Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH3:23])[C:13]3=[O:24])=[CH:8][C:7]=2F)=O)[CH2:3][CH2:2]1.CO.O.[NH2:29][NH2:30]>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:6]3[C:7](=[CH:8][C:9]([N:12]4[CH2:16][CH2:15][N:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][C:22]=5[CH3:23])[C:13]4=[O:24])=[CH:10][CH:11]=3)[NH:30][N:29]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: Cc1ccncc1N1CCN(c2ccc(C(=O)C3CC3)c(F)c2)C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccncc1N1CCN(c2ccc3c(C4CC4)n[nH]c3c2)C1=O
Temperature: 120 °C
Yield: 31.97 %

Procedure:
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-198b: 175 mg, 0.516 mmol) in hydrazine hydrate solution (10 mL) was taken in a reaction flask. The flask was refluxed at 120° C. overnight. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was cooled to room temperature and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3), followed by hexane and ether wash, afforded 55 mg of the product (31.97% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][OH:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:9]([CH3:10])[CH3:11])[O:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: CC(C)C(=O)c1ccc(Br)cc1
Product: CC(C)C1(c2ccc(Br)cc2)OCCCO1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 62, part (i), but starting from 1-bromo-4-(2-methylpropanoyl)benzene and 1,3-propanediol there was thus obtained (in 42% yield) 2-(4-bromophenyl)-2-isopropyl-1,3-dioxane (4.25 g), b.p. 116° C. at 0.4 mm Hg 1H NMR (acid free CDCl3): 0.8 (d, 3H), 1.15-1.25 (m, 1H), 1.85 (m, 2H), 2.0-2.1 (m, 1H), 3.68 (d of t, 2H), 3.75-3.85 (m, 2H) 7.15-7.25 (m, 2H), 7.45-7.55 (m, 2H): mass spectrum (CI+) 285 (M+H)+.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:4]
Reactant: O=C(CNC(=O)c1ccccc1)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CNC(=O)c1ccccc1)c1ccccc1
Yield: 109.6 %

Procedure:
Thiosemicarbazide (1.33 g, 14.6 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-benzamide (3.5 g, 14.6 mmol), prepared in the previous step, in 53 ml of methanol plus 4 ml of 1N HCl plus 3.75 ml of water and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 5.0 g of an off-white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.64 g, 80%) as a white solid, mp 171-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH2:21][C@@H:22]2[C@@H:29]3[C@@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[C@H:24]([N:32]3[C:36]4[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH2:42][C:43]5[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=5[O:51][CH3:52])[C:35]=4[CH:34]=[CH:33]3)[CH2:23]2)[CH2:17]1>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH:18]([N:20]([CH2:21][C@@H:22]4[C@H:29]5[O:28][C:27]([CH3:31])([CH3:30])[O:26][C@H:25]5[C@H:24]([N:32]5[C:36]6[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH2:42][C:43]7[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=7[O:51][CH3:52])[C:35]=6[CH:34]=[CH:33]5)[CH2:23]4)[CH2:53][CH:54]4[CH2:56][CH2:55]4)[CH2:19]3)=[N:1][C:2]=2[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 53.4 %

