Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=12.C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[I:49]I>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:10]([I:49])=[CH:11][C:3]=12
Reactant: II
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(F)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)c(F)cnc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 231A (3.560 g, 11.46 mmol) in tetrahydrofuran (75 mL) at 78° C. was added dropwise 2M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (11.46 mL, 22.91 mmol). The mixture was stirred at −78° C. for 30 minutes and iodine (5.82 g, 22.91 mmol) in tetrahydrofuran (25 mL) was added. After stirring at −78° C. for 3 hours, the reaction was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated until most solvent was removed. The suspension was diluted with ethyl acetate and warmed with a heat gun. Heptanes were added to the suspension and the mixture was stirred for 1 hour. The solid was filtered, washed with heptanes/ethyl acetate (1:1), and vacuum oven-dried to give the title compound. The filtrate was concentrated and triturated with heptanes/ethyl acetate (1:1) to give additional title compound. MS (ESI+) m/z 436.9 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1>C(#N)C.O>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[OH:11])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:55]=[CH:56][CH:57]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(CCCOCCCCCCCBr)c1
Reactant: O=c1ccc2c([C@@H](O)CNCc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(CCCOCCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Yield: 46.1 %

Procedure:
5-[(1R)-2-(Benzylamino)-1-hydroxyethyl]-8-(benzyloxy)quinolin-2(1H)-one (48 mg) was dissolved in acetonitrile (2 ml). N,N-diisopropylethylamine (0.042 ml), and 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (43 mg) were added to the solution, which was heated at reflux for 72 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4) and evaporated in vacuo. The residue was purified on a silica SPE cartridge eluting with ethyl acetate-cyclohexane mixtures to give the title compound (36 mg). LCMS RT=2.76 min
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.CN.[CH:37]([OH:39])=[O:38].ClC1C=[C:43]([N:47]2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:37]([OH:39])=[O:38].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:47][CH3:43])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN
Solvent: C1CCOC1
Solvent: O=CO
Product: CNCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and methylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 26 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:15]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@@H](OCCCCO)CC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@@H](OCCCCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, cis-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzenesulfonamide was treated with methane-sulfonyl chloride to yield cis-methanesulfonic acid 4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless viscous oil, MS: 468 (MH+, 1 Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[N:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2cnnn2c1
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccc2cnnn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=220.3 (M+H), can be prepared in accordance with the general method of example 1 from 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (example 34, step 1) and phenylacetylene.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[C:3]=1[C:4]([O-:6])=O.[Li+].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([N:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:4]([N:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:58]([CH:55]3[CH2:57][CH2:56]3)[CH2:59][CH2:60]2)=[O:6])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of 120 mg (0.355 mmol) lithium 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 3 mL dry N,N-dimethylformamide was added 0.30 mL (1.773 mmol) N-ethyldiisopropylamine and 163 mg (0.425 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 74 mg (0.425 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred for 18 hours at room temperature and evaporated. The residue was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 100:0) to provide 45 mg (26%) of the title compound as a light yellow foam (30%). MS (ESI): m/z=488.07 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[C:17]([CH:18]=[O:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:13]2[C:17]([CH2:18][OH:19])=[CH:16][O:15][C:14]=2[Si:20]([CH2:23][CH3:24])([CH2:25][CH3:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC[Si](CC)(CC)c1occ(C=O)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1occ(CO)c1-c1ccccc1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0 M solution in hexane, 1.48 ml, 1.48 mmol) was added dropwise to a solution of 3-phenyl-2-triethylsilyl-4furaldehyde (422 mg, 1.48 mmol) in tetrahydrofuran (10 ml) at 0 degrees under argon. This mixture was warmed to room temperature, quenched with ice-cold 5% (V/V) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. The dried extracts (magnesium sulfate) were concentrated to an oil which was purified by flash chromatography on silica using 20% ethyl acetate/hexanes to give the title compound. IR (neat): 3300 (broad); 2953 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 441.3 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23](O)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl-].[NH4+].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([NH2:30])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(N)=O)cc1OCC2

