Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:17]([CH2:31][OH:32])[CH:16]=2)=[N:7]1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[C:3]=1[C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:17]([CH:31]=[O:32])[CH:16]=2)=[N:7]1)=[O:5]
Reactant: O=C(OCc1ccccc1)c1ccc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3ccccc23)cc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(-c2nn(C(=O)c3c(Cl)cccc3C(F)(F)F)c3ccccc23)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of benzyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-indazol-3-yl)-2-(hydroxymethyl)benzoate (G-3) (0.4 g, 0.71 mmol) in DCM (10 mL) was added Dess-Martin periodinane (0.45 g, 1.07 mmol), and the mixture was stirred at rt for 24 h. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resulting crude oil was used in the next step without further purification. LCMS (ESI)′ calc'd for C30H19ClF3N2O4 [M+H]+: 563. found: 563.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)c1csc(Br)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(N2CCOCC2)n1
Yield: 93.4 %

Procedure:
A solution of methyl 2-bromothiazole-4-carboxylate (0.20 g, 0.901 mmol) in THF (10 mL) was treated with morpholine (0.17 mL, 1.94 mmol) and refluxed for 18 h. The reaction was then diluted with ethyl acetate and washed with sat. NaHCO3 (1×), brine (1×) and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% AcOEt/CH2Cl2) to give the title material (0.192 g, 92%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.44 (s, 1H) 3.82 (s, 3H) 3.75 (m, 4H) 3.45 (m, 4H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH2:35][CH3:36])[CH:29]=1)[NH2:27]>>[CH2:35]([O:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:33]=[CH:32][N:31]=1)[CH3:36]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: CCOc1cc(NN)ccn1
Product: CCOc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-ethoxypyridine according to the method described for example 43. MS: M=444.2 (M+H)+
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH2:31][CH3:32])[C:22]=1[CH3:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:13]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:8]=[C:7]([C:5]([N:1]5[CH2:4][CH2:3][CH2:2]5)=[O:6])[S:15][C:14]=34)=[CH:27][CH:28]=2)[N:23]([CH2:31][CH3:32])[C:22]=1[CH3:33])=[O:20]
Reactant: CCn1c(C)c(C(=O)NC)c2ccc(O)cc21
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCn1c(C)c(C(=O)NC)c2ccc(Oc3ccnc4cc(C(=O)N5CCC5)sc34)cc21

Procedure:
This material was prepared by the reaction of 2-(azetidin-1-ylcarbonyl)-7-chlorothieno[3,2-b]pyridine 25a with 1-ethyl-6-hydroxy-2-methyl-1H-indole-3-carboxylic acid methylamide 71e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ8.47 (1H, d, J=5.5 Hz), 7.75 (2H, m), 7.16 (1H, d, J=1.7 Hz), 7.01 (1H, dd, J=1.7, 8.4 Hz), 6.56 (1H, d, J=5.5 Hz), 5.91 (1H, bs), 4.59 (2H, m), 4.28 (2H, m), 4.11 (2H, m), 3.05 (3H, d, J=4.0 Hz), 2.72 (3H, s), 2.45 (2H, m), 1.33 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 449, found 449.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.C1C=CC2N(O)N=[N:34]C=2C=1.CCN=C=NCCCN(C)C>>[F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:34])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ccc(-c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)Cc1ccc(-c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
A 25 mL round bottom flask was charged with 2-(4-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)acetic acid (50 mg, 0.136 mmol), HOBT (46 mg, 0.34 mmol), and EDCI (65 mg, 0.34 mmol). The flask was flushed with nitrogen and then DMF was added (1 mL). After stirring at rt for 1 h, the solution was cooled to 0° C. and then charged with ammonium hydroxide (0.5 mL). The reaction was stirred at 0° C. for 1 h and was then diluted with brine (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (33 mg, 66%) as a colorless oil. 1H NMR (CD3OD) δ 8.49 (s, 1H), 8.38 (d, 1H, J=5.6 Hz), 8.10 (dd, 1H, J=10.4, 2.4 Hz), 7.99 (m, 1H), 7.45 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.28 (m, 1H), 6.93 (d, 1H, J=5.6 Hz), 3.44 (s, 2H); MS(ESI+) m/z 368.18 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11](OC)=O)[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)=O>O>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[NH:3][C:2](=[O:1])[NH:6][C:5]=2[CH:7]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2[nH]c(=O)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling reaction mass was poured in mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 litres) and ammonia solution (˜800 ml). After that pH was adjusted to 5.6 with ammonia solution. Precipitate was filtered and rinsed with water. Yield 39.5 g (84%).
Reaction SMILES: C(OC([C:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1)=O)C.[OH-].[K+]>C(O)CO>[CH:6]1[NH:7][CH:8]=[C:9]2[C:14]