Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9]1.[NH:18]1[C:22]2C=CC=C[C:21]=2[N:20]=[N:19]1.C(=O)C>CCCCCC>[N:18]1([CH:22]([NH:17][C:15]2[CH:14]=[CH:13][C:12]3[O:8][CH2:9][O:10][C:11]=3[CH:16]=2)[CH3:21])[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[N:20]=[N:19]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccccc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: CC=O
Solvent: CCCCCC
Product: CC(Nc1ccc2c(c1)OCO2)n1nnc2ccccc21

Procedure:
[Step 1] 10 mL of a toluene suspension containing 1.4 g (10 mmol) of benzo[d][1,3]dioxol-5-amine were added to 10 mL of a toluene suspension containing 1.2 g (10 mmol) of benzotriazole followed by stirring. 10 mL of a toluene solution containing 0.62 mL (11 mmol) of acetoaldehyde were dropped therein followed by stirring for 18 hours at room temperature. Following completion of the reaction, 10 mL of n-hexane were added followed by filtering out the solid. The solid was washed with n-hexane and dried under reduced pressure to obtain 2.7 g of N-[1-(1H-benzo[d][1,2,3]triazol-1-yl)ethyl]benzo[d][1,3]dioxol-5-amine in the form of a pale brown solid (94%).
Reaction SMILES: CC1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Na+].[CH3:14][C:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[CH2:24]([CH:26]1[CH:52]=[C:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48][CH:47]([O:55][CH3:56])[CH:46]2[O:57][C:42]([OH:61])([CH:43]([CH3:60])[CH2:44][CH:45]2[O:58][CH3:59])[C:41](=[O:62])[C:40](=[O:63])[N:39]2[CH:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[C:33](=[O:64])[O:32][CH:31]([C:65]([CH3:76])=[CH:66][CH:67]2[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([O:74][CH3:75])[CH2:68]2)[CH:30]([CH3:77])[CH:29]([O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[CH2:28][C:27]1=[O:86])[CH3:25]>O1CCCC1>[CH2:24]([CH:26]1[CH:52]=[C:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48][CH:47]([O:55][CH3:56])[CH:46]2[O:57][C:42]([OH:61])([CH:43]([CH3:60])[CH2:44][CH:45]2[O:58][CH3:59])[C:41](=[O:62])[C:40](=[O:63])[N:39]2[CH:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)[C:33](=[O:64])[O:32][CH:31]([C:65]([CH3:76])=[CH:66][CH:67]2[CH2:72][CH2:71][C:70]([OH:73])([CH2:14][C:15](=[O:16])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:69]([O:74][CH3:75])[CH2:68]2)[CH:30]([CH3:77])[CH:29]([O:78][Si:79]([C:82]([CH3:83])([CH3:84])[CH3:85])([CH3:81])[CH3:80])[CH2:28][C:27]1=[O:86])[CH3:25]
Reactant: CC(=O)Cc1ccccc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)(CC(=O)Cc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
A solution of 20 mL of a 1.0M solution of sodium hexamethyldisilamide in tetrahydrofuran was cooled to -78° C. in an ice bath under nitrogen. Then a solution of 3.0 g (20 mmole) of benzyl methyl ketone in 10 mL of dry THF was cooled to -78° C. and added dropwise by canula to the first solution. After 5 min., a pre-cooled (-78° C.) solution of 4.5 g (5 mmole) of 17-ethyl-1-hydroxy-12-[2'-(4"-oxo-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 9) in 10 mL of dry tetrahydrofuran was added dropwise over 5 minutes and the solution was stirred at -78° C. under nitrogen. After 1 h, the reaction was quenched by addition of 2 mL of glacial acetic acid in 10 mL of dry tetrahydrofuran. Ether was added and the mixture was partitioned between ether and water and the aqueous layer was washed with ether. The two ether extracts were sequentially washed with saturated KHCO3 solution and brine, then the combined extract was dried over MgSO4, filtered and concentrated. The oily residue was purified by HPLC (silica gel, Waters RCM) using 1:3:6 acetonitrile: methyl-tert-butylether:hexanes to afford 2.36 g (46%) of the title compound as a colorless foam; NMR (CDCl3) shows distinct AB pattern at 2.6 ppm; MS (FAB) 1044 (M+Li).
