Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:21]=[O:22]>>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[CH:21]=[O:22])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2ccnn2C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2c(C=O)cnn2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (300 mL) was cooled to 0° C. and treated with phosphorus oxychloride (80 g, 0.52 mol). After completion of the addition, the resulting mixture was warmed to room temperature and stirred for 1 hour. 5-(4-Methylphenyl)-1-methyl-1H-pyrazole (C2) (30.0 g, 174 mmol) was added and the reaction mixture was heated to 120° C. and stirred overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice-water (700 mL), then adjusted to a pH of approximately 8 with saturated aqueous sodium carbonate solution. The resulting mixture was extracted with dichloromethane (4×300 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 1:100 to 1:30 ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 28.2 g, 141 mmol, 81%. 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.81 (s, 3H), 7.33 (br AB quartet, JAB=8 Hz, ΔνAB=17 Hz, 4H), 8.04 (s, 1H), 9.60 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C@H]1N[C@H](C)CC1>>[CH3:6][C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:25])[N:1]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]3=[CH:14][C:13]=2[CH:12]=1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Reactant: C[C@@H]1CC[C@@H](C)N1
Product: C[C@H]1CC[C@H](C)N1CCCOc1ccc2c(c1)cc1n2CCNC1=O
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available), to give the desired product as a white solid (7%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 96.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (28 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.I[C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1.CC([O-])=O.[K+].CN(C=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].CCCCCC.CCOCC>[O:22]1[C:19]2[CH:20]=[CH:21][C:16]([C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12][C:13]#[N:14])=[CH:17][C:18]=2[O:24][CH2:23]1
Reactant: COc1cc(/C=C/C#N)cc(OC)c1
Reactant: Ic1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCO3)c1
Reaction time: 1 h
Yield: 31 %

Procedure:
(E)-3-(3,5-dimethoxy-phenyl)-acrylonitrile (0.4 g, 2.1 mmol), 4-iodo-1,2-(methylenedioxy)benzene (0.75 g, 3 mmol), Pd(OAc)2 (0.047 g, 0.21 mmol), KOAc (0.62 g, 6.3 mmol) and tetrabutylammonium bromide (0.75 g, 2.3 mmol) were placed in a microwave vial, DMF (3 mL) added and the reaction mixture degassed. The vial was placed in the microwave oven (Emrys Optimizer) at 150° C. for 1 hour. The contents were poured into a water-EtOAc mixture (40 mL, 1:1) and filtered through Celite® washing the filtrate with EtOAc. The organic layer was separated and the crude product isolated by CC (silica gel, hexanes:EtOAc, 3:1 to 1:1). Sonication of the purified solid with an ether:hexane mixture yields (E) 3-benzo[1,3]dioxol-5-yl-3-(3,5-dimethoxy-phenyl) -acrylonitrile (0.2 g, 0.65 mmol) in 31% yield: m.p 95-96° C.; 1H NMR (CDCl3) δ 6.85-6.82 (m, 1H, Ar), 6.79-6.78 (m, 2H, Ar), 6.55-6.52 (m, 3H, Ar), 6.01(s, 2H, CH2), 5.63(s, 1H, CH), 3.8 (s, 6H, 2CH3). Anal. Calcd. for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.69; H, 5.12; N, 4.46.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.C(O)(=O)C.CO>[Pd].C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A stirred mixture of 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (500 mg), 10% Pd-C (50% wet, 1.0 g) and acetic acid (50 ml) was hydrogenated at 70° C. and at atmospheric pressure for 3 hours. Methanol (20 ml) and chloroform (20 ml) were added to the mixture and the whole was heated at 60° C. for 5 minutes. The mixture was filtered hot and the filtrate was concentrated in vacuo. A solution of the residue in ethyl acetate was successively washed with saturated aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. The solvent was removed and the residue was recrystallized from ethanol to yield 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl}-2,4-thiazolidinedione (the same compound as that obtained in Example 12) as crystals (415 mg, 82.7%). m.p. 113°-114° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2cccnc2N(CC#CCN2CCCCC2)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(CCCCN2CCCCC2)c2ccccc21
Yield: 35 %

Procedure:
Prepared analogously to Example 8 from 5,11-dihydro-11-[4-(1-piperidinyl)-but-2-ynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in a yield of 35% of theory. Colourless crystals, m.p. 131°-132° C. (ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 3-hydroxypropanoate (2 g, 13.68 mmol) in dry DCM (50 ml), pyridine (3.32 ml, 41.0 mmol) was added. The solution was cooled to 5° C., and (chloromethanetriyl)tribenzene (3.81 g, 13.68 mmol) was added portion-wise; the ice cooling was removed and stirring was continued for 20 hours. The solvent was evaporated and the residue was portioned between EtOAc and water; the organic layer was washed with a 3% aqueous solution of citric acid, with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (petroleum ether:EtOAc=95:5) affording tert-butyl 3-(trityloxy)propanoate (3.5 g, 9.01 mmol, 65.8% yield, MS/ESI+ 411.3 [MNa]+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(N(CC)CC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:11][CH2:12][CH2:13][S:14]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NCCS
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1ccc(C2NCCS2)cc1

