Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].Br[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:19](=[O:20])[C:14]3[N:15]=[C:16]([CH3:18])[S:17][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:21]=1)[CH3:5]>O1CCOCC1.CS(C)=O>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:19]([OH:20])[C:14]3[N:15]=[C:16]([CH3:18])[S:17][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:21]=1)[CH3:5]
Reactant: Cc1nc2c(=O)c3ccc(C(C)Br)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2O

Procedure:
A solution of sodium borohydride (0.31 g) and the product from step (x) (1.35 g) in 1,4-dioxan (40 ml) and dimethyl sulphoxide (10 ml) was stirred at room temperature for 18 hours. The reaction was quenched with water (4 ml) before solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate which was washed with saturated aqueous sodium bicarbonate and saturated brine. The organic phase was collected, dried (MgSO4) and evaporation of solvent under reduced pressure gave a yellow oil which was purified by chromatography, eluting with 20% isohexane in ethyl acetate.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:4]2=[N:3][CH:2]=1.C(O)C>[Pd].C1(C)C=CC=CC=1>[CH:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[CH:22][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1
Reactant: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N[C@@H]1CCc2ccccc2-n2ccnc21
Reaction time: 64 h
Yield: 83.7 %

Procedure:
Combine benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate (120.0 g, 359.9 mmol) and ethanol (2.0 L) in a Büchi hydrogenator and add 10% palladium on carbon (Pd/C) (10.0 g, 9.4 mmol) slurried in toluene (200 ml). Hydrogenate (60 psi, ambient temperature) the mixture for approximately 64 hours. Filter the mixture through diatomaceous earth and wash the cake with THF (300 ml). Concentrate the filtrate under reduced pressure to give the title compound (60 g, 84%) as a white foam: MS (m/z): 200 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.O[N:52]1[C:56](=[O:57])[C:55]2=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]2[C:53]1=[O:62].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:27][N:52]2[C:56](=[O:57])[C:55]3[C:54](=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:53]2=[O:62])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCc2ccccc2)cc1)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of (R)-benzyl 3-(4-(benzyloxy)phenyl)-2-hydroxypropanoate (Compound XLIII-1) 18.1 g (50.0 mmol) in dichloromethane 80 ml, trifluoromethanesulfonic anhydride 10.1 ml (60.0 mmol) and 2,6-lutidine 8.74 ml (75.0 mmol) were added and the mixture was stirred at room temperature for 0.5 hr. N-hydroxyphthalimide 8.16 g (50.0 mmol) and triethylamine 10.5 ml (75.0 mmol) were added to the reaction mixture and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate 500 ml and washed with saturated sodium bicarbonate solution 500 ml, water 500 ml and brine 500 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 15.0 g (yield 59%).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:35])([F:34])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:14][C:9]2=[N:8][N:7]=1.O.CO>C1COCC1>[F:35][C:5]([F:4])([F:34])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
Lithium hydroxide monohydrate (381 mg, 9.08 mmol) was added to ethyl 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (820 mg, 1.82 mmol) in a mixture of THF (20 mL), water (10 mL) and MeOH (5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated then the residue was suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (575 mg, 74.8%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[C:60]([CH3:62])[CH:59]=[CH:58][C:57]=1[S:63](Cl)(=[O:65])=[O:64]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:57]1[CH:58]=[CH:59][C:60]([CH3:62])=[CH:61][C:56]=1[O:55][CH3:54])(=[O:65])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(C)cc1OC)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (25 mg) was reacted with 2-methoxy-4-methylbenzenesulfonyl chloride to afford (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methoxy-4-methyl-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (20 mg) was hydrolyzed according to General Procedure B to give the title compound (16 mg). LCMS (m/z): 919.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[CH:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:2]1
Reactant: Nc1ccsc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thiophen-3-amine (see Galvez, C., et al, J. Heterocycl. Chem. (1984), 21:393-5) (5.70 g, 57.0 mmol) and triethylamine (5.82 g, 58.0 mmol) in dichloromethane (100 mL) was added pentanoyl chloride (6.93 g, 57.0 mmol) dropwise at 0° C. The reaction mixture was stirred at ambient temperature overnight and quenched with water (50.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound: MS (ES+) m/z 184.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][C:13]([C:19]([O:21]C)=[O:20])=[CH:12][C:11]=3[CH:23]=2)=[CH:4][CH:3]=1.Cl>COCCOC>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[S:16](=[O:17])(=[O:18])[CH2:15][CH2:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=3[CH:23]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(Cl)s3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc(Cl)s3)ccc2S(=O)(=O)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
In 1,2-dimethoxyethane (11.5 ml) was dissolved methyl 7-(5-chloro-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (230 mg), and to the mixture was added 6N hydrochloric acid (9.2 ml). The mixture was stirred at 100° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-(5-chloro-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (200 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:25]=[O:27])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C=Nc1cc(Oc2ncccn2)c(Cl)cc1F

