Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:32]([CH:28]3[CH2:29][CH2:30][CH2:31][O:27]3)=[O:33])[CH2:15][CH2:14]2)[C:10]=1[CH3:11]
Reactant: O=C(O)C1CCCO1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)C2CCCO2)CC1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), tetrahydro-furan-2-carboxylic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THF was heated under microwave irradiation at 120° C. for 30 minutes. Mixture was purified by HPLC to give compound C164 as a yellow solid (78 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.85-2.17 (m, 8H), 2.21 (s, 3H), 3.10 (s, 3H), 3.75-3.80 (m, 2H), 3.86-3.91 (m, 2H), 3.96-4.01 (m, 2H), 4.68 (t, 1H), 5.40-5.45 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.21 (s, 1H). Exact mass calculated for C22H26FN3O6S 479.2, found 480.3 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>C(OC(=O)C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([CH3:15])[CH:3]=1)([CH3:26])[CH3:25]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccc1OC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C#C[Si](C)(C)C)ccc1OC1CCCCO1
Temperature: 58 °C
Yield: 98 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 13.36 g of 1-iodo-4-perhydro-2H-pyrane-2-yloxy-3-methylbenzene prepared in Step 2-1, 0.24 g of dichlorobis(triphenylphosphine)palladium, 0.24 g of triphenylphosphine, 0.12 g of copper iodide (I), and 12.75 g of triethyl amine were suspended in 50 g of ethylacetate under a nitrogen atmosphere, and heated up to 58° C. under stirring. Then a solution of 6.20 g of trimethylsilylacetylene and 6.20 g of ethylacetate was added dropwise at 58 to 64° C. over 2 hours. The resulting mixture was stirred at the same temperature for 3 hours, cooled down to room temperature, and filtered. The residue was washed with ethylacetate, and the resulting filtrate was concentrated at 60° C. under a pressure of 20 Torr. The concentrate was purified through silica gel chromatography using hexane mixed with 0.1 wt % triethyl amine as an eluting solvent, to thereby obtain 11.87 g of 2-(4-(trimethylsilylethynyl)-2-methylphenoxy)perhydro-2H-pyrane at 98% yield.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].ClC1C=CC(C2CC(=O)C(=CN(C)C)C(=O)C2)=CC=1>>[CH3:18][N:19]([CH:21]=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)[CH2:12][C:11]1=[O:13])[CH3:20]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CN(C)C=C1C(=O)CC(c2ccc(Cl)cc2)CC1=O
Product: Cc1ccc(C2CC(=O)C(=CN(C)C)C(=O)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from 5-p-tolyl-cyclohexane-1,3-dione (1.0 g, 4.85 mmol), example 1/c, and N,N-dimethylformamide dimethylacetal (5 ml), following the procedure described for 5-(4-chloro-phenyl)-2-dimethylaminomethylene-cyclohexane-1,3-dione (example 2/a stage 1) except that the reaction was stirred at ambient temperature for 16 h.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O>[C:5]([N:3]=[C:2]=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1ccccc1
Reaction time: 0.03 h

Procedure:
Ammonium thiocyanate (12.35 g) was dissolved in acetone (AR grade, 120 ml) and benzoylchloride (17.3 ml) was added dropwise with stirring over 2 mins. The temperature rose from 22° C. to 38° C. over the addition and a white precipitate formed. The reaction was stirred at room temperature for a further 75 mins and then filtered, and washed with acetone (20 ml) to give a solution of benzoylisothiocyanate. This was added dropwise with stirring to the amine solution, over 40 mins. The temperature rose from 23° C. to 36° C. during the addition. A thick cream precipitate formed. The reaction was allowed to stir at room temperature for 16 hours and then the product was collected by filtration, washed with water (30 ml), sucked dry and then dried in vacuo at 60° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([F:19])=[C:6]([I:20])[C:3]=1[C:4]#[N:5].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO.O>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:8]3[C:7]([F:19])=[C:6]([I:20])[C:3]([C:4]#[N:5])=[C:2]([NH:30][C@H:28]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH3:29])[N:9]=3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1c(Cl)nc(Nc2cc(C3CC3)[nH]n2)c(F)c1I
Solvent: CCCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Yield: 20 %

Procedure:
A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-4-iodonicotinonitrile (Method 39, 0.28 g, 0.69 mmol), (5)-1-(4-fluorophenyl)ethanamine (0.19 g, 1.3 mmol), and DIEA (0.11 g, 0.90 mmol) in n-BuOH (1 ml) was heated to 140° C. for 18 hours. The reaction was diluted with water (10 ml), extracted with DCM (2×20 ml) and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.07 g, 20%). MS: Calcd.: 506. Found: [M+H]+ 507.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17]Cl)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17][O:34][C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CCl)cs1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(Cl)cc3)cc2)cs1
Yield: 45.4 %

