCCCC>[CH3:51][O:52][C:53]([CH2:54][NH:55][C:8]([C:3]1[C:2]([SH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])=[O:56]
Reactant: O=C(O)c1ncccc1S
Reactant: COC(=O)CN
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CNC(=O)c1ncccc1S

Procedure:
1.69 g of 3-mercaptopyridine-2-carboxylic acid were dissolved in 20 ml of DMF and 7.5 ml of N-ethylmorpholine, 1.7 g of 1-hydroxy-1H-benzotriazole, 5 g of N-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide methyl-p-toluenesulfonate and 4.3 g of glycine methyl ester hydrochloride were added successively at room temperature and whilst stirring. After having been stirred for 12 hours, the mixture was partitioned between a saturated aqueous solution of ammonium chloride and dichloromethane and the organic phase was dried and concentrated by evaporation; the residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptane); yield, 0.65 g of colourless crystals of m.p. 178°-179° C. (ethyl acetate/heptane).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[ClH:5].[Al+3:6].[Cl-].[Cl-].[Cl-]>>[C:2]([Cl:5])([CH3:3])([CH3:1])[CH3:4].[Al+3:6].[Cl-:5].[Cl-:5].[Cl-:5]
Reactant: C=C(C)C
Reactant: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)Cl

Procedure:
A continuous process for preparing low molecular weight polyisobutylene having an Mn in the range of 700 to 3,000 and a molecular weight distribution less than about 2.0 from a feedstream mixture of C4 hydrocarbons containing at least about 6% by weight isobutylene in a continuous stirred reactor maintained at a reaction temperature of about -50° to +30° C., the reactor having a feedstream inlet and a separate AlCl3 catalyst inlet, which comprises injecting gaseous HCl, in an amount of 25 to 200 ppm parts by weight of feedstream and in the absence of AlCl3, into said feedstream at a point prior to its entry into the reactor in a manner sufficient to permit substantially complete reaction of the HCl with isobutylene to form t-butyl chloride before contact with AlCl3 such that the resulting pre-reacted feedstream at the point of reactor entry contains less than 1.0 ppm HCl, and simultaneously adding the pre-reacted feedstream and the AlCl3 catalyst to the reactor and contacting the pre-reacted feedstream with said catalyst in the reaction mixture to form the polyisobutylene, withdrawing the reaction mixture from the reactor, quenching the reaction with aqueous alkali and separating therefrom the polyisobutylene product.