Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.[NH2:25][C:26]1[CH:35]=[C:34](F)[C:33]([CH3:37])=[C:32]2[C:27]=1[C:28](=[O:45])[C:29]([C:42]([OH:44])=[O:43])=[CH:30][N:31]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>CS(C)=O>[NH2:25][C:26]1[CH:35]=[C:34]([N:15]2[CH2:16][CH2:17][C@@H:13]([C:10]3([NH:8][CH3:9])[CH2:11][CH2:12]3)[CH2:14]2)[C:33]([CH3:37])=[C:32]2[C:27]=1[C:28](=[O:45])[C:29]([C:42]([OH:44])=[O:43])=[CH:30][N:31]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: Cc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3cc(N)c4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3C)C2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 19.9 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (690 mg, 2.25 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (4 ml), 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (250 mg, 850 μmol) was added thereto and heated under reflux in an oil bath of 70° C. for 24 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml) and saturated saline solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 70.0 mg (20%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of 1 g (3.75 mmol) of trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol in 10 ml of dimethylformamide is mixed with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine. This mixture is heated to 50° C. for 6 hours with stirring, then water is added and the mixture is extracted with methylene chloride. The organic phase is dried, evaporated down in vacuo and the residue remaining is purified by column chromatography (aluminium oxide basic, activity stage III, ICN; petroleum ether/ethyl acetate=15:1). Colourless oil. Yield: 0.79 g (69% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](B1OC(C)(C)C(C)(C)O1)=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:33]2[N:53]=[CH:54][C:55](I)=[C:32]2[N:31]=1>O1CCOCC1.O>[Cl:29][C:30]1[CH:35]=[C:34]([N:36]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:33]2[N:53]=[CH:54][C:55]([C:6]3[CH:7]=[N:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=4)=[C:32]2[N:31]=1
Reactant: CC1(C)OB(c2cnc3ccc(F)cc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (3.65 mmol, 996.4 mg), K3PO4 (9.12 mmol, 1933.6 mg), and PdCl2(dppf)CH2Cl2 (0.30 mmol, 248 mg) was added to a solution of 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.04 mmol, 1684.3 mg) in dioxane (18 mL) and H2O (3 mL). The resulting solution was stirred at 80° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=3.36 Min (5 min run, UV254nm). Mass calculated for, M+ 581.2, observed LC/MS m/z 582.2 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Temperature: 40 °C
Yield: 16.7 %

Procedure:
[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetic acid (100 mg, 0.30 mmol), (4-methoxyphenyl)methanol (204 mg, 1.48 mmol), TEA (123 μL) and DMAP (9 mg, 0.074 mmol) were dissolved in DCM (10 mL). DMF 81 mL) and EDC (113 mg, 0.59 mmol) was added and the solution was stirred at 40° C. over night. Aqueous K2CO3 (1M, 50 mL) was added and the reaction mixture was extracted with DCM. The organic phases were combined, dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC affording the title compound (23 mg, 17%). 1H NMR (CDCl3, 400 MHz) δ 1.69 (s, 9H), 3.54 (s, 2H), 3.77 (s, 3H), 4.98 (s, 2H), 5.79 (t, 1H), 6.83 (d, 2H), 7.17 (d, 2H), 7.32-7.40 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 27.7, 45.4, 55.5, 61.8, 67.6, 109.6, 114.2, 124.4, 127.0, 128.9, 130.1, 130.7, 131.5, 134.8, 159.2, 160.2, 168.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15][C:14]3=[O:23])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[CH3:25][N:26](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:23]=[C:14]1[N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]#[N:26])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15]1
Reactant: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2csc(N3C(=O)OCC3CC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-2-one (0.53 g, 1.3 mmol), prepared in step 3 of Example 67, and zinc cyanide (91 mg, 0.78 mmol) were dissolved in 15 mL of DMF. The mixture was purged with nitrogen for 15 min, tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) was added, and the mixture was heated at 120° C. for 3 h. The mixture was cooled and diluted with ethyl acetate and poured into 200 mL of water. The mixture was extracted with ethyl acetate, the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (25% hexane in methylene chloride) afforded racemic 4-{2-[2-oxo-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-3-yl]-1,3-thiazol-4-yl}benzonitrile (364 mg, 79%) as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([SH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20]Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20][S:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12][CH2:20][C:19]2[CH:18]=[C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(S)cc(S)c1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1