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy) benzenamine (2 g) and triethyl amine (1.7 g) were dissolved in anhydrous ethyl acetate (75 ml) and stirred under ice cooling. Triphosgene (2.5 g) dissolved in ethyl acetate (75 ml) was slowly added to the stirred solution. The solution was heated at reflux for 2 hr and filtered. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isocyanatophenoxy)-pyrimidine which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[O:26]=[C:12]1[C:13]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:18])=[CH:14][CH:15]=[CH:16][N:11]1[CH:6]1[C:2]2[C:3](=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:4][CH2:5]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Cl)cccc32)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(-c4ccccc4)cccc32)c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a mixture of 1-(4-chloro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (200 mg, 1.0 eq) in DME (4 mL) was added phenylboronic acid (3.5 eq), Pd(PPh3)2Cl2 (0.2 eq) and aqueous Na2CO3 (2M, 2 mL). The mixture was stirred at 120° C. for 30 mins by microwave. At the end of reaction 50 mL of H2O was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 2-oxo-1-(4-phenyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (21 mg, 10%). MS (ESI) 408.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ12.93 (s, 1H), 8.71 (br, 2H), 8.53 (d, J=3.9 Hz, 1H), 8.15 (d, J=3.3 Hz, 2H), 7.84 (d, J=3.9 Hz, 1H), 7.57 (d, J=4.5 Hz, 2H), 7.50 (t, J=4.5 Hz, 2H), 7.37-7.43 (m, 3H), 7.17 (d, J=4.5 Hz, 1H), 6.61-6.69 (m, 2H), 3.15-3.25 (m, 1H), 3.05-3.15 (m, 1H), 2.60-2.75 (m, 1H), 2.50 (s, 6H), 2.10-2.15 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:39]([F:40])=[CH:38][C:17]3[N:18]4[C:27](=[O:28])[N:26]([NH:29]C(OC(C)(C)C)=O)[C:25](=[O:37])[CH:24]=[C:19]4[N:20]([CH:21]4[CH2:23][CH2:22]4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:29][N:26]1[C:25](=[O:37])[CH:24]=[C:19]2[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:16]3[CH:15]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:39]([F:40])=[CH:38][C:17]=3[N:18]2[C:27]1=[O:28]
Reactant: CC(C)(C)OC(=O)Nn1c(=O)cc2n(C3CC3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)cc3n2c1=O
Solvent: O=C(O)C(F)(F)F
Product: Nn1c(=O)cc2n(C3CC3)c3cc(N4CCNCC4)c(F)cc3n2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 7-[4-(tert-butoxycarbonyl)-1-piperazinyl]-5-cyclopropyl-8-fluoro-3,5-dihydro-1,3-dioxopyrimido-[1,6-a]benzimidazol-2(1H)-carbamate (0.145 g, 0.26 mmol) is dissolved in 1 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The reaction solution is concentrated, treated with 1 ml of H2O, adjusted to pH 8 with saturated aqueous NaHCO3 solution and stirred at room temperature for 1 hour. The suspension is cooled to 0° and suction filtered. The product is chromatographed on silica gel (eluent: CHCl3 /EtOH/NH4OH 80:20:1) and recrystallized from ethanol. There is obtained 2-amino-5-cyclopropyl-8-fluoro-7-(1-piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione. Yield: 43 mg (46%); m.p. 232°-234°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C[Al](C)C.[Br:28][C:29]1[C:33]2=[N:34][CH:35]=[CH:36][N:37]=[C:32]2[S:31][C:30]=1[C:38](OCC)=[O:39]>C1(C)C=CC=CC=1>[Br:28][C:29]1[C:33]2[C:32](=[N:37][CH:36]=[CH:35][N:34]=2)[S:31][C:30]=1[C:38]([NH:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:21]#[N:22])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])=[O:39]
Reactant: CCOC(=O)c1sc2nccnc2c1Br
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (230 mg, 0.697 mmol) in toluene (4 mL) was added trimethylaluminum (1.393 mL, 2.79 mmol). After stirring for 15 min, ethyl 7-bromothieno[3,2-b]pyrazine-6-carboxylate 41 (200 mg, 0.697 mmol) in toluene (4 mL) was added and stirred overnight at 60° C. Quenched with 0.5N NaOH solution and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by chromatography (0-10% EtOAc in CH2Cl2) gave the title compound 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (268 mg, 72.0%). NMR (400 MHz, CDCl3) 1.80 (s, 6H), 2.49 (s, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.74 (m, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.95 (s, 1H), 8.00 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 9.10 (s, 1H). (m/z)=534 and 536 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17]C#N)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:20]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:17][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:14]([CH3:16])[N:15]=2)=[O:9])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SC#N
Reactant: ClCCN1CCOCC1
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCCN1CCOCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(4-methyl-5-thiocyanato-thiazol-2-yl)-urea and N-(2-chloroethyl)morpholine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]([S:45](Cl)(=[O:47])=[O:46])([CH3:44])[CH3:43]>C(#N)C>[CH:42]([S:45]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:47])=[O:46])([CH3:44])[CH3:43]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 38.9 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0303 g, 0.0656 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0550 mL, 0.394 mmol) and isopropanesulfonyl chloride (0.0220 mL, 0.197 mmol) to obtain 4-isopropanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0145 g, yield 39%).
Reaction SMILES: Br[CH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[NH2:9][CH2:10][CH2:11][OH:12]>ClC=C(Cl)Cl.[OH-].[Na+]>[OH:12][CH2:11][CH2:10][NH:9][CH2:2][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: BrCC1=CCCCC1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC=C(Cl)Cl
Product: OCCNCC1=CCCCC1
Reaction time: 72 h
Yield: 62 %

