Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:19][O:20][NH:21][CH3:22]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([O:20][CH3:19])[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a stirred solution of 4-bromobenzoyl chloride (20.0 g, 91.1 mmol) in dichloromethane (300 mL) at −78° C. was added triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine hydrochloride (9.33 g, 95.6 mmol). The resulting solution was allowed to warm to room temperature, stirred for 1.5 hours, and then concentrated. The residue was triturated in acetone and the resulting solid was dissolved in ethyl acetate washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84%). To a solution of 4-bromo-N-methoxy-N-methylbenzamide (3.0 g, 12.29 mmol) in THF (30 mL) at 0° C. under nitrogen was added 2-thienyllithium (1.0 M in THF, 15 mL, 15 mmol) slowly over 10 minutes. The solution was stirred at 0° C. for 1 hour, poured into a saturated aqueous ammonium chloride solution (150 mL), and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ether to give (4-bromophenyl)(thien-2-yl)methanone as a brown solid (1.1 g, 34%). MS (ES) m/z 266.9.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:31]2[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]2)=[O:26])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Oc1ccc(Oc2ccccc2)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
A solution of the carbonate(45 g, 0.13 mol) produced in Example 1 in 250 mL of methylene chloride was added dropwise under nitrogen over three hours to a solution of 4-hydroxypiperidine (14.3 g, 0.14 mol) and triethylamine (19.7 mL, 0.14 mol) in 250 mL of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 4 hours and at room temperature overnight. The reaction was extracted one time with 1N HCl and then multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 39.27 g of a light yellow solid. Recrystallization from diisopropyl ether-methanol gave 31.78 g (79%) of the title compound as an off-white crystalline solid, mp 130-133° C.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=2)=[N:4][CH:3]=1
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(Nc2ncc(Br)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Yield: 41.7 %

Procedure:
5,8-dibromoimidazo[1,2-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CHCl3 (3×40 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10%-20% DCM/MeOH to afford the title compound as a pale yellow solid (200 mg, 0.43 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:18]=[CH:17][N:16]([CH3:19])[C:5]2=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+].[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[Br:22][C:18]1[C:4]2[C:5](=[N:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([F:1])[CH:3]=2)[N:16]([CH3:19])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2cc(F)c(OCc3ccccn3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2cc(F)c(OCc3ccccn3)nc21
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a stirred solution of 5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 3.89 mmol) in DMF (30 mL), cooled to 15° C. under a nitrogen atmosphere, is added sodium hydroxide (0.171 g, 4.28 mmol), followed by N-bromosuccinimide (0.761 g, 4.28 mmol) portionwise over 5 minutes. After 15 minutes, the reaction is poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 100% EtOAc in hexane, to give the title compound as a light yellow solid (1.195 g, 3.55 mmol). MS (m/z): 336/338 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)[CH3:2].[CH:19]1([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:29][C:28]2[CH:30]=[CH:31][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:26][CH:27]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a well stirred solution of 3-(4-formylbenzoylamino)propionic acid ethyl ester (13.8 g, 55.3 mmol) in ethanol (150 mL) was added a solution of 4-cyclohexylaniline (9.70 g, 55.3 mmol) in ethanol (75 mL). The mixture was heated to reflux for 30 minutes, and then acetic acid (50 mL) and sodium cyanoborohydride (3.50 g, 55.5 mmol) were added. After 10 minutes of additional heating, the mixture was cooled on an ice-bath. The solid precipitate was collected by filtration, washed several times with cold water and dried in a vacuum oven overnight to afford 18.16 g (80%) of 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}propionic acid ethyl ester.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH3:29])[CH:9]=[C:10]2[C:15]=1[N:14](C(OCC(C)C)=O)[CH:13]=[C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]2=[O:28])(=O)C.BrN1C(=O)CCC1=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)C>ClCCl>[CH:5]([C:6]1[CH:7]=[C:8]([CH2:29][N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][C:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]2[OH:28])=[O:4]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc2c(C=O)cc(CN3CCOCC3)cc2c1O