Procedure:
N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((cyclopropylmethyl)(((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanamide (1.1 g, 1.4 mmol) in Acetic acid (5 ml) was heated at 60° C. overnight. The solution was concentrated and purified by flash chromatography (DCM/7N NH3 ion MeOH 93:7) to yield the desired compound (0.57 g) as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[S:13][C:6]=12.[H-].[Na+].[CH2:28](Cl)[O:29][CH3:30]>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:28][O:29][CH3:30])[CH:18]=3)[S:13][C:6]=12
Reactant: COCCl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4c[nH]cn4)sc23)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a solution of 7-(2-fluoro-4-nitrophenoxy)-2-(1H-imidazol-4-yl)thieno[3,2-b]pyridine (93) (WO 2006010264) (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. was added NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture was allowed to warm to room temperature over 0.5 h then re-cooled to 0° C. MOMCl (74 mg, 1.1 eq, 0.92 mmol) was added and mixture was allowed to warm to room temperature over 20 hours, concentrated and partitioned between EtOAc and water. The EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (100% hexane to 100% acetone) to afford the title compound 94 (126 mg, 36% yield). MS (m/z): 401.0 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[C:13]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37](OC)=[O:38])=[N:31][N:30]=2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)=[CH:16][N:17]=1>ClCCl>[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:25]([CH3:27])[CH3:26])=[O:28])=[CH:22][CH:23]=2)=[N:14][C:13]=1[C:29]1[O:33][C:32]([C:34]2[CH:43]=[CH:42][CH:41]=[C:36]([CH2:37][OH:38])[CH:35]=2)=[N:31][N:30]=1
Reactant: COC(=O)c1cccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4cccc(CO)c4)o3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Diisobutylaluminium hydride (810.0 μL. of 1 M, 0.8100 mmol) in dichloromethane was added dropwise to a solution of methyl 3-[5-[3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]benzoate (120 mg, 0.2700 mmol) in CH2Cl2 (6 mL) at 0° C., the solution darkened upon addition. The resulting solution was stirred at 0° C. for 30 min and allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 4 h and then quenched by addition of 1M HCl (3 mL). The resulting mixture was filtered through a Celite pad and washed with dichloromethane (2×5 mL). The layers were separated and the aqueous layer extracted further with dichloromethane (2×10 mL) and combined organic extracts dried over MgSO4 and concentrated in vacuo. The residue was purified using by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (20.3 mg, 18% yield); 1H NMR (400 MHz, DMSO) d 2.98 (m, 6H), 4.66 (s, 2H), 7.55 (m, 2H), 7.63 (m, 2H), 7.80 (br s, 2H), 8.04 (m, 1H), 8.16 (m, 3H) and 8.99 (s, 1H) ppm; MS (ES+) 417.23
Reaction SMILES: [C:1]1(SC[Li])C=CC=CC=1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:22][CH2:21]1>>[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:1])=[C:25]([O:30][CH3:31])[C:24]=2[O:32][CH2:33][O:34][CH3:35])[CH2:21][CH2:22]1
Reactant: [Li]CSc1ccccc1
Reactant: COCOc1ccccc1C1(c2ccc(O)c(OC)c2OCOC)CC1
Product: COCOc1ccccc1C1(c2ccc(OC)c(OC)c2OCOC)CC1

Procedure:
When an initial charge of 3.3 moles of phenylthiomethyl lithium per mole of olefin was employed, the product was 1-(2-methoxymethoxyphenyl)-1-(4-hydroxy-3-methoxy-2-methoxymethoxyphenyl)-cyclopropane, an oil obtained in 33 percent yield and identified by proton NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:12][CH2:11]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.C(O)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[CH:27][S:28][C:29]=2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:24])[CH2:14][CH2:15]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3ncsc3NC(=O)OC(C)(C)C)cnn2C)CC1
Yield: 75 %