Procedure:
A solution of 1-bromomethyl-1-cyclohexene (3.25 g) and 2-aminoethanol (6 mL) in trichloroethylene (40 mL) was heated at the reflux temp. for 3 d, cooled to room temp., and diluted with a 1N NaOH solution (30 mL). The aqueous layer was extracted with CH2Cl2 (4×20 mL) and the combined organic layers were washed with H2O (30 mL) and a saturated NaCl solution (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by vacuum distillation to give N-hydroxyethyl-N-cyclohex-1-enylmethylamine as a colorless oil (1.78 g, 62%): bp 92-94° C. (6 mmHg),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][N:14]=[N+]=[N-])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][NH2:14])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2ccoc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cc(F)cc2ccoc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
A solution 2-(5-fluoro-benzofuran-7-yloxy)-ethylazide (0.82 g, 3.7 mmol) and triphenylphosphine (1.17 g, 4.4 mmol) in tetrahydrofuran (50 ml) and water (2 ml) was allowed to stir for 18 hours at room temperature. The solvent was removed under vacuum. Chromatography (30% methanol-methylene chloride plus ammonium hydroxide) afford 0.55 g (73%) of product as a yellow oil: MS ESI 196 m/e (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Yield: 66.2 %

Procedure:
A solution of tert-butyl (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (120 mg, 0.22 mmol) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 64 mg (65%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.55-1.86 (m, 4 H) 2.01-2.14 (m, 1 H) 2.66-2.85 (m, 2 H) 2.87-3.04 (m, 1 H) 3.32 (dd, J=11.77, 2.35 Hz, 1 H) 4.39 (br. s., 1 H) 6.20 (d, J=5.84 Hz, 1 H) 7.12-7.66 (m, 8 H) 8.47 (s, 1 H), [M+H]+ 439.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 57%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:22])C=1.FC1C(C2CO2)=CC(OC)=C(C=1)C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:11][O:22]2)[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: C=Cc1cc(F)c(C#N)c(OC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COc1cc(C2CO2)c(F)cc1C#N
Product: COc1cc(C2CO2)cc(F)c1C#N

Procedure:
The title compound was prepared from 2-fluoro-6-methoxy-4-vinylbenzonitrile using m-CPBA in an analagous fashion to that described for 5-fluoro-2-methoxy-4-(oxiran-2-yl)benzonitrile (Step H) above: 1H NMR (500 MHz, CDCl3) δ 6.75 (dd, J=9.1, 0.9 Hz, 1H), 6.71 (d, J=0.9 Hz, 1H), 3.97 (s, 3H), 3.90 (dd, J=4.0, 2.5 Hz, 1H), 3.21 (dd, J=5.5, 4.0 Hz, 1H), 2.73 (dd, J=5.5, 2.5 Hz, 1H).
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([O:18]C)[CH:7]=1>O>[I:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([OH:18])[CH:7]=1
Reactant: COc1cc(I)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: O
Product: Oc1cc(I)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
1.83 ml of boron tribromide is added dropwise at 0° C. under a nitrogen atmosphere to a solution containing 6 g of 4-iodo 2-methoxy biphenyl. Agitation is carried out for one hour at 0° C. then for 5 hours at 20° C. and the reaction medium is poured into a water and ice mixture. The suspension obtained is agitated for 15 minutes and extraction is carried out with methylene chloride. The organic phases are collected, dried and evaporated under reduced pressure. In this way 5.65 g of 4-iodo 2-hydroxy biphenyl is obtained.