Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][C:6]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[OH-].[Na+].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[OH:14])=[CH:7][C:6]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(O)CC2
Reaction time: 16 h
Yield: 86.5 %

Procedure:
3.53 g of 6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone was dissolved in 35 ml of methanol and 10 ml of 1 N sodium hydroxide solution and, at 5° C., combined in incremental portions with 0.8 g of sodium borohydride. After 16 hours at 20° C., the mixture was concentrated, mixed with 40 ml of water and 26 ml of 1 N hydrochloric acid, and vacuum-filtered. Recrystallization from ethanol yielded 3.07 g of N-[6-(2,4-difluorophenoxy)-1-hydroxy-5-indanyl]methanesulfonamide, mp 127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][C:19]=3[F:36])[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)cc(F)c2/C1=C/c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (3.2 g, 15 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-4-fluoro-1,3-dihydro-indol-2-one (1.5 g, 4.7 mmol) prepared in Example 69 in dichloromethane (60 mL) were added triethylamine (9.6 mL, 69 mmol) and AgF (3 g, 24 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (20 mL), and DBU (2.5 g, 16 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white solid (1.8 g, 71%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1S(Cl)(=O)=O.CN1C=CN=C1.[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:45])[C@H:25]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:26]([OH:36])[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:20][O:21][N:22]=[CH:23][C@@H:24]([F:45])[C@H:25]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:26]([O:36][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON=C[C@@H](F)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON=C[C@@H](F)[C@H](OCc1ccccc1)[C@@H](COCc1ccccc1)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 92 %

Procedure:
1.26 g of 2,4,5-trichlorobenzenesulfonyl chloride and 0.430 mL of 1-methylimidazole were added to a solution of 1.09 g of (2R,3R,4R)-2-fluoro-4-hydroxy-3,5-bis(benzyloxy)pentanal O-methyloxime in 10.4 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 14.5 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. A solid was removed by filtration, and the organic layer was then fractionated. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.50 g of (2R,3R,4R)-2-fluoro-3,5-bis(benzyloxy)-4-(2,4,5-trichlorophenoxy)pentanal O-methyloxime in the form of a colorless oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl[C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[CH2:2]1[C:41]2[C:35](=[CH:36][CH:37]=[C:38]([NH:39][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:40]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-chloroaniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.67 (d, 1H, J=5.2 Hz), 7.18 (t, 1H, J=7.0 Hz), 7.26-7.32 (m, 4H), 7.38 (d, 1H, J=7.7 Hz), 7.49-7.66 (m, 4H), 7.73 (d, 1H, J=8.9 Hz), 7.84 (d, 1H, J=8.7 Hz), 8.06 (s, 1H), 8.35 (d, 1H, J=5.4 Hz), 8.45 (d, 1H, J=8.9 Hz), 8.90 (d, 1H, J=6.8 Hz), 9.79 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=553.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2o1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1

Procedure:
4-[N-Methyl-N-(5-chloro-2-benzoxazolyl)amino]phenol (0.00255 mol, 0.7 g, prepared as above), ethyl 2-bromopropionate (0.00255 mol, 0.46 g) and potassium carbonate (0.00255 mol, 0.35 g) were mixed in methyl ethyl ketone (5 ml) and heated under reflux for 6 hours. The solvent was then evaporated, the residue taken into water (25 ml) and twice extracted with diethyl ether (25 ml). An oily residue was obtained which was purified by preparative thin layer chromatography on silica gel, eluent toluene/diethyl ether. Yield 0.75 g, mp 68.0°-68.6° C.; ir, and pmr spectra and analysis consistent with assigned structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][CH2:2][C:3]1([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2(CO)CCOCC2)c2nc(C3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1(CO)CCOCC1)c1c[nH]c2ncc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide (0.15 g, 0.33 mmol) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was dissolved in MeOH (10 mL) and H2O (1 mL) and Et3N (2 mL) were added. The reaction mixture was stirred at room temperature overnight then concentrated. The residue was triturated with Et2O to afford 96 mg (92%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (4-hydroxymethyl-tetrahydro-pyran-4-yl)-amide as an off-white solid. MS: (M+H)+=317; mp=294.0-296.0.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[C:9]([C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[N:13]1[CH:14]=[CH:15][C:10]([C:9]2[C:17]3[C:18](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:19](=[O:20])[O:21][CH:22]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccncc1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1occ(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
Sodium hydride (purity 60%, 2.0 g) was suspended in dimethylformamide (100 mL), and trimethylsulfoxonium iodide (11 g) was added, and the mixture was stirred at room temperature for 1 hr. Then, methyl 2-isonicotinoylbenzoate (11 g) was added, and the mixture was further stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 4-(pyridin-4-yl)isocoumarin (4.9 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][N:10]=[C:9]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:8]=1.[ClH:25]>CO.O1CCOCC1>[ClH:25].[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12]([C:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][N:10]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3ccccn3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl]piperidine-1-carboxylate 39 g (111 mM) in methanol 50 is added 100 ml solution of HCl in dioxane and stirred at room temperature for 3 hrs. Solid precipitated is then filtered and washed with cold acetonitrile to obtained 2-[3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl]pyridine dihydrochloride as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[O:7][C:8]([CH3:40])([CH3:39])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17](OC(OC4C=CC=CC=4)=S)[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:38])[C:5]=2[CH:4]=1)#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:42]=[CH:41][C:6]2[O:7][C:8]([CH3:40])([CH3:39])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22])=[CH:13][C:12]3=[O:38])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C(CCO[Si](C)(C)C(C)(C)C)OC(=S)Oc3ccccc3)cc2=O)c2cc(C#N)ccc2O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)C=C(n2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Yield: 92.5 %