Procedure:
By an operation similar to that in Example 2-1 and using 2-{[4-(chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.49 g) obtained in Example 1 and 4′-chlorobiphenyl-4-ol (772 mg), 2-[(4-{[(4′-chlorobiphenyl-4-yl)oxy]acetyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (864 mg) was obtained. By successive operations similar to those in Example 2-2 and 2-3 using 568 mg thereof, the title compound (299 mg) was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:13]=[C:12](C(F)(F)F)[S:11][CH:10]=2)[CH:5]=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(COC)OC.C(OCC)(=O)C.O>[CH3:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[N:7]=[C:6]([O:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:20]([F:31])([F:30])[F:19])[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)nc(Oc2csc(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccsc2C(F)(F)F)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of 6-bromo-4-methyl-2-{[5-(trifluoromethyl)-3-thienyl]oxy}pyridine (1.16 g, 3.43 mmol) in dimethoxyethane is treated with tetrakis(triphenylphosphine) Pd (79 mg, 0.069 mmol), stirred at room temperature for 30 minutes under N2, treated with α,α,α-trifluoro-p-tolylboronic acid (0.72 g, 3.77 mmol), NaHCO3 (0.95 g, 11.32 mmol) and water, heated at reflux temperature for 1.5 hours, cooled to room temperature, diluted with a mixture of ethyl acetate and water to give a two phase mixture. The phases are separated and the organic phase is set aside. The aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are combined with the organic phase, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give an amber oil residue. The residue is chromatographed (silica gel, ethyl acetate/hexanes, 5/95) to give the title product as a clear oil, which solidified upon drying in a Kugelrohr, to a waxy white solid, 1.22 g (88% yield), mp 52.5-55.5° C., identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:27]=1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 42.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.00 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)aniline (374 mg, 1.50 mmol) to afford the desired product (182 mg, 43%) as a light orange solid. ESI MS m/z 424 [C22H22BrN3O+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:26](=[O:35])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])=[CH:33][CH:32]=1
Reactant: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc12
Reactant: NCC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Product: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(Cl)cc3)nc12

Procedure:
Adapted from the procedure of example 5 using the product of example 9 and 1-amino-3-(4-chloro-phenyl)-propan-2-one hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[F:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:40][NH2:41])=O)=[N:36][CH:37]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=3)=[N:40][N:41]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1ccc(F)cn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ccc(F)cn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.146 g, 0.5 mmol) in Dichloromethane (DCM) (3 mL) was added triethyloxonium tetrafluoroborate (0.100 g, 0.525 mmol). The solution was then stirred, under argon, for 10 minutes before 5-fluoro-2-pyridinecarbohydrazide (I24) (0.093 g, 0.600 mmol) was added. The solution was then stirred for a further hour before the solvent was concentrated and n-butanol (3.00 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-direct automated HPLC, and the solvent evaporated in vacuo. The remaining solid was then triturated with ether and dried in a vac-oven to yield the product in 0.045 g.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]2[C:15]=1[C:16]([N:34]1[C:42]3[C:37](=[N:38][CH:39]=[C:40]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:41]=3)[C:36]([CH3:50])([CH3:49])[CH2:35]1)=[C:17]([CH3:33])[C:18]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:26])=[N:19]2>CS(C)=O.C1COCC1>[CH3:49][C:36]1([CH3:50])[C:37]2=[N:38][CH:39]=[C:40]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[CH:41]=[C:42]2[N:34]([C:16]2[C:15]3[C:20](=[CH:21][C:22]([F:24])=[CH:23][C:14]=3[F:13])[N:19]=[C:18]([C:25]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:7][CH2:26]3)[C:17]=2[CH3:33])[CH2:35]1
Reactant: C=C(c1ccccc1)c1nc2cc(F)cc(F)c2c(N2CC(C)(C)c3ncc(N4CCOCC4)cc32)c1C
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1c(C2(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Reaction time: 0.5 h