Reaction time: 0.17 h

Procedure:
A stirred solution of 3-ethyl 1-isobutyl 8-((acetyloxy)methyl)-6-methyl-4-oxo-1,3-(4H)-quinolinedicarboxylate (Preparation 26, 3.0 g) and N-bromosuccinimide (3.0 g) in dichloromethane (300 mL) is irradiated with a 650 watt sun lamp for 20 min. Morpholine (15 mL) is added to the solution. After 10 min, ethanol (20 mL) is added, and the solvents are removed at 50° C./20 mm. The reaction is repeated on the same scale. The reaction mixtures are combined and partitioned between chloroform (250 mL) and water (150 mL). The chloroform layer is washed twice with water, and the chloroform is evaporated. The residual oil is chromatographed on silica gel (1% methanol/chloroform) to give 2.15 g of the title compound. Physical characteristics: M.p. 202-204° C.; 1H NMR (CDCl3) δ1.43, 2.50, 3.69, 3.74, 4.42, 8.19, 8.59, 8.67, 10.18, 11.8. Anal. Found: C, 62.42; H, 5.92; N, 8.03.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[BrH:39]>CC(O)=O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([Br:39])[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Br
Solvent: CC(=O)O
Product: N[C@H]1CCCC[C@H]1Nc1nc(Br)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (200 mg, 0.364 mmol) and hydrobromic acid in HOAc (10 mL) was stirred at 90° C. for 6 h. The mixture was concentrated under reduced pressure, and the resulting crude material was reconstituted in MeOH (1.0 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-30% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (38 mg, 30%). [M+H] calc'd for C13H16BrFN4O, 343; found, 343.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Yield: 27.3 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.34 mmol), 4-aminobenzamide (93 mg, 0.68 mmol) and trimethylsilyl chloride (TMSCl) (0.100 mL, 0.79 mmol) inn-butyl alcohol (4 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (50 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][N:28]=1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:9][N:8]1[C:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: Cc1ncc(C=O)cn1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 90 °C
Yield: 51.7 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (300 mg, 0.88 mmol) in anhydrous DMF (5 mL) were added 2-methylpyrimidine-5-carbaldehyde (108 mg, 0.88 mmol) and Iron (III) chloride hexahydrate (0.88 g, 0.24 mmol). The dark brown solution was heated to 90° C. for 14 hour in an open air vessel. The reaction mixture was cooled to room temperature and poured over ice (5 g). The resulting mixture was extracted with ethyl acetate (50 mL), the organic layer was washed with brine (10 mL), and dried over MgSO4. The solution was filtered, and concentrated under reduced pressure. The resulting solids were triturated with 15 mL of diethyl ether (15 mL) for 30 min. The precipitate was collected by vacuum filtration to give 201 mg (51% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.16 (s, 2H), 8.33 (s, 1H), 7.18-7.11 (m, 1H), 6.98-6.87 (m, 3H), 4.55 (t, 1H), 3.86 (s, 3H), 2.71 (s, 3H), 2.34 (dd, 2H), 1.84 (d, 2H); MS (EI) for C23H23N9O: 442.3 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:29][NH2:30])=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:29][NH:30][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36](=[O:37])[O:35][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
DIPEA (1.1 g, 8.3 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.0 g, 2.48 mmol) in DMF (10 mL). 3-((tert-Butoxycarbonyl)amino)propanoic acid (0.39 g, 2.07 mmol) and HATU (0.90 g, 2.48 mmol) were then added. The reaction mixture was stirred at 0° C. for 1 h and then was quenched with saturated sodium chloride (50 mL). The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 2:1 hexanes/EtOAc) to afford tert-butyl (3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl)carbamate (1.0 g, 87%). ESI-MS (EI+, m/z): 462 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@@H:5]1[C:9]([OH:11])=[O:10].C(S)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Solvent: CCCCS
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of (+)-cis chrysanthemic acid (1.0 g) in toluene (9 g) was added n-butanethiol (107 mg). Irradiation with a high pressure mercury lamp (100 W) was made for one hour. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (0.9 g). The optical isomer ratio of the product was (+)-cis, 3.0%; (-)-cis, 2.1%; (+)-trans, 46.6%; and (-)-trans, 48.3%.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1Cl)=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:32])=[O:20])[CH3:17]>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.C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[CH:1]=[CH2:2])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:32])=[O:20])[CH3:17]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCOC(=O)c1cnc2c(Cl)cccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)OCC)cnc2c(Cl)cccc12