Procedure:
The procedure of Example 1 was repeated, except that the reactants consisted of 18.5 g. of 4-bromobenzaldehyde and 27 g. of 2-aminoethanethiol hydrochloride, and the reaction mixture also contained 10 ml. of triethylamine. Since removal of solvent left a solid residue, the material was recrystallized from benzene/hexane to give 2-(4-bromophenyl)thiazolidine, m.p. 105°-7°. The following elemental analysis was obtained:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:41])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 0.40 g (0.94 mmol) of the product of Example 37 in 10 mL of DMF was added 0.047 g (1.171 mmol) of a 60% suspension of sodium hydride in minena oil. The resulting mixture was stirred at room temperature for 0.5 h and then 0.277 mL (1.873 mmol) of t-butylbromoacetate was added in one portion. Th reaction mixture was stirred for an additional 18 h and then diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.423 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 524.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]=[O:19].[CH:25]([Mg]Br)([CH3:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=1[CH:18]([OH:19])[CH:25]([CH3:27])[CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(C)cc3C(O)C(C)C)c2cc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylbenzaldehyde (105.3 mg) was dissolved in tetrahydrofuran (3 ml) to prepare a solution, and the solution was then cooled to −78° C. A 0.68 M tetrahydrofuran solution (0.6 ml) of isopropylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-2-methyl-1-propanol (11.5 mg, yield 10%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1)=O.[Li].[H-].O>C1COCC1>[OH:2][CH2:3][C:5]1[O:6][C:7]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([OH:16])=[CH:10][C:8]=2[CH:9]=1
Reactant: COC(=O)c1cc2cc(O)c(C)c(C)c2o1
Agent: [H-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O)cc2cc(CO)oc2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester (231 mg) prepared as in Example 2, was dissolved in THF and lithium alumininum hydride (93 mg) was added. The mixture was stirred at room temperature for 4 h. Then the solution was poured into water and extracted with ethylacetate. The ethyl acetate was washed with water and brine, dried over MgSO4 and concentrated. Purification by silica gel column eluting with 50% EtOAc in hexane gave 89 mg of 2-Hydroxymethyl-6,7-dimethyl-benzofuran-5-ol. 1HNMR (CD3OD, 300MHz) δ: 6.75, 1H), 6.47 (s, 1H), 4.61 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H) ppm. 13CNMR (CD3OD, 75 MHz) δ: 155.87, 150.51, 148.68, 124.69, 119.93, 119.20, 103.01, 101.62, 56.32, 10.43, 10.29 ppm. MS: 175 (M—OH)+.
Reaction SMILES: [CH3:1][CH:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[OH-].[Li+].C1COCC1.CO>O>[CH3:1][CH:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:13]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:9])[CH3:10])(=[O:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 292.5 %

Procedure:
Methyl 4-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethoxy)phenyl]benzoate (30 mg, 0.077 mmol), lithium hydroxide (11 mg, 0.268 mmol), THF (1.2 mL), methanol (0.4 mL) and deionized water (0.4 mL) were combined in a 15 mL round bottomed flask and stirred at room temperature overnight. The reaction mixture was concentrated in-vacuo, and dissolved in 1 N sodium hydroxide. This solution was acidified (pH=2) with 1 N hydrochloric acid, and was extracted three times with methylene chloride. The organic extractions were combined, washed with 15 mL water, dried with magnesium sulfate, filtered, and concentrated in-vacuo, yielding 85 mg of yellow solid. This material was further purified using a 1000 uM rotor on a Chromatotron in a 1:1 methylene chloride:ethyl acetate solvent system to provide the title compound (65 mg, 100%) as waxy brown paste.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([CH:21]2[CH2:30][CH2:29][C:24]3(OCC[O:25]3)[CH2:23][CH2:22]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1.Cl>C1COCC1>[CH3:31][C:2]([CH3:1])([CH3:32])[C:3]#[C:4][C:5]1[S:9][CH:8]=[C:7]([N:10]([CH:21]2[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]2)[C:11]([C@@H:13]2[C@@H:18]([CH3:19])[CH2:17][C:16]([CH3:20])=[CH:15][CH2:14]2)=[O:12])[CH:6]=1
Reactant: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC3(CC2)OCCO3)[C@@H](C)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC1=CC[C@H](C(=O)N(c2csc(C#CC(C)(C)C)c2)C2CCC(=O)CC2)[C@@H](C)C1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
(1S,6S)-4,6-Dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide (5.6 g, 12 mmol) was dissolved in THF (70 mL) and treated with 4M HCl (35 mL). The reaction mixture was heated to 45° C. and stirred for 2.5 h. THF was removed in vacuo, and the aqueous layer was thrice extracted into ethyl acetate. The combined organic layers were washed with saturated NaHCO3(aq), water, and brine, dried over MgSO4, filtered, and concentrated to give (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-oxo-cyclohexyl)-amide (5.05 g, 12 mmol).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.S(=O)(=O)(O)[OH:23]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:23])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Product: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
A mixture of 3.0 g of 7-(α,α,α-trifluoro-m-tolyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005) and 150 ml of concentrated sulfuric acid was stirred at room temperature for 4 hours. The solution was then carefully poured into ice water with stirring. The white precipitate formed was collected, washed with water and then with saturated sodium bicarbonate until it was neutral. The solid was heated with one liter of isopropyl alcohol and filtered. The white solid was dried in vacuo and gave the product of the example as a colorless solid, m.p. 256°-258° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].N1C=CN=C1.[Cl-].[C:16]([SiH:20]([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: C[SiH](C)C(C)(C)C
Reactant: OCc1ccccc1Br
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.6 %