Procedure:
Methyl 3,5-dimercaptobenzoate (20.0 g, 100.0 mmol), 3,5-di-tertiarybutylbenzyl bromide (molecular weight 283.25, 57.0 g, 201.2 mmol) and potassium carbonate (molecular weight 138.21, 28.0 g, 202.6 mmol) were dissolved in 350 ml of acetone and the mixture was heated under reflux for 12 hours. The acetone and salts were removed, and the residue was purified by means of chromatography with dichloromethane as the developing solvent, giving methyl 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzoate as needles.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39](O)=[O:40])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH2:46]([O:48][C:49](=[O:64])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2([CH3:63])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1)[CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)[C:39]([N:60]3[CH2:61][CH2:62][C:57]([N:54]4[CH2:53][CH2:52][N:51]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:64])[CH2:56][CH2:55]4)([CH3:63])[CH2:58][CH2:59]3)=[O:40])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1
Reactant: CCOC(=O)CN1CCN(C2(C)CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C2(C)CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.10 mL (0.72 mmol) triethylamine were added to a mixture of 250 mg (0.45 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 140 mg (0.49 mmol) ethyl[4-(4-methyl-piperidin-4-yl)-piperazin-1-yl]-acetate (Example A8b) and 160 mg (0.50 mmol) TBTU in 2 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac. and the residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 nach 30:1). The fractions containing the product were combined, evaporated down i. vac. and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2s1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(CO)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In tetrahydrofuran (20 ml), 2-methylbenzothiazole-5-carboxylic acid (0.97 g, 5.00 mmol) prepared in the Step 37-1-1 was dissolved, and triethylamine (0.66 g, 6.50 mmol) was added thereto. Under an ice cooling, ethyl chloroformate (0.71 g, 6.50 mmol) was added to the mixture. Under an ice cooling, the resulting mixture was stirred for 30 minutes. Under an ice cooling, sodium borohydride was suspended in ethanol (20 ml), and the above reaction solution was slowly added to the suspension. The mixture was allowed to warm to a room temperature and stirred for one hour. To the mixture, 3-N hydrochloric acid was added, and the resulting mixture was stirred for 10 minutes. Then, chloroform was added thereto, and the resulting mixture was neutralized with a saturated sodium bicarbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (ethyl acetate:methanol=20:1 to 10:1) to give the title compound (0.52 g, 58%) as a light-yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:30]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-Carboxylate (step 1 of Example 1) and 3-methylphenylboronic acid in substantially the same manner, as described in step 2 of Example 1. The product was obtained as a solid. Mass spectrum (ESI, [M+H]+) m/z 384. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.63 (d, 1H, J=7.70 Hz), 7.60 (d, 1H, J=8.47 Hz), 7.48 (s, 1H), 7.44 (d, 1H, J=7.95 Hz), 7.39 (s, 1H), 7.33 (t, 1H, J=7.63 Hz), 7.14 (d, 1H, J=7.49 Hz), 7.07 (d, 2H, J=7.94 Hz), 6.93 (d, 2H, J=7.94 Hz), 5.82 (s, 2H), 4.29 (q, 2H, J=7.17 Hz), 2.37 (s, 3H), 2.21 (s, 3H), and 1.30 ppm (t, 3H, J=7.18 Hz).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[S:7][N:6]=1)(=O)=O.CS(C1N=C(C2C=CC=CC=2Cl)SN=1)=O.[CH2:32]([OH:36])[C:33]#[C:34][CH3:35].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[S:7][N:6]=[C:5]([O:36][CH2:32][C:33]#[C:34][CH3:35])[N:9]=1
Reactant: CS(=O)(=O)c1nsc(-c2ccccc2Cl)n1
Reactant: CC#CCO
Agent: CS(=O)c1nsc(-c2ccccc2Cl)n1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2ccccc2Cl)n1
Reaction time: 1 h

Procedure:
In 3 ml of N,N-dimethylformamide, 400 mg of a mixture of 3-methylsulfonyl-5-(2-chlorophenyl)-1,2,4-thiadiazole and 3-methylsulfinyl-5-(2-chlorophenyl)-1,2,4-thiadiazole and 114 mg of 2-butyne-1-ol were dissolved, to the resulting solution was added 65 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 1 hour, and further stirred at room temperature for 1 hour. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 210 mg of 5-(2-chlorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (8) of the present invention).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]#[N:13])[C:4]=1[OH:14])#[N:2].[C:15](C1C=C([N+]([O-])=O)C=C(C#N)C=1N)#N.C(C1C=C([N+]([O-])=O)C=C(C#N)C=1Cl)#N.CO.[OH-].[Na+]>>[C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]#[N:13])[C:4]=1[O:14][CH3:15])#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc(C#N)c1O
Reactant: N#Cc1cc([N+](=O)[O-])cc(C#N)c1N
Agent: N#Cc1cc([N+](=O)[O-])cc(C#N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C#N)cc([N+](=O)[O-])cc1C#N

