Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:11][C:12]3[CH2:13][C:14]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=5)=[N:19][N:18](COCC[Si](C)(C)C)[C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[S:11][C:12]3[CH2:13][C:14]4[C:20]([C:21]5[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=5)=[N:19][NH:18][C:15]=4[C:16]=3[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)c(F)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(OC)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 76.3 %

Procedure:
2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.43 g, 0.8 mmol) was dissolved in MeOH and treated with concentrated HCl (0.25 mL, 8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.24 g, 0.61 mmol) as yellow solid in 76% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([F:27])[F:26])[CH:20]=3)[C:10](=[O:28])[NH:9]2)=[CH:4][CH:3]=1.O.[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][CH:25]([F:26])[C:21]1[CH:20]=[C:19]([N:11]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[C:17]=3[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:30]#[N:31])=[CH:7][CH:6]=3)[NH:9][C:10]2=[O:28])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)F)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CCC3)cc1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromophenyl)-1-(3-(difluoromethyl)-phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 33, 75 mg, 0.168 mmol), zinc cyanide (34 mg, 0.290 mmol) and tetrakis(triphenylphosphine)-palladium(0) (20 mg, 17 μmol) in N,N-dimethylformamide (1 mL) is heated at 110° C. for 2 h and cooled to room temperature. Water is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 100:0 to 0:100). Yield: 30 mg; ESI mass spectrum [M+H]+=394; Retention time HPLC: 0.53 min (X012_S01).
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:23][CH2:24][NH:25][C:26]([O:28]C(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=O)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O>[OH:15][C:11]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:23][CH2:24][NH:25][C:26](=[O:28])[C:6]3=[CH:14][C:13]=2[CH:12]=1
Reactant: CCOC(=O)c1cc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1CCNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1cc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
The solution of 10.1 g (21.8 mmol) 1-(2-tert-butoxycarbonylamino-ethyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole-2-carboxylic acid ethyl ester in 100 mL dichloromethane was cooled to 0° C. and 50.1 mL (74.7 g, 0.65 mol) trifluoroacetic acid were added dropwise within 5 min. The cooling bath was removed and after 1.5 hours the volatile components were removed at a rotary evaporator. The residue was dissolved in methanol and 12.1 g (87.5 mmol) potassium carbonate was added under cooling. The suspension was stirred for 64 hours at room temperature and then diluted with water. The solution was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The brown residue (5.3 g) was taken up in 20 mL tetrahydrofuran, the suspension was cooled to 0° C. and 21.8 mL (21.8 mmol; 1M solution in tetrahydrofuran) tetra-n-butylammonium fluoride solution was added. The cooling bath was removed and after 1 h stirring at room temperature the suspension was diluted with ethyl acetate and 10% aqueous ammonium chloride solution. Filtration gave a first batch of the product. The mother liquor was extracted six times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and partially evaporated. The formed suspension was filtered and the filter cake was washed with ethyl acetate to give a second batch of compound, in total 1.9 g (43%) of a light brown solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].[NH2:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.061 mL of pyridine and 0.086 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenethylbenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature and a saturated sodium hydrogen carbonate aqueous solution was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid, aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-phenethylbenzoate.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:8]([NH:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21]2)[S:15][CH3:16])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([SiH2:5][O:6][C:7]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:8]([NH:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21]2)[S:15][CH3:16])([CH3:11])[CH:9]=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(CO)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
N-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-2-hydroxy-1-methyl-ethyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (1.90 g) from Stage 2 above in dichloromethane (55 ml) was treated with Dess-Martin periodinane (1.615 g). The reaction mixture was stirred at R.T. for 1 h 30 and then, quenched with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The reaction mixture was vigorously stirred at rt. for 50 minutes after which time the two phases were separated. The organic layer was washed thrice with sat. aqueous. NaHCO3. After separation, the organic phase was dried over sodium sulphate, filtered and evaporated to yield 1.694 g of N-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-1-methyl-2-oxo-ethyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a crude product along with minor impurities. The crude mixture was used in the next step without any further purification.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH:37]=[C:36]3[C:31]([C:32](=[O:38])[NH:33][CH:34]=[N:35]3)=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=1.[OH-].[K+]>O1CCOCC1.[Na+].[Cl-]>[F:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][C:28]2[CH:37]=[C:36]3[C:31]([C:32](=[O:38])[N:33]([CH2:6][CH:7]4[CH2:11][CH2:10][CH2:9][N:8]4[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:34]=[N:35]3)=[CH:30][CH:29]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Reactant: O=c1[nH]cnc2cc(C#Cc3cccc(F)c3)ccc12
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC1Cn1cnc2cc(C#Cc3cccc(F)c3)ccc2c1=O
Temperature: 25 °C
Yield: 290.1 %