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][NH:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]([S:42](Cl)(=[O:44])=[O:43])[CH:34]=[CH:35][C:36]=1[O:37][C:38]([F:41])([F:40])[F:39]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18](=[O:20])[CH3:19])[CH2:15][CH2:14][N:13]2[S:42]([C:33]2[CH:34]=[CH:35][C:36]([O:37][C:38]([F:39])([F:40])[F:41])=[C:31]([I:30])[CH:32]=2)(=[O:44])=[O:43])=[O:11])=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(I)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)c(I)c2)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 3 and triethylamine (66 μl) in chloroform (0.4 ml) was added, with stirring at room temperature, 3-iodo-4-trifluoromethoxybenzenesulfonyl chloride (68 mg). After stirring at room temperature for 1 hr, the reaction mixture was directly purified by thin layer chromatography (methanol:chloroform=1:15) and recrystallized from water-containing methanol to give the title compound (53 mg).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5].[C:12]([O:18][CH2:19][CH:20]=[CH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>CC(O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]2[C:13]([C:12]([O:18][CH2:19][CH:20]=[CH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:17])=[C:14]([CH3:16])[NH:1][C:2]([CH3:11])=[C:3]2[C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5])[CH:34]=[CH:35][CH:36]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: CC(=O)CC(=O)OCC=Cc1cccnc1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCC=Cc2cccnc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
387 mg (2.51 mmol) of 2-cyanoethyl 3-aminocrotonate, 547 mg (2.49 mmol) of (3-(pyridine-3-yl)-2-propene-1-yl) acetoacetate, and 0.285 ml (2.51 mmol) of 3-chlorobenzaldehyde were heated at 80° C. under stirring in 20 ml of 2-propanol overnight. 2-Propanol was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (chloroform/methanol=100:1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][NH2:17]>O1CCOCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:17][CH3:16])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CN
Solvent: C1COCCO1
Product: CNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in 1,4-dioxan (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added methylamine (40 wt % solution in water, 2.10 mL, 24.3 mmol) and the reaction mixture was stirred for 6 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. THF was removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before to be extracted with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum, to give 6-methoxy-2-(methylamino)quinoline-3-carbaldehyde SLA 28150 as an orange oil (1.44 g, 98% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].C(N(CC)CC)C.[OH-].[K+]>N1C=CC=CC=1.O>[CH:18]([C:3]1[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:6]2[C:11]([C:2]=1[N:26]([CH3:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:28])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CN(C)C1=C(C=O)C(c2ccccc2)Oc2ccccc21
Temperature: 2 °C
Reaction time: 60 h

Procedure:
A solution of 1.0 g 4-chloro-3-formyl-flav-3-ene and 0.68 g sarcosin ethyl ester hydrochloride in 10 ml pyridine is cooled at 10°-15° C. One adds 0.97 g triethylamine and warms at 55° C. for 60 hours. After cooling to 2° C., 0.74 ml 50% potassium hydroxide solution is added. After 10 minutes, one adds 37 ml water. The mixture is extracted with dichloromethane, dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel using dichloromethane as eluant. The solid is crystallized in dichloromethane. Pure 3-formyl-4-(N-methyl-N-ethoxycarbonylmethylamino)flav-3-ene is obtained as yellow crystals; m.p. 158°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