Procedure:
A suspension of trimethylsulfoxonium iodide (29.6 mg, 0.135 mmol) in dry DMSO (0.3 mL) was treated with potassium tert-butoxide (1.0M in THF, 0.135 mL, 0.135 mmol) at rt under a N2 atmosphere. The resulting solution was stirred for 30 min. A solution of 4-(1-(5,7-difluoro-3-methyl-2-(1-phenylvinyl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (46 mg, 0.090 mmol) in dry THF (0.836 mL) was added dropwise to the stirring solution, and the reaction was stirred for 3 h. The reaction was then quenched with 1N HCl, and the product extracted twice with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure to give a crude residue that was purified by reverse-phase HPLC (0-80% acetonitrile in water) to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(1-phenylcyclopropyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.62-7.73 (1H, m), 7.49-7.53 (1H, m), 7.19-7.25 (2H, m), 7.12-7.19 (1H, m), 7.03-7.11 (2H, m), 6.98 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.51-5.55 (1H, m), 3.80-3.89 (1H, m), 3.68-3.80 (4H, m), 3.51-3.61 (1H, m), 2.86-2.97 (4H, m), 2.10-2.15 (3H, m), 1.71-1.79 (1H, m), 1.55-1.64 (2H, m), 1.49-1.54 (3H, m), 1.45-1.49 (1H, m), 1.41-1.45 (3H, m). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH:24]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:28]([NH2:30])=[O:29].[OH-].[Na+].[CH:33](O)=O>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:24][N:30]([CH3:33])[CH:28]=[O:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Reactant: NC=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNc1ccc(CN(C)C=O)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (3.6 g, 0.0094 mol), formamide (48 mL) and formic acid (6 mL) was heated to 170° C. under N2 for 8 hours. The mixture was poured into ice-water, basified with 35% NaOH and extracted with chloroform. The organic layer was separated, washed with water (2x), then brine and was dried over Na2SO4 and concentrated in vacuo to afford 3.88 g of N-[[1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]-N-methylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[OH-:14].[K+].[CH3:16]O>>[Cl:1][C:2]1[CH:11]=[C:10]([O:14][CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Product: COc1cc(Cl)nc2ccc(C)cc12

Procedure:
To 2,4-dichloro-6-methylquinoline (4.1 g, 19 mmol) in methanol (34 ml) was added KOH (1.42 g) and the resulting solution was heated under reflux for 2.5 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and half-concentrated brine. The organic layer was concentrated and chromatographed (silica gel, EtOAc:hexanes 1:5→1:3). 4-Chloro-2-methoxy-6-methylquinoline eluted first, then 2,4-dichloro-6-methylquinoline, followed by the colourless crystalline title compound, (1.97 g, 49%). δH (CDCl3) 2.52 (s, 3H), 4.05 (s, 3H), 6.71 (s, 1H), 7.53 (dd, J=8.6, 2.0, 1H), 7.83 (d, J=8.6, 1 H), 7.90 (br, s, 1 H); MS (AP+) 208 (MH+, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:4]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[O-:16][C:17]#N.[K+]>O>[Cl:9][C:7]1[C:6]([Cl:10])=[CH:5][C:4]2[N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:17](=[O:16])[NH:2][C:3]=2[CH:8]=1
Reactant: N#C[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
To a stirred mixture of 31.2 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minutes-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15° and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48% ) of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethylethanamine and 260 parts of dichloromethane are added dropwise 7.4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux temperature. The reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[Cl:25]C(OC(Cl)C)=O>ClCCCl>[ClH:25].[CH2:18]([C@H:9]1[NH:8][CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN[C@H](Cc2ccccc2)C1
Product: Cl
Temperature: 90 °C
Yield: 41.9 %

Procedure:
(2R)-1,2-Dibenzyl-4-methanesulfonylpiperazine (2.2 g; 6.4 mmol) was dissolved in dry 1,2-dichloroethane (20 ml) under an atmosphere of nitrogen. The mixture was placed on an ice-bath and a solution of α-chloroethyl chloroformate (1.0 g; 7.04 mmol) in dry 1,2-dichloroethane (10 ml) was added keeping the temperature between 0 and 5° C. When addition is complete stirring is continued for 15 minutes on the ice-bath. The reaction mixture is heated slowly to 90° C. on an oil-bath and heated at reflux temperature for 1 h. The major part of the solvent was allowed to evaporate and the residue was allowed to cool on an ice-bath. Methanol (20 ml) was added and the mixture was heated at reflux temperature for 1 h. The mixture was allowed to cool to ambient temperature, diethyl ether (30 ml) was slowly added and the mixture was stirred for 30 minutes. The solid was isolated by filtration, washed with diethyl ether, and dried to give 0.78 g of (3R)-3-benzyl-1-methanesulfonylpiperazine hydrochloride. M.p. 204-208° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:15]=1[O:23][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 8.55 (0.0515 moles) of 2,3,5,6-tetrafluorophenol, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 300 ml of absolute ethanol to give 11.36 g (73% yield) of purified 2-(2,3,5,6-tetrafluorophenoxy)-5-nitrobenzonitrile, mp 152.5°-154.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19])#[N:2].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.C(O)C.[H][H]>C(O)(=O)C.O>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)cc1F
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NCc1ccc(C(=O)NC2CCCCCC2)cc1F
Reaction time: 0.5 h

Procedure:
Add 4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), 10% NYC (Degussa type E101, 250 mg), ethanol (25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (805 mg, 92%). MS (ES+) m/z: 265.3 (M+H)+.