Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[CH2:6].Cl[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[C:19]1([P:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[CH3:10])[CH:5]=[CH2:6])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=Cc1ccc(C)c(Br)c1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C)c(P(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Mg (0.72 g, 30 mmol) was placed in a 50 mL of round-bottom flask. The flask was dried and filled with nitrogen. Anhydrous THF (10 mL) was injected first and followed by injection of a half amount of a solution of 3-bromo-4-methyl-styrene (3.94 g, 20 mmol) in anhydrous THF (10 mL). After an exothermic reaction started, the second half of the solution was added. The resulting Grignard reagent was added to a solution of chlorodiphenylphosphine (5.25 g, 25 mmol) in anhydrous THF (10 mL) at 0° C. After the addition, the reaction mixture was warmed to the room temperature and stirred for another 20 h. Then, it was poured into a saturated NH4Cl aqueous solution (10 mL) at 0° C. and extracted with anhydrous THF (3×20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated to a volume of 5 mL. Hexane was added into the resulting oil to precipitate by-products. After filtration and concentration, the residue was purified by a flash column chromatography (hexane/EAC=4/1) to afford 2.42 g of the desired product (39% yield). 1H NMR (300 MHz, CDCl3) δ 2.36 (3H, s), 5.06 (1H, d, J=10.9 Hz), 5.42 (1H, d, J=17.6 Hz), 6.48 (1H, q, J=10.9, 17.6 Hz), 6.79 (1H, q, J=2.1, 5.8 Hz), 7.20–7-34 (11H, m); 13C NMR (75 MHz, CDCl3) δ 20.8, 21.1, 113.0, 126.2, 128.5, 128.6, 128.8, 130.2, 130.3, 130.7, 133.9, 134.1, 135.1, 136.0, 136.3, 136.5, 141.7 ppm; 31P NMR (121 MHz, CDCl3) δ−12.34 ppm; IR (neat) 3057 (m), 3016 (s), 2974 (m), 1957 (w), 1900 (w), 1819 (w), 1629 (m), 1589 (m), 1479 (s), 1435 (s), 1380 (m), 1306 (w), 1262 (m), 1179 (m), 1152 (m), 1093 (m), 1028 (m), 992 (m), 911 (s), 830 (s), 699 (s); MS m/z 302 (M+) 223, 183, 165, 152, 115, 78; HRMS calcd for C21H19P 302.1224, found 302.1227.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 31.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (97 mg, 0.20 mmol) obtained in Example 86, step 2 and cyclopropanesulfonamide (120 mg, 1.00 mmol), the title compound (37 mg, 32%) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[C:16]1([C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=[CH:25][CH:26]=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[OH:27][CH:26](/[CH:25]=[CH:24]/[CH:23]=[C:22]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: O=CC=CC=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/C=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A 60% dispersion of sodium hydride (0.095 g of dispersion, 0.057 g of NaH, 2.4 mmol) was triturated with anhydrous THF (3×20 ml). The pure sodium hydride was then suspended in anhydrous THF (10 ml) and cooled to 0° C. Methyl acetoacetate (0.227 g, 1.95 mmol) was added dropwise. After stirring the resulting colorless solution for 10 minutes at 0° C., butyllithium in hexanes (0.96 ml, 2.5M, 2.4 mmol) was added dropwise via syringe. After stirring the reaction mixture for another 10 minutes at 0° C., a solution of 5,5-diphenyl-2,4-pentadienal (0.410 g, 1.75 mmol) in anhydrous tetrahydrofuran (10 ml) was added slowly via syringe. After completion of the addition, the reaction was stirred for 10 minutes at 0° C. The reaction mixture was then quenched by pouring it into saturated aqueous ammonium chloride. After stirring vigorously for 5 minutes, the phases were separated and the aqueous phase was extracted with ether (3×25 ml). The combined organic phases were washed with saturated aqueous sodium bicarbonate (40 ml) and water (2×40 ml), dried over magnesium sulfate and concentrated in vacuo to give 0.610 g (98% yield) of methyl (E)-5-hydroxy-9,9-diphenyl-3-oxo-6,8-nonadienoate as a viscous liquid. Since this material was quite pure and unstable on silica gel, it was carried onto the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:26]2[CH2:30][N:29](C(OC(C)(C)C)=O)[C@H:28]([CH2:38][OH:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:26]2[CH2:30][NH:29][C@H:28]([CH2:38][OH:39])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C[C@H]1CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC[C@@H]1C[C@@H](c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1