Procedure:
To a solution of tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (0.86 g, 3.42 mmol, 5.4 equiv) and 7-((3-fluorophenyl)ethynyl)quinazolin-4(3H)-one (0.15 g, 0.57 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added KOH (0.38 g, 6.98 mmol, 12 equiv). The reaction mixture was stirred at reflux overnight. After it was cooled to room temperature, the reaction mixture was diluted with saturated NaCl and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give 0.74 g of the desired product. MS (ESI): 448 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Br:11])[CH:5]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]=1[CH2:10][Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Br)c1
Yield: 95.5 %

Procedure:
A mixture of methyl-3-bromo-4-methylbenzoate (40 g, 0.17 mol), NBS (34 g, 0.19 mol) and benzoylperoxide (4.0 g) in CCl4 (500 mL) was refluxed for 6 h. The reaction mixture was cooled and filtered off the solid. The filtrate was concentrated under vacuum to give 2-bromo-4-methoxycarbonylbenzyl bromide (50 g, 93%) as a solid.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([N:21]1[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trityl chloride (9.5 g, 34.3 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to an ice-cooled solution of imidazole-4-carboxaldehyde (3 g, 31.2 mmol) and triethylamine (17 ml, 125 mmol) in N,N-dimethylformamide (30 ml) and the solution was stirred for 2 hours. The reaction was then allowed to warm to room temperature, and was stirred for a further 18 hours. Water (200 ml) was added, and the resulting pink solid was collected and dried, then dissolved in dichloromethane (200 ml). The resulting solution was washed with water (2×100 ml), dried (MgSO4) and evaporated under reduced pressure. The product was recrystallised from ethanol to afford the title compound as a solid, 7.8 g. 1H-NMR (CDCl3, 400 MHz) δ: 7.06 (m, 6H), 7.32 (m, 9H), 7.48 (s, 1H), 7.58 (s, 1H), 9.82 (s, 1H). Microanalysis found: C, 81.54; H, 5.37; N, 8.24. C23H18N2O requires C, 81.63; H, 5.36; N, 8.28%.
Reaction SMILES: N1C=CC(C2C(C3C=CC(OCC4C=NC5C(=CC=CC=5)N=4)=CC=3)=NN(CC(F)(F)F)C=2)=CC=1.[CH3:35][N:36]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[C:38]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)=[N:37]1.[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66]O)[CH:62]=[CH:61]2>>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][CH:59]=[C:60]2[C:65]=1[N:64]=[C:63]([CH2:66][O:53][C:50]1[CH:51]=[CH:52][C:47]([C:38]3[C:39]([C:41]4[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=4)=[CH:40][N:36]([CH3:35])[N:37]=3)=[CH:48][CH:49]=1)[CH:62]=[CH:61]2
Reactant: COc1cccc2ccc(CO)nc12
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Product: COc1cccc2ccc(COc3ccc(-c4nn(C)cc4-c4ccncc4)cc3)nc12

Procedure:
Following the procedure for the preparation of 2-{4-[4-Pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline but substituting 4-(1-Methyl4-pyridin4-yl-1H-pyrazol-3-yl)-phenol and (8-Methoxy-quinolin-2-yl)-methanol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=6.2 Hz, 2 H), 8.15 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.3 Hz,1H), 7.55 (s, 1H), 7.44 (m, 1 H), 7.37 (m, 3 H), 7.15 (d, J=5.8, Hz, 2 H), 7.07 (d, J=7.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 2 H), 5.46 (s, 2H), 4.08 (s, 3 H), 3.94 (s, 3H); MS: (M+H m/z=423.1).
Reaction SMILES: Cl.[C@@H:2]12[N:9]([CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])[C@@H:6](CC1)[CH2:5][NH:4][CH2:3]2.[CH3:24][C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1.CCN(C(C)C)C(C)C>C(O)C>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:4]1[CH2:3][CH2:2][N:9]([CH2:10][C@@H:11]([OH:12])[C:13]2[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][CH2:16]3)[CH2:6][CH2:5]1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@H](O)CN2CCN(CC(O)c3ccc4c(c3)C[C@@H](C)OC4=O)CC2)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1(3H)-one (INTERMEDIATE 12) (150 mg, 0.54 mmol) in ethanol (2 mL) was added (3R)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (INTERMEDIATE 23) (110 mg, 0.54 mmol) and Hunig's base (95 uL, 0.54 mmol). The mixture was heated to 80° C. for 20 hours. The solvent was removed using rotary evaporation and the crude oil was purified via by silica gel chromatography (0-7% MeOH in DCM) to yield (3R)-6-(1-hydroxy-2-(4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)-3-methylisochroman-1-one as a diastereomeric mixture.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:36][CH:37]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(CN4CCOCC4)cc3)cc2s1