Procedure:
In 40 ml of anhydrous toluene, is dissolved 1.20 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-phenoxythiocarbonyloxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 39. Then, 0.66 g of 2,2'-azobisisobutyronitrile and 1.16 g of tri-n-butyltin hydride are added at room temperature and reacted at 100° C. for 30 minutes. After the reaction, the reaction mixture is directly purified by silica gel column chromatography using 1/1 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 0.83 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ON=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
N-chlorosuccinimide (5.50 g, 41.3 mmol) was added in portions to a solution of benzaldehyde oxime (5.0 g, 41.3 mmol) in DMF (34 ml) such that the temperature did not rise above 35° C. The mixture was stirred at ambient temperature for 2 hours and then cooled with an ice bath. Water was added and the aqueous mixture extracted with ether. The organics were combined, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation to give the title compound (6.43 g, 100%) as an oil. NMR (CDCl3): 7.4 (m, 3H), 7.8 (d, 2H), 8.9 (bs, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:29][N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][C:33]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)([OH:36])[CH2:32][CH2:31]1
Reactant: CN1CCC(=O)CC1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5, 198 mg, 0.5 mmol) was dissolved in THF (10 ml), cooled to −78° C. and treated with nBuLi (1.6M in hexane, 0.94 ml, 1.5 mmol) for 15 minutes. N-methyl-4-piperidone (231 μl, 2 mmol) in THF (0.2 ml) was added rapidly and the reaction mixture stirred for 15 minutes at −78° C., then poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via preparative HPLC to give the title compound as colorless crystals, which crystallized from ether. Yield: 40 mg (19%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH2:19])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:28][C:29]([NH:19][C:14]12[CH2:17][CH2:18][C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)([CH2:16][CH2:15]1)[CH2:12][CH2:13]2)=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C23CCC(N)(CC2)CC3)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C23CCC(NC(=S)NC(=O)c4ccccc4)(CC2)CC3)cc1
Yield: 97.4 %

Procedure:
To a 100 mL round-bottomed flask equipped with magnetic stirring was added 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-amine (120 mg, 429 μmol) in 2 mL of CH2Cl2, and benzoyl isothiocyanate (63.6 μl, 472 μmol). The reaction was stirred at ambient temperature for ca. 26 h, and then it was concentrated in vacuo to give 1-benzoyl-3-(4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-yl)thiourea (mass=185 mg, Mass spec. m/z+ion=443.2). The crude reaction product was taken onto the next step without further purification.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Cl)(Cl)Cl>C(O)C.O>[CH2:12]([O:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1ccc(OCCCCCCCC)cc1