Procedure:
2.0 g of (2-bromophenyl)methanol are placed in a round-bottomed flask and dissolved in 100 ml of tetrahydrofuran. 1.1 g of 1H-imidazole are added thereto, followed by 2.1 g of tert-butyldimethylsilane chloride, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolysed with water, and the organic phase, which has been extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 2.66 g of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:12][C:11]([C:29](OC)=[O:30])=[N:10]1.[F-].[K+].Cl.[CH:36]([OH:39])([CH3:38])[CH3:37]>>[NH2:26][S:25]([C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C:13]3[N:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[C:11]([C:29]([O:39][CH:36]([CH3:38])[CH3:37])=[O:30])[CH:12]=3)=[CH:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:28])=[O:27]
Reactant: CC(C)O
Reactant: COC(=O)c1cc(-c2ccc(-c3cccc(S(N)(=O)=O)c3)s2)n(-c2cc(Cl)ccc2Cl)n1
Agent: Cl
Agent: [F-]
Agent: [K+]
Product: CC(C)OC(=O)c1cc(-c2ccc(-c3cccc(S(N)(=O)=O)c3)s2)n(-c2cc(Cl)ccc2Cl)n1
Temperature: 82.5 °C

Procedure:
Into a 25 mL flask was weighed 114 mg (224 mmol) of methyl 1-(2,5-dichlorophenyl)-5-(5-(3-sulfamoylphenyl)thiophen-2-yl)-1H-pyrazole-3-carboxylate, 156 mg of KF, 4 mL of isopropyl alcohol, and 200 μL of concentrated HCl. The reaction was heated at 80-85° C. for 3 days. The reaction was then washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. Product was further purified by silica gel flash chromatography (Jones Flashmaster, 25 g SiO2, gradient elution from 20% ethyl acetate to 60% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless powder, yield: 53.3 mg (44%). 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.44-7.51 (m, 3H), 7.21 (d, J=4 Hz, 1H), 7.13 (s, 1H), 6.81 (d, J=4 Hz, 1H), 5.33 (heptet, J=6 Hz, 1H), 5.08 (s, 2H), 1.41 (d, J=7 Hz, 6H); MS (ES): 536 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[C:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18]>ClCCCl.ClCCl.O>[C:17]([N:20]1[CH2:25][CH2:24][N:23]([C:8]([NH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(C(=O)Nc2ccncc2)CC1
Temperature: 60 °C
Reaction time: 9 h
Yield: 77 %

Procedure:
To a solution of O-phenyl N-(4-pyridyl)carbamate (446 mg) in 1,2-dichloroethane (5 ml) was added a suspension of 1-acetylpiperazine (1.12 g) in 1,2-dichloroethane (20 ml) at ambient temperature. The mixture was heated at 60° C. with stirring for 9 hours. The mixture was cooled to ambient temperature, and diluted with dichloromethane and water. The aqueous phase was separated and adjusted to pH 11.5 with sodium hydroxide solution. Excess sodium chloride was added to the aqueous solution. The mixture was extracted with a mixture of dichloromethane and methanol (about 10:1) and the organic phase was washed with brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 100 ml, dichloromethane:methanol aqueous ammonia=10:1:0.1). After rinse with diisopropyl ether, 1-acetyl-4-(4-pyridylaminocarbonyl)piperazine (398 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([SH:8])[CH2:5][NH:6][CH3:7].[OH-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C(=O)(O)[O-].[Na+]>CCOCC>[CH2:14]([S:8][C:4]([CH2:3][O:2][CH3:1])([CH2:9][O:10][CH3:11])[CH2:5][NH:6][CH3:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCC(S)(COC)COC
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CNCC(COC)(COC)SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.8 %

Procedure:
1,1-Bis(methoxymethyl)-2-(methylamino)ethanethiol (6 g) was stirred with aqueous sodium hydroxide (60 cm3, 2M) for a short time and then benzyl chloride (4.3 g) was added. This mixture was stirred at room temperature for 3 h and then made slightly acidic (~pH 4) by the addition of dilute hydrochloric acid. The mixture was extracted with chloroform, and the chloroform then removed under reduced pressure to give a viscous oil which gave a solid on trituration with ether. The free amine was liberated from the hydrochloride salt by the addition of saturated aqueous sodium bicarbonate and then extracted into chloroform. The chloroform extracts were dried (Na2SO4) and the solvent removed under reduced pressure to give the amine (3.5 g) as a brown oil.