Procedure:
A solution of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate (0.15 g, 0.244 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a clear gum (98 mg, 96%). This gum (97 mg, 0.182 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7N ammonia in MeOH to give 283 as an off-white solid (39 mg, 84%). 1H NMR (400 MHz, d4-MeOD) δ 7.97 (s, 1H), 7.44 (s, 1H), 3.71 (s, 3H), 3.21-3.07 (m, 4H), 2.65 (d, J=6.6 Hz, 2H), 1.83 (d, J=12.5 Hz, 2H), 1.60-1.47 (m, 1H), 1.43-1.30 (m, 2H). LCMS (ES+) m/z 336 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][N:13](C(=O)[C@H](OC)C3C=CC=CC=3)[CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[B-](CC)(CC)CC.Cl.[NH4+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO[C@@H](C(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)C1)c1ccccc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc([C@H]2CNCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Synthesized according to General Procedure 35. To a stirring solution of (R)-1-((S)-2-(3,4-dichlorophenyl)-morpholino)-2-methoxy-2-phenylethanone (620 mg, 1.63 mmol) and THF (9 mL), under N2, at 0° C., was added a solution of Super-hydride in THF (1.0 M, 10.3 mL, 10.3 mmol) dropwise over 10 minutes. The solution was stirred at 0° C. for 30 minutes. The solution was poured into 1M aqueous HCl solution (20 mL). The solution was then basified with NH4OH and extracted with CH2Cl 2 (3×50 mL). Purified via silica gel chromatogrophy using 10% MeOH in CH2Cl2 to obtain the desired morpholine, arbitrarily assigned the (S) configuration, as a clear oil (250 mg, 1.1 mmol, 67% yield). 1H-NMR (400 MHz, CDCl3) δ 7.50-7.49 (m, 2H), 7.19 (dd, J=1.6, 8.3 Hz, 1H), 4.47 (dd, J=2.4, 10.4 Hz, 1H), 4.09 (s, 1H), 4.08 (dd, J=1.9, 12.9 Hz, 1H), 3.82-3.75 (m, 1H), 3.09 (dd, J=2.5, 12.5 Hz, 1H), 2.97 (dd, J=3.1, 10.2 Hz, 2H), 2.72-2.69 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=232.3; tR=0.65 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([N+:37]([O-:39])=[O:38])=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1.[ClH:40].CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:26].[ClH:40].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:27]4[C:36]5[C:31](=[CH:32][C:33]([N+:37]([O-:39])=[O:38])=[CH:34][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: Cc1cc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)nc(N)n1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5cc([N+](=O)[O-])ccc45)cc3)cc2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of C3 (235 mg, 0.58 mmol) in EtOH (20 mL) and H2O (10 mL) was added 4-chloro-7-nitroquinoline (132 mg, 0.63 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 5 h., diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc/Charcoal/Celite to give Cpd. GG5 (317 mg 94%) as a yellow solid.; m.p (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 12.9 (br, 1 H, N+H), 10.81 (brs, 2H, 2×NH), 10.44 (s, 1H, NH), 8.93 (d, J=9.3 Hz, 1H, ArH), 8.81 (d, J=1.9 Hz, 1H, ArH), 8.66 (d, J=6.6 Hz, 1H, ArH), 8.46 (d, J=8.9 Hz, 1 H, ArH), 8.05-7.98 (m, 8H, ArH & NH2), 7.47 (d, J=8.8 Hz, 1H, ArH), 6.94 (d, J=6.6 Hz, 1H, ArH), 6.26 (s, 1H, ArH), 2.32 (s, 3H, CH3); HRMS (FAB+) calc. for C27H23N8O3 (M+1) m/z 507.1893, found 507.1885.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([C:20]3[N:21]=[CH:22][NH:23][CH:24]=3)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 88.1 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(3′-methoxy[1,1′-biphenyl]-4-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (960 mg) and pyridine hydrochloride (354 mg), the colorless amorphous title compound (483 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:27][C:28]([NH:14][C:13]1[C:8]([O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (200 mg, 0.82 mmol) and benzoyl isothiocyanate (133 μL, 0.99 mmol, 1.2 eq) in DCM (10 mL) was heated at reflux for 1 h. The mixture was cooled to rt and evaporated to give the crude product. Purification by flash chromatography (silica, 0-50% EtOAc/hexane gradient) provided Example 217a as a white fluffy powder. (M+H)+=406.29.
Reaction SMILES: COC1C(OC)=CC2SC(/C=C/C#N)=CC=2C=1.[ClH:18].[OH:19][NH:20][C:21](=[NH:37])/[CH:22]=[CH:23]/[C:24]1[S:28][C:27]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:26]=2[CH:25]=1>>[ClH:18].[OH:19][NH:20][C:21](=[NH:37])[CH:22]=[CH:23][C:24]1[S:28][C:27]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:26]=2[CH:25]=1
Reactant: COc1cc2cc(/C=C/C(=N)NO)sc2cc1OC
Agent: COc1cc2cc(/C=C/C#N)sc2cc1OC
Agent: Cl
Product: COc1cc2cc(C=CC(=N)NO)sc2cc1OC

Procedure:
Using the procedure described in Example 2 (E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile was converted into (E)-N-hydroxy-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-prop-2-ene-imidamide hydrochloride, m.p. 188°-198° C. (decomp.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-])=O)[CH:6]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[NH2:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)cc(C(F)(F)F)c1
Yield: 73.1 %