Procedure:
(2S,4S)-tert-butyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.084 g, 0.154 mmol) in 2 mL DCM was added trifluoroacetic acid (0.200 mL) After 3 d, the reaction mixture was concentrated, dissolved in DMSO, filtered, and purified by RPHPLC, gradient, 10-100% ACN/TFA in H2O/TFA. Product-containing fractions were concentrated in vacuo to give ((2S,4S)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)pyrrolidin-2-yl)methanol. MS (ESI) m/z: Calculated: 445.2; Observed: 445.8 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([OH:41])[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH3:33])(=[O:23])=[O:22])[C:16](=[O:34])[C:15]2([O:41][C:9](=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:35]1[S:36][CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(OC(=O)Nc3ccc(Cl)cc3)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
4-Chlorophenyl isocyanate (32 mg, 0.208 mmol) and DMAP (5 mg) were successively added to a solution of Example 62 (100 mg, 0.21 mmol) in toluene (20 ml) and stirred at 90° C. for 30 min. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The organic phase was washed with dilute citric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from methanol resulted in 80 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:13][C:14]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:15]=1>>[Cl:13][C:14]1[N:15]=[C:16]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:17]=[C:18]([NH:12][S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]
Reactant: Cc1ccc(NS(N)(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C)cn1
Yield: 17 %

Procedure:
According to the procedure described in referential Example 1e), 5-methyl-pyridine-2-sulfamic acid amide (252 mg, Referential Example 20) was reacted with 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (410 mg, Referential Example 1d)) to give 5-methyl-pyridine-2-sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (100 mg). tR=4.02 min (LC); [M+H]+=499.33 (ES+);
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][O:28][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
In a four necked round bottom flask, triphosgene (5.45 g, 55.1 mmol) was dissolved in toluene (80 mL) under argon. After cooling at 0° C., pyridine (4.8 mL, 58.8 mmol) was added dropwise during 1 h and the resulting suspension stirred for further 1 h at 0° C. 3-phenyl-1-propanol (5 mL, 36.8 mmol) was added dropwise in 30 min. After stirring at rt for 24 h, the solid was filtered off and the solvent removed under vacuum, yielding the title compound (6.2 g, 85%) as pale yellow oil, which was used in the next step without further purification. FTIR (cm−1): 3086, 3065, 3027, 2995, 2932, 2862, 1776, 1743, 1603, 1496, 1454, 1262, 1148, 745, 699.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:6])(=[O:38])[CH3:37]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(NC(C)=O)c2)c1
Yield: 84.8 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (216.0 mg, 0.45 mmol) and acetic anhydride (0.051 ml, 0.54 mmol), the procedure of Inventive Example 97 was repeated to obtain 197.5 mg (84.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)=[CH:11][C:10]=1[CH3:24])C1C=CC=CC=1.C(O)C.[H][H]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:24][C:10]1[CH:11]=[C:12]([N:15]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1O
Yield: 86.7 %

Procedure:
A mixture of 1-(4-(benzyloxy)-3-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (670 mg, 2.0 mmol), 20% palladium hydroxide on activated carbon (50 mg), ethanol (20 ml), and THF (20 ml) was shaken under 40 psi of hydrogen gas at the ambient temperature for 3 days and at +50° for 1 day, to drive reaction to completion. The reaction was filtered through a pad of Celite and the mother liquor was concentrated to obtain the target product as a colorless solid (420 mg, 86%). MS (M+1): 243.0.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1>C(O)C.C[O-].[Na+]>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:4][N+:1]([O-:3])=[O:2])([OH:12])[CH2:8][CH2:7]1
Reactant: CN1CCC(=O)CC1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(O)(C[N+](=O)[O-])CC1
Yield: 73.4 %

Procedure:
Nitromethane (6.6 mL, 122.0 mmol) and sodium methoxide (0.94 mL of 25 wt % in methanol, 4.1 mmol) were added to a solution of 1-methyl-4-piperidone (10 mL, 81.3 mmol) in ethanol (10 mL). After 30 minutes more ethanol (15 mL) was added to facilitate stirring. The reaction mixture was stirred at ambient temperature for 2 days and then filtered. The isolated solid was rinsed with ether to provide 10.39 g of 1-methyl-4-nitromethylpiperidin-4-ol as a white powder. An additional 1.18 g was isolated from the filtrate.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].CN(C)C=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:1](=[O:2])[O:25][C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19]2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(NNC(=O)C(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)oc2=O)cc1

Procedure:
12 ml of a (20%) solution of phosgene in toluene are added dropwise, at room temperature, to a mixture of 50 ml of toluene, 0.1 ml of N,N-dimethylformamide and 2.3 g of N-(4-methoxyphenyl)-N′-pivaloyl-hydrazine. The reaction mixture is stirred at reflux for 7 hours and then concentrated. After purification of the residue on silica gel, 1-methoxy-4-(5-oxo-2-tert-butyl-3,4-diaza-1-oxa-cyclopent-2-en-4-yl)-benzene is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20](O)([CH3:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1>C1COCC1>[C:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:22])=[CH2:21]
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Solvent: C1CCOC1
Product: C=C(C)c1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
2-[5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-propan-2-ol 115 (0.4 g, 1.3 mmol) and Burges Reagent (0.4 g, 1.7 mmol) in THF (10 ml) were heated to reflux. After 30 min, the reaction was cooled, concentrated and the product was purified by column chromatography on silica gel (10% EtOAc/Hexane) to give 116 as a solid (0.29 g, 77%).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([CH2:17][N:18]([CH3:20])[CH3:19])[S:15][CH:16]=1)=[N:4][C:5]#[N:6].[ClH:21].C([OH:24])C>>[ClH:21].[ClH:21].[CH3:1][NH:2][C:3]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[C:14]([CH2:17][N:18]([CH3:19])[CH3:20])[S:15][CH:16]=1)=[N:4][C:5]([NH2:6])=[O:24]
Reactant: CNC(=NC#N)NCCSCc1csc(CN(C)C)n1
Reactant: CCO
Agent: Cl
Product: CNC(=NC(N)=O)NCCSCc1csc(CN(C)C)n1
Reaction time: 96 h