Procedure:
330 mg (3.75 mmol) of morpholine and 40 mg (0.56 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 23A) in 1.5 ml of a 6:1 mixture of methanol and acetic acid. 2 h at room temperature and 6 h at 80° C. are followed by purification by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 87.7 mg (88% of theory) of the title compound.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1>CC(C)=O.O>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]([C@@H:4]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:3][CH:2]=[O:1])[CH:10]=[CH:9][N:8]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1cc([C@H](CC(O)CO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 18 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3,4-dihydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (0.710 g, 1.42 mmol) in acetone (18 mL) and water (9 mL) was added NaIO4 (608 mg, 2.84 mmol). After 18 hours, the mixture was filtered through diatomaceous earth washing with acetone (3×20 mL). The acetone was removed in vacuo and the aqueous layer was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organics layers were dried over magnesium sulfate, filtered, and evaporated to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide as white solid which was used without purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([O:47][C:48]1[CH:49]=[C:50]([CH:66]=[CH:67][CH:68]=1)[CH2:51][N:52]1[CH:56]=[C:55](B2OC(C)(C)C(C)(C)O2)[CH:54]=[N:53]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:40]([O:47][C:48]1[CH:49]=[C:50]([CH:66]=[CH:67][CH:68]=1)[CH2:51][N:52]1[CH:56]=[C:55]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:54]=[N:53]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(OCc4ccccc4)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 69.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazine-1-carboxylate (Intermediate 66K) (300 mg, 0.454 mmol) was coupled with 1-(3-(benzyloxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64E) (195 mg, 0.500 mmol) using sodium carbonate (145 mg, 1.364 mmol) and Pd(dppf)Cl2 (17 mg, 0.022 mmol) in toluene/ethanol/water (3/3/2 mL) to afford 250 mg (69% yield) of the titled compound after purification by column (Silica gel 60/120) using 0.5% methanol in DCM as eluent. MS: m/z=796.3 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26]C(C)C)[N:17]=[CH:16]1>C(Cl)Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:17]=[CH:16]1
Reactant: COC(=O)CCCCCCCn1cnc(-c2ccccc2OC(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCCCCCCn1cnc(-c2ccccc2O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
Add aluminum(III) chloride (3.84 g, 29 mmol) to a suspension of 8-[4-(2-isopropoxyphenyl)imidazol-1-yl]octanoic acid methyl ester (5.16 g, 14 mmol) in methylene chloride (150 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for 6 hours. Dilute the mixture with saturated aqueous sodium sulfate (50 mL) and remove the solvent under reduced pressure. Dilute the residue with ethyl acetate (300 mL), wash with brine (100 mL), dry over sodium sulfate, and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (2:8 to 3:7), to provide 8-[4-(2-hydroxyphenyl)imidazol-1-yl]octanoic acid methyl ester (2.63 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[O:32][C:33]([CH2:36]Br)=[CH:34][CH:35]=1)=[O:30])[CH3:27]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:36][C:33]4[O:32][C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])=[CH:35][CH:34]=4)[CH:21]=3)[C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(CBr)o1
Reactant: O=c1[nH]cc(C2c3ccc(Cl)cc3C=Cc3cc(Cl)ccc32)c(=O)[nH]1
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(Cl)cc4C=Cc4cc(Cl)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (0.54 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.34 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.55 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.C(O)(=O)C.CO>[CH:17]1([NH:23][C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(C(=O)c2cccc(NC(=O)NC3CCCCC3)c2)CC1
Yield: 92.2 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and cyclohexyl isocyanate (44 μL, 0.344 mmol) in methylene chloride (2 mL) were mixed for 72 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (2 mL). Cyclohexyl isocyanate (44 μL, 0.344 mmol) and poly(4-dimethyaminopyridine) (82 mg, 0.115 mmol) were added and the reaction mixture was mixed for 5 days. The reaction mixture was filtered and the filter cake was washed with methanol. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 36.4 mg (93%) of the title compound.