Procedure:
Stir the mixture of 1-(methylsulfonyl)-3-nitro-5-(trifluoromethyl)benzene (2 g, 7.43 mmol), Pd/C (10%, 500 mg) in methanol (100 mL) under hydrogen atmosphere at room temperature for 15 hrs. Filter off the solid and concentrate the filtrate under reduced pressure. Purify the residue with flash chromatography (silica gel, EtOAc:PE=1:5) to afford the desired product (1.3 g, 73%). MS: (M+23): 262.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:40])[C:16]3[C:21]([N:22]=2)=[C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:19]=[C:18]([N:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]2[CH2:38][CH3:39])[N:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41].CCOCC>C(Cl)Cl.CO.O1CCOCC1>[ClH:41].[CH2:38]([C:30]1[N:29]([C:18]2[N:17]=[C:16]3[C:21]([N:22]=[C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:15]3[CH3:40])=[C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:19]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1)[CH3:39]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOCC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCNCC3)n(C)c2n1
Yield: 93 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidine-1-carboxylic acid tert-butyl ester (390 mg, 0.71 mmol) in DCM (20 mL) and MeOH (5 mL) was added 4M HCl in dioxane (20 mL). The resulting mixture was allowed to stir for 4 h at r.t. before Et2O (80 mL) was added. The resulting precipitate was collected by filtration, washed with Et2O and dried in vacuo affording 2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-yl-9H-purine hydrochloride (322 mg, 93%). LCMS (method I): RT 2.43 min [M+H]+ 447.2
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[C:27]([C:29]1[CH:34]=[C:33]([CH:32]=[CH:31][CH:30]=1)[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:28]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-phenylboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=446 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=O)[C:9]1C(=CC=C[CH:17]=1)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>CC(C)=O.O1CCCC1>[CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])[CH3:8]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1ccccc1
Temperature: 10 °C

Procedure:
N-isopropylaniline is synthesized as follows: A mixture of 233 g. (2.5 moles) of aniline, 5 l. of tetrahydrofuran and 250 ml. of acetone is stirred at 24°-25° C. under nitrogen for 2 hours and coooled to 10° C., 675 g. (4.06 moles) of phthalic acid is added rapidly, the resulting suspension is stirred at 10° C. under nitrogen, and 100 g. (2.64 moles) of powdered 98% sodium borohydride is added over a period of 25 minutes with stirring under nitrogen, during the course of which the temperature rises to 28° C. The reaction mixture is stirred under nitrogen at 28° C. for 15 minutes and at 60°-61° C. for 2 hours, cooled to 25° C. and siphoned portionwise into 2.0 l. of 20% sodium hydroxide solution at a rate such that the temperature does not exceed 20° C. The organic phase is separated, 1.0 kg. of anhydrous potassium carbonate is added, the mixture is stirred at 20°-25° C. for 20 minutes, the solid is removed by filtration and washed twice with 250 ml. portions of tetrahydrofuran, the washings are combined with the filtrate, and the tetrahydrofuran is distilled at 20-100 mm. Hg. and a maximum temperature of 55° C. The resulting residual oil is fractionally distilled through a 35 cm. Vigreux column to obtain the 97.4% pure product (295 g. (84.4%)). B.p. 62°-64° C./1 mm. Hg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Yield: 88.8 %

Procedure:
4-Bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 ml, 17.84 mmol) in toluene was added piperidine (27 μl) and the reaction mixture was refluxed for 1 hour with a Dean-Stark separator. The solvent was removed under reduced pressure, the residue triturated with warm ethyl acetate, filtered to yield the desired product as a yellow solid (4.03 g, 89% yield). LC/MS: (PS-A2) Rt 3.44.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=1)[CH2:9][OH:10])(C)(C)C.[ClH:25]>CO>[ClH:25].[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1cccc(CN2CCOCC2)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CO)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(R)-[2-Hydroxy-1-(3-morpholin-4-ylmethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (2.1 g, 6.25 mmol) in methanol (22 mL) was added hydrochloric acid (2.0M in ethyl ether) (10.88 mL, 21.8 mmol) and reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under vacuum to provide the title compound as a pale green solid (quantitative yield).