2,4-Difluorobiphenyl (21.2 g, 111 mmol) was dissolved in chloroform (120 mL) and chlorosulfonic acid (12.5 mL, 188 mmol) was added dropwise. The reagents were stirred overnight at room temperature. The reaction was concentrated in vacuo and the residue was taken up into EtOAc (100 mL) and washed with water (3×25 mL). The organics were shaken with brine, whereupon a flocculent solid formed. This was filtered and washed with EtOAc and dried to give 2′,4′-difluorobiphenyl sulfonic acid as an off-white solid (12.1 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>O.C(O)C.[Fe]>[NH2:28][C:26]1[CH:25]=[CH:24][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Compound 1b (400 mg) was dissolved in a water-ethanol (1:1) mixture (10 mL), and iron powder (1.0 g) and ammonium chloride (1.0 g) were added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was filtered through Celite to thereby remove iron powder, and water (100 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL). The organic phase was washed with saturated brine (100 mL) and dried over sodium sulfate, followed by concentration under reduced pressure, to thereby yield compound 1c (335 mg, yield: 93%).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:34]=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a white powder. HPLC (Condition 4) tR=5.4 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.64 (m, 1H) 1.73-1.92 (m, 1H) 2.11-2.27 (m, 1H) 2.85-3.03 (m, 1H) 3.11-3.39 (m, 5H) 4.60 (t, J=1.00 Hz, 1H) 7.41-7.64 (m, 2H) 7.74-7.87 (m, 1H) 7.91-8.00 (m, 1H) 8.04 (d, J=2.35 Hz, 1H) 8.50 (s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+].Cl>O.CS(C)=O.ClC1C=CC=CC=1Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:19])[F:20])[CH:13]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: CS(C)=O
Product: Oc1cc(Cl)nnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
3.0 g (purity: 90%; 16.4 mmol) of 4-hydroxy-3,6-dichloropyridazine, 7.96 g (49.1 mmol) of 3-trifluoromethylphenol, and 2.03 g (purity: 97%; 49.1 mmol) of sodium hydroxide were added to a mixture of 19.1 g of 1,2-dichlorobenzene and 3.0 g of dimethyl sulfoxide and matured at 180° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of pure water was added to the cooled mixture. A 35% aqueous hydrochloric acid solution was added to the resultant mixture so that the pH of the aqueous phase was adjusted to 2.1, and then the deposited solids were taken out by filtration. 25 mL of methyl t-butyl ether was added to the solids to obtain a slurry. The resultant solids were dried under a reduced pressure to obtain 3.32 g of 6-chloro-3-[3-(trifluoromethyl)phenoxy]-4-pyridazinol in the form of pale brown solids (yield: 69.7%).
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:31]=[CH:30][C:19]([CH2:20][NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[S:23])=[CH:18][CH:17]=1>C1C=CC=CC=1>[F:27][C:26]([F:28])([F:29])[CH2:25][N:24]=[C:22]1[N:21]([CH2:20][C:19]2[CH:30]=[CH:31][C:16]([C:15]([F:33])([F:14])[F:32])=[CH:17][CH:18]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:23]1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(C(F)(F)F)cc1
Solvent: c1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1
Yield: 60 %

Procedure:
1.00 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.45 g of 1-(4-trifluoromethylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of benzene, and the solution was heated under reflux for 4 hours. After the reaction, benzene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography [silica gel; eluent: hexane/ethyl acetate (10/1)] to give 1.27 g of the captioned compound.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>CN(C)C=O.CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([N:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(C2(C(=O)c3ccc(Cl)cc3)CC2)CC1
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A solution of 29.6 g (0.1 mol) of 4-chlorophenyl 1-bromo-3-chloropropyl ketone in 30 ml of dimethylformamide is added dropwise to a mixture of 10.4 g of N-methyl piperazine and 14 g of potassium carbonate in 30 ml of dimethylformamide at room temperature. Stirring is continued for 3 hours, after which a solution of 9 g of potassium hydroxide in 30 ml of methanol is added dropwise. The reaction mixture is stirred for a further hour at 50° C. and evaporated down in vacuo. The residue is taken up in ethyl acetate/water, and the organic phase is separated off, washed with water, dried over sodium sulphate and evaporated down in vacuo. The residue is chromatographed over silica gel using chloroform/ethanol (97:3). 14 g (50.3% of theory) of 1-(4-chlorobenzoyl)-1-(4-methylpiperazin-1-yl)-cyclopropane are obtained as a reddish oil, which can be directly used further.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)[CH3:4].[Mg].[CH:19](=[O:21])[CH3:20].[BH4-].[Na+]>>[Cl:17][C:7]1[CH:6]=[C:5]([CH:3]([CH3:4])[CH2:2][CH:19]([OH:21])[CH3:20])[CH:10]=[CH:9][C:8]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(CBr)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: CC=O