Procedure:
Hydroquinone (10.00 g, 9.08×10−2 mol) was dissolved in 100 ml of ethanol. After addition of KOH (10.79 g, 0.192 mol), the solution was stirred under reflux for 20 min. 1-Bromooctane (33.0 ml, 0.191 mol) was added dropwise to the light brown solution over 1 h, followed by stirring under reflux for 3 h. After cooling, CHCl3 and H2O were added to the reaction mixture and the organic layer was collected. The aqueous layer was further washed with CHCl3. The combined organic layers were washed with aqueous NaHCO3 and dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with 1:1 hexane:CHCl3 as the eluent. Yield=27.33 g (90% based on 10.00 g of hydroquinone). 1H NMR (300 MHz, CDCl3): δ 6.82 (s, 4H, Ph-H), 3.90 (t, 4H, J=6.6 Hz, —OCH2—), 1.75 (quint, 4H, J=7.0 Hz, —OCCH2—), 1.37-1.51 (m, 4H, —OCCCH2), 1.17-1.37 (m, 16H, —CH2—), 1.20-1.49 (m, 24H, —CH2—), 0.88 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 334.287 (M+) (calcd 334.287).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH:20]=[O:21]>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=1[CH2:20][OH:21]
Reactant: CC[Si](CC)(CC)c1cc(C=O)c(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(CO)c(C)o1
Temperature: 25 °C

Procedure:
LiAlH4 (1.0M solution in hexane, 0.51 ml, 0.51 mmol) was added dropwise to a solution of 5-methyl-2-triethylsilyl-4-furaldehyde (230 mg, 1.03 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. The stirring solution was allowed to warm to room temperature gradually over 1/2 hour. The reaction was quenched with 10% aqueous HCl and the organics were extracted into ethyl ether. The combined fractions were washed with H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by filtration through silica using 10% ethyl ether/hexanes to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:27][CH:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(C=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN1CCC(CN(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine and 1-methylpiperidine-4-carbaldehyde using standard reductive amination conditions yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-ylmethyl)-amine, which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Acid/base work-up and trituration with ether yielded 335. 400 MHz 1H NMR CDCl3: 9.30 (s, 2H), 7.26 (s, 1H), 5.30 (br s, 2H, NH2), 4.04 (t, 4H, J 4.5), 3.90 (t, 4H, J 4.5), 3.80 (s, 2H), 2.87 (d, 2H, J 11.5), 2.33 (d, 2H, J 7.1), 2.30 (s, 3H), 2.28 (s, 3H), 1.93 (t, 2H, J 11.7), 1.83 (d, 2H, J 13.1), 1.57-1.51 (m, 1H), 1.32-1.22 (m, 2H). LC-MS (m+1)=469.35
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[N:11]1[CH2:14][CH2:13][CH2:12]1.[H][H]>CO.[Pt]=O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: C1=C(N2CCC2)CCc2ccccc21
Agent: O=[Pt]
Solvent: CO
Product: c1ccc2c(c1)CCC(N1CCC1)C2

Procedure:
The crude product from Step 1 was dissolved in methanol (1 litre) and reduced at room temperature over platinum oxide (5 g) with hydrogen at 120 p.s.i. (about 8.3×105Pa). After 21/2 h, the solution was filtered and evaporated in vacuo. The residue was purified by chromatography (silica; methanol) to give the product (2.5 g as an oil).
Reaction SMILES: C(N1CCN2C=C(C(OCC)=O)C(O)=C2C1=O)C1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:45]=[CH:46][CH:47]=1)[CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[CH:35]=[C:36]([C:39]([O:41]CC)=[O:40])[C:37]([OH:38])=[C:31]2[C:30]1=[O:44]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:45]=[CH:46][CH:47]=1)[CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[CH:35]=[C:36]([C:39]([OH:41])=[O:40])[C:37]([OH:38])=[C:31]2[C:30]1=[O:44]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1cccc(Cl)c1)CC2
Agent: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccccc1)CC2
Product: O=C(O)c1cn2c(c1O)C(=O)N(Cc1cccc(Cl)c1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 2, except that ethyl 2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C@@H:4]([NH3+:6])[CH3:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27](I)=[C:28]([CH3:31])[CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:2][C@H:3]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=4)[C@@H:4]([NH2:6])[CH3:5])=[C:28]([CH3:31])[CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: COc1cccc([C@@H](O)[C@H](C)[NH3+])c1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Agent: [Cl-]
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1

Procedure:
Prepared as described in Example 1 from (1R,2S)-1-hydroxy-1-(3-methoxyphenyl)propan-2-aminium chloride (185 mg, 0.85 mmol) and 1-(4-fluorophenyl)-5-iodo-6-methylindazole (300 mg, 0.85 mmol). Yield 224 mg (65%).