Reaction time: 2 h

Procedure:
Tributylvinyltin (2.8 ml) and tetrakistriphenylphosphinepalladium (171 mg) were added to a toluene solution (20 ml) containing 2.0 g (7.4 mmol) of ethyl-4,8-dichloroquinoline-3-carboxylate obtained in the same manner as in Production Example 4b, followed by stirring for 2 hours under heating under reflux. The reaction solution was filtered through Celite and the filtrate was concentrated. Then, the residue was purified by silica gel chromatography, to give 1.92 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(OCC)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 67 g (0.520 mol) of p-chlorophenol and 29.5 g (0.520 mol) of KOH pellets is heated to 100° C. for 2 hours under a pressure of about 5 mm Hg. Thereafter 117 g (0.625 mol) of p-bromoanisole and 1 g of copper powder are added and the mixture is then heated to about 220°-230° C. for 5 hours. The cooled reaction mixture is taken up in diethyl ether and after removing the inorganic salts by filtration the filtrate is washed with 2 N sodium hydroxide solution and with water. The solvent is driven off under reduced pressure, drying is carried out with sodium sulphate and 133 g of an orange-coloured oil are obtained. Purification of this oil by distillation under reduced pressure given 70 g of a white crystalline mass which is insoluble in water.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:19])[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C1C2C3C(=CC(F)=CC=3)N(CCO)C=2CCC1)=O)C.N1C=CC=CC=1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>ClCCl>[CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:13]3[C:12](=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]([CH2:20][CH2:21][O:22][S:56]([CH3:55])(=[O:58])=[O:57])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)C(=O)C1CCCc2c1c1c(F)cccc1n2CCO
Agent: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 1 %

Procedure:
To a solution of a mixture of 5-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (42) and 7-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (743 mg, 2.2 mmol) in dichloromethane (30 mL) was added pyridine (1.74 g, 22.0 mmol, 1.8 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (1.01 g, 8.8 mmol, 0.7 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was purified by semi preparative HPLC eluting with water (A) and methanol (B) (Gemini 5u, C18, 110A, 150×21 mm, 50-95% B over 20 min, 21 mL/min) to afford 10 mg (1%) of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid and 30 mg (9%) of a mixture of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester and methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) as a white solid. Using these purification conditions, methanesulfonic acid 2-(4-diethylcarbamoyl-5-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 10) could not be isolated as a single component. The structure of methanesulfonic acid 2-(4-diethylcarbamoyl-7-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.18 (3H, t, J=7 Hz, N(CH2CH3)2), 1.39 (3H, t, J=7 Hz, N(CH2CH3)2) 1.70-2.30 (4H, m, 2- and 3-CH2), 2.58 (3H, s, OSO2CH3), 2.60-2.80 (2H, m, 1-CH2), 3.40-3.65 (4H, m, N(CH2CH3)2), 4.02 (1H, t, J=6 Hz, 4-CH), 4.20 (2H, t, J=7 Hz, NCH2CH2O Ms), 4.35 (2H, t, J=7 Hz, NCH2CH2O Ms), 6.70-6.85 (1H, m, NCCHCFCHCH), 6.90-7.00 (1H, m, NCCHCFCHCH), and 7.05-7.15 (2H, m, NCCHCFCHCH).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:51]1[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=1)[CH:48]([CH3:50])[CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:56]([C:54]3[N:55]=[C:51]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:52][CH:53]=3)=[O:57])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-isobutylthiazole-4-carboxylic acid (example 72, step d) (0.08 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. and the resulting yellow solution allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.24 g.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.C(Br)C.[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccccc2sc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CN1CCC(C2(O)c3ccccc3Sc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 1.2 l g. (0.05 mol) of magnesium turnings covered by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of 4-chloro-N-methylpiperidine (from 8.5 g., 0.025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is initiated, the remainder of the chloro compound in about 20 ml. of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-Bromothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours, and then stirred at room temperature 3 days. The reaction mixture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9(1-methyl-4-piperidyl)thioxanthene-9-ol, m.p. 225.5°-226° C.