Procedure:
2,6-Dicyano-4-nitro-phenol, used in Example 12, was prepared according to generally known processes: 2,6-dicyano-4-nitro-aniline is converted by a Sandmeyer reaction into 2,6-dicyano-4-nitro-chlorobenzene of melting point 218°-219.5°C, reacted with methanol/sodium hydroxide to give 2,6-dicyano-4-nitro-anisole of melting point 144°-148°C, and the latter subsequently split with sodium iodide in dimethylformamide to give 2,6-dicyano-4-nitro-phenol of melting point 228°-231°C. The last two stages correspond to a process indicated in Belgian Pat. No. 764,117.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].O>C(Cl)Cl>[Br:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:20].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: O=C(Cl)c1ccccc1Br
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1Br)[c-]1cccc1
Temperature: 0 °C
Yield: 81 %

Procedure:
Ferrocene (10.0 g, 53.8 mmol) was dissolved in CH2Cl2 (50 mL) in a 250 mL round-bottom flask with argon inlet and dripping funnel and cooled to 0° C. Then aluminum (III) chloride (7.88 g. 59.1 mmol) was suspended in CH2Cl2 (50 mL) in a dropping funnel and o-bromobenzoyl chloride (12.4 g, 7.4 mL, 56.4 mmol) was added dropwise using a syringe. The resulting solution was added by drops of the ferrocene from the dropping funnel. An intense dark purple color appeared. After 2 h of stirring water (15 mL) was slowly added at 0° C. After the end of the hydrolysis, which progressed with strong generation of Gases, the solution was diluted with CH2Cl2 (100 mL) and washed with potassium carbonate solution (50 mL) and a saturated salt solution (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by column chromatography (pentane/tert-butylmethyl ether=4/1). Ketone 1 (16.1 g, 43.6 mmol), 81%) was obtained as a dark red solid (mp: 102° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][C:21]([N:25]([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])([CH3:24])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:23][CH2:22][C:21]([N:25]([CH2:26][CH:27]=[CH2:28])[CH2:29][CH:30]=[CH2:31])([CH3:24])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Yield: 20.6 %

Procedure:
Following general procedure F, {6-Bromo-4-[4-(diallylamino)-4-methylcyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (96 mg, 0.198 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (86 mg, 0.297 mmol) to afford the desired product (23 mg, 27%) as a yellow solid: ESI MS m/z 564 [C32H35Cl2N3O2+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:8]([CH:12]=O)=[CH:9][S:10][CH:11]=1)=[O:5])[CH3:2].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH3:26][C:24]([CH3:27])([O:23][C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][CH2:12][C:8]2[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][S:10][CH:9]=2)[CH2:20][CH2:19]1)=[O:22])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Nc1cscc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Nc1cscc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 28.2 g (0.142 mol) of 4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol) of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml of toluene was refluxed using a water separator until water formation had ceased. The solvent was removed in vacuo, the residue was dissolved in 300 ml of methanol and at room temperature combined batchwise with 5.5 g (0.145 mol) of sodium borohydride. The mixture was stirred for a further hour at room temperature, then evaporated down in vacuo and the residue was distributed between water and tert. butyl-methylether. The organic phase was dried over sodium sulphate and freed from solvent in vacuo. The oily residue was further processed without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:22])C(=O)C1.O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cn2ccnc(Cl)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc2c(Cl)nccn2c1Br
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol) in acetonitrile (600 mL) was added NBS (8.9 g, 50.1 mmol), and benzoyl peroxide (90 mg, 0.37 mmol). The mixture was then heated to reflux for 1 h, cooled to r.t., and water (1800 mL) was added. The resulting solids were filtered, washed with water, and air dried to give the title compound (11 g). LRMS (ESI) calc (M+H)+=289.9/291.9. found 290.0/292.0
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 10.0 (bs, 1H), 7.59 (dd, 1H, J=3.8, 1.2 Hz), 7.36 (dd, 1H, J=5.0, 1.2 Hz), 7.19 (d, 2H, J=8.4 Hz), 7.05 (dd, 1H, J=5.0, 3.8 Hz), 7.02 (d, 2H, J=8.0 Hz), 6.83-6.80 (m, 4H), 4.17 (t, 2H, J=6.4 Hz), 3.29 and 3.14 (d of Abq, 2H, J=13.8 Hz), 2.96 (t, 2H, J=6.4 Hz), 2.35 (s, 3H), 2.27 (s, 3H), 1.38 (s, 3H). IR (KBr) 3420, 1715, 1509, 1225 cm−1. HRMS (ES+) m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1714.