Procedure:
About 0.6 g. of N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-cyanoguanidine were dissolved in 8 ml. of 1.5 N aqueous hydrochloric acid. The resulting solution was allowed to remain at ambient temperature for about four days. Volatile constituents were then removed by evaporation in vacuo. The resulting residue, comprising N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-aminocarbonylguanidine dihydrochloride formed in the above reaction, was dissolved in ethanol and the ethanol removed by evaporation. The residue obtained thereby was recrystallized from isopropanol. The crystalline product was collected and digested with ethyl acetate. The ethyl acetate was removed by evaporation and the product obtained was crystallized from isopropanol to yield N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethyl-N"-aminocarbonylguanidine dihydrochloride melting at 156.5°-159.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1>S(=O)(=O)(O)O.C(O)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A mixture of 6.0 g of ethyl(2,3,4,5-tetrafluorobenzoyl)acetate, 5.8 g of ethyl orthoformate and 6.3 g of acetic anhydride was refluxed for 2 hours. After distillation under reduced pressure, the residue was dissolved in 50 ml of ethanol. To this solution, 2.8 g of 2-aminomethylthiazole was added, followed by stirring for 2 hours, while ice cooling. The reaction product was added to 100 ml of ice water, and the resulting crystal was collected by filtration and dried. The 8.0 g crystal obtained was dissolved in 50 ml of dimethylformamide, and 2.0 g of 60% oily sodium hydride was added, followed by heating and stirring at 100 to 110° C. for 2 hours. The reaction product was added to 100 ml of ice water and extracted with dichloromethane (100 ml ×3). The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure, to yield 5.4 g of ethyl 1-(thiazol-2-yl)methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate. Next, 5.0 g of this ester was dissolved in a mixture of 3 ml of sulfuric acid, 20 ml of acetic acid and 18 ml of water, followed by stirring at 110° to 120° C. for 1.5 hours. The reaction product was added to 100 ml of ice water to cause crystallization. The resulting crystal was collected by filtration, washed with water and dried to yield 4.4 g of the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:22])([F:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:20])=[CH:10][CH:9]=1)([OH:7])[CH3:6].C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>C(Cl)Cl>[F:22][C:4]([F:3])([F:21])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:35]([C:32]3[CH:33]=[CH:34][O:30][CH:31]=3)(=[O:37])=[O:36])[CH2:16][C@@H:15]2[CH3:20])=[CH:12][CH:13]=1)([OH:7])[CH3:6]
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: C[C@H]1CNCCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(S(=O)(=O)c2ccoc2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (100 mg, 0.277 mmol) and triethylamine (0.115 mL, 0.830 mmol) in CH2Cl2 (4.0 mL) was added 3-furansulfonyl chloride (55.3 mg, 0.332 mmol, Ryan Scientific, Inc., Mt. Pleasant, S.C.). After 30 min at room temperature, the reaction was concentrated and purified via column chromatography (12 g of silica, 0 to 70% EtOAc in hexanes) to yield 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol (25 mg) as a mixture of two isomers.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[NH2-].[Na+].[C:15](#[N:17])[CH3:16]>>[CH3:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([CH2:16][C:15]#[N:17])=[O:12]
Reactant: COC(=O)c1ccccc1OC
Reactant: CC#N
Agent: [NH2-]
Agent: [Na+]
Product: COc1ccccc1C(=O)CC#N
Yield: 84 %

Procedure:
In agreement with this data the condensation of 2-methoxybenzoic acid methyl ester with acetonitrile using sodamide/liquid ammonia gives 2-methoxybenzoylacetonitrile in 84% yield, in contrast this same reaction using sodium hydride in benzene only leads to a 27.4% reaction yield. (Kawase, Bull, Chem. Soc. Japan, Vol. 35 (1962), pages 1869-1871.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH2:28])=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[N:3]=1
Reactant: Cc1ccc(CN)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[N:12]1([CH2:7][C:6]2[CH:5]=[C:4]([OH:3])[CH:11]=[CH:10][CH:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCC2)c1

Procedure:
Sodium borohydride (15.2 g) was added to a solution of 3-hydroxybenzaldehyde (48.8 g) and pyrrolidine (66.4 ml) in ethanol. After 18 hours the ethanol was removed and the residual oil was acidified with hydrochloric acid and washed with ethyl acetate. The aqueous solution was then basified with ammonia and extracted with ethyl acetate. Evaporation of the organic extracts yielded the title compound as an off-white solid (21.4 g), m.p. 100°-102°. TLC Silica; methanol; 0.88 ammonia (80:1)Rf 0.48.