Agent: [BH4-]
Agent: [Mg]
Agent: [Na+]
Product: CC(O)CC(C)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
4-(3-Chloro-4-cyclohexyl-phenyl)-2-pentanol was prepared analogous to Example 64 from a Grignard reagent, prepared from 91.55 gm (0.29 mol) of 1-bromo-2-(3-chloro-4-cyclohexyl-phenyl)-propane and 7.08 gm (0.291 mol) of magnesium, and 14.2 gm (0.32 mol) of acetaldehyde, followed by reduction with sodium borohydride. The above compound was obtained as a mixture of the two possible pairs of diastereomeric isomers. The colorless oil (39.5 gm; 48% of theory) was not sufficiently heat-stable for distillation, and therefore had to be chromatographically purified (silicagel; benzene as the eluant).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:13][C:14]([F:24])([F:25])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[NH:19])[O:18][CH2:6][CH3:7]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccccc1C(F)(F)F
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 39.2 g of triethyloxonium tetrafluoroborate in 325 ml of methylene chloride is treated with 32.5 g of o-trifluoromethyl-benzamide. After stirring at room temperature for 48 hours the reaction mixture is poured on to a mixture of 10% sodium carbonate solution and ice and the resulting mixture is extracted three times with methylene chloride. The combined extracts are then washed twice with 10% sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The oily, brown residue is distilled in a high vacuum. There is obtained pure ethyl o-trifluoromethyl-benzimidate, b.p. 67° C./0.15 mmHg.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[OH:39][CH2:40][CH2:41][NH:42][CH2:43][CH2:44][OH:45]>>[OH:39][CH2:40][CH2:41][N:42]([CH2:43][CH2:44][OH:45])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:8][CH2:7]1
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN([C@H]1CC[C@H](CCCCN(CCO)CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with 2-(2-Hydroxy-ethylamino)-ethanol to give trans N-(4-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 481 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]1.C(OC([N:50]1[C:54]2=[N:55][CH:56]=[CH:57][C:58](Br)=[C:53]2[CH:52]=[CH:51]1)=O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]I>[CH3:42][C:37]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:3]2[S:4][C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:9][C:8]([C:58]4[CH:57]=[CH:56][N:55]=[C:54]5[NH:50][CH:51]=[CH:52][C:53]=45)=[N:7][C:6]=3[C:2]=2[CH3:1])[CH2:32][CH2:33]1)([CH3:41])[C:38]([NH2:40])=[O:39]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)c(C)c2n1
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(-c3ccnc4[nH]ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of 2-[4-(7-methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (200 mg, 0.28 mmol), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butylester (100 mg, 0.34 mmol), Pd(Ph3)4 (33 mg, 0.028 mmol) and CuI (65 mg, 0.34 mmol) in toluene (5 mL) was purged with argon, then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was then dissolved in DCM/TFA (8 mL/8 mL) and stirred for 2 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 696 as a white powder (0.036 g, 24%). LCMS (Method F): RT 5.68 min, [M+H]+ 535.2. 1H NMR (CDCl3, 400 MHz) δ 9.42-8.74 (m, 1 H); 8.59-7.95 (m, 1 H); 7.92-7.49 (m, 1 H); 7.46-7.35 (m, 2 H); 7.14-7.06 (m, 1 H); 5.27 (s, 1 H); 4.09 (t, J=4.2 Hz, 4); 3.92 (t, J=4.2 Hz, 4 H); 3.85 (s, 2 H); 2.66-2.61 (m, 4 H); 2.53 (s, 3 H); 1.63-1.58 (m, 4 H); 1.26 (s, 6 H)
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[CH2:8]([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>C1COCC1>[CH3:8][C:5](=[CH2:6])[CH2:7][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5 M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to −78° C., 3-bromo-2-methylproene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concnetrated. The residue was redissolved in water and extracted with ether (100 mL). The aquious layer was acidified (3 N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concnetrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.