Procedure:
Following the procedures of Example 215, 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid, ammonium chloride, and HATU were reacted to give 351. M/z 353.1, calc. 352.16. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 7.91 (s, 2H), 7.48 (s, 1H), 7.04 (d, J=8.2, 1H), 6.97 (s, 1H), 6.92 (s, 1H), 5.95-5.81 (m, 1H), 4.50 (d, J=5.8, 4H), 3.38 (s, 2H), 1.48 (d, J=6.5, 6H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>C1COCC1>[Cl:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[OH:1])[O:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH2:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2cc(Cl)c(O)cc2O1
Reaction time: 40 h
Yield: 52 %

Procedure:
A solution of ethyl 7-hydroxychroman-2-carboxylate (5.0 g, 22.5 mmol) in THF is treated with N-chlorosuccinimide (NCS) (3.6 g, 27 mmol), stirred for 40 hr and concentrated in vacuo. The resultant residue is purified chromatographically (silica gel/20% EtOAc in hexanes as eluent) to give the title product, 3.0 g (52% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17][C:18]3[NH:19][C:20]4[C:21]([N:26]=3)=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.[CH3:27]I>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([CH2:16][S:17][C:18]3[N:19]([CH3:27])[C:20]4[C:21]([N:26]=3)=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: COc1cccc(-c2nc(CSc3nc4ncccc4[nH]3)no2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(CSc3nc4ncccc4n3C)no2)c1
Temperature: 1 °C
Reaction time: 0.25 h

Procedure:
THF (3 ml) was added to a mixture of sodium hydride (60%, 8 mg, 0.2 mmol) and 2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-imidazo[4,5-b]pyridine (24.6 mg, 0.072 mmol) and the resulting mixture was stirred at 1° C. for about 15 min. Methyl iodide (20 μL, 0.32 mmol) was added the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched by the addition of dichloromethane (10 ml) and water (2 ml). After vigorous stirring, the organic extracts (10 ml, plus 3×5 ml) were eluted through a Chem Elut Extraction Column (Varian, cat #1219-8002). Purification using SPE chromatography (5 g silica) using 25/25/50 to 50/25/25 ethyl acetate/dichloromethane/hexane yielded two products. The first product to elute was 2-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-1H-imidazo[4,5-b]pyridine (6 mg, 23%). 1H NMR (CDCl3), δ (ppm): 8.46 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.42 (t, 1H), (m, 2H), 5.67 (q, 1H), 3.88 (s, 3H), 3.71 (s, 3H), 2.01 (d, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CCNCC1.C([O-])(C)(C)C.[K+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[N+:35]([C:32]1[CH:33]=[CH:34][C:29]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:30][CH:31]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: OC1CCNCC1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO−K+ in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[I:31])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O)(C)(C)C.[ClH:32]>O1CCOCC1>[Cl-:32].[CH2:14]([O:13][C:11]([CH2:10][C@@H:9]([NH3+:8])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[I:31])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1I)CC(=O)OCc1ccccc1
Reactant: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(I)c(OC[C@H]([NH3+])CC(=O)OCc2ccccc2)c1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
11.9 g (22.1 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-(5-cyano-2-iodophenoxy)butanoate was dissolved in 120 ml of 4 N solution of hydrogen chloride in dioxane. The solution was stirred at 0° C. for one hour and then at room temperature for 2 hours. The solvent was distilled off. 50 ml of a mixed solvent of hexane/ethyl acetate in a volume ratio of 1:1 was added to the oily residue thus obtained. The precipitate formed was taken by the filtration to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH3:13])=[N:4][C:3]=1[NH:14][CH2:15][CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24].Cl>C1(C)C=CC=CC=1>[CH3:24][N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][NH:17][C:8]([C:6]1[C:5]([O:12][CH3:13])=[N:4][C:3]([NH:14][CH2:15][CH3:16])=[C:2]([Cl:1])[N:7]=1)=[O:10]
Reactant: CN1CCCC1CN
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNc1nc(OC)c(C(=O)NCC2CCCN2C)nc1Cl

Procedure:
To 30 ml. of toluene were added 3.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 3.0 g. of 2-aminomethyl-1-methylpyrrolidine and the mixture was refluxed for 4 days. The reaction mixture was acidified with hydrochloric acid at room temperature and then extracted twice each time with 30 ml. of water. From the toluene layer, 0.9 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered. The extracts were combined, basified with aqueous ammonia and extracted three times each time with 30 ml. of chloroform. The extracts were combined and evaporated to dryness. By adding 50 ml. of ether to the residue formed, 1.0 g. of crystals of N-(1-methylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide were obtained. The colorless acicular crystals obtained by recrystallizing the product from a mixture of benzene and n-hexane melted at 126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[S:10])=[O:7])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]>O1CCCC1>[NH2:18][C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[NH:13][C:9](=[S:10])[NH:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: NC(=O)c1ccccc1N
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1NC(=S)NC(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a stirred mixture of 10.5 g of 4-chlorobenzoyl isothiocyanate in 100 ml of tetrahydrofuran was added a mixture of 6.8 g of 2-aminobenzamide in 200 ml of tetrahydrofuran. After stirring for 3 hours, the solid was collected, giving 14.3 g of the desired product as grey crystals, mp 204°-206° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@:9]1([CH3:44])[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[N:25]=[C:24]([CH3:35])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C@H:11]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:52][CH2:53][O:54][CH2:55][CH2:56]I>CC(N(C)C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:34][C:29]1[CH:28]=[C:27]([N:26]2[C:22]([CH:19]3[CH2:18][CH2:17][N:16]([C:14]([C@@H:12]4[CH2:13][C@@:9]([CH3:44])([N:8]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)[CH2:10][C@H:11]4[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])=[O:15])[CH2:21][CH2:20]3)=[CH:23][C:24]([CH3:35])=[N:25]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: Cc1cc(C2CCN(C(=O)[C@@H]3C[C@@](C)(N)C[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: ICCOCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CCN(C(=O)[C@@H]3C[C@@](C)(N4CCOCC4)C[C@H]3c3ccc(F)cc3F)CC2)n(-c2ccc(F)c(Cl)c2)n1
Temperature: 110 °C

Procedure:
The product from Example 6 (17.2 mg, 0.027 mmol) in DMA (1 mL) was treated with cesium carbonate (63.3 mg, 0.194 mmol) and 2-iodoethyl ether (15.8 mg, 0.049 mmol) at rt. The mixture was heated at 110° C. for 16 h, then cooled to rt and filtered. The filtrate was directly purified by RP-HPLC (15 to 100% acetonitrile/water+0.05% TFA) to afford the title compound. HPLC/MS: 601.4/603.4 (M+1); Rt=2.92 min (LC4).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.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.C(O)C>[Cl:25][C:23]1[CH:22]=[C:21]([C:26]2[N:27]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=2)[CH:20]=[C:19]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:24]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Clc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Clc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
In a stream of argon, 0.52 g (2.36 mmol) of 9-phenanthreneboronic acid, 0.91 g (2.15 mmol) of 2-(3-bromo-5-chlorophenyl)-4,6-diphenyl-1,3,5-triazine and 24.8 mg (0.022 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent comprised of 80 mL of toluene and 10 mL of ethanol, and the temperature of the obtained suspension was elevated to 60° C. 6.45 mL (6.45 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 18 hours. The resultant reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was dissolved in chloroform and the obtained solution was filtered by celite. The filtrate was distilled to remove all volatile materials to give 1.02 g of an intermediate 2-[3-chloro-5-(9-phenanthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as grayish white solid (yield: 91%).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=[C:12]3[C:11]2=[O:23])[CH2:6][CH2:5]1)[CH3:3].[H][H].C(O)(=O)C.C(O)C>C(O)(=O)C.[Pd]>[OH2:15].[ClH:1].[NH2:20][C:17]1[CH:16]=[C:13]2[C:14](=[O:15])[N:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:2][CH3:3])[CH2:5][CH2:6]3)[C:11](=[O:23])[C:12]2=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: CCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCN1CCC(N2C(=O)c3ccc(N)cc3C2=O)CC1
Product: O
Yield: 144 %

Procedure:
A solution of 1.7 grams (0.005 mole) of 1-ethyl-4-(4-nitrophthalimido)piperidine hydrochloride in 60 milliliters of glacial acetic acid was hydrogenated over 0.1 grams of 10% palladium on carbon catalyst at 50 p.s.i. After the theoretical uptake of hydrogen, a little acetic acid/ethanol mixture was added to dissolve precipitated solid; the catalyst was filtered off, the solvents evaporated and the residue trituated with ether to give a yellow solid. Recrystallisation from methanol gave 1.18 grams of 4-(4-aminophthalimido)-1-ethylpiperidine hydrochloride hydrate, m.p. 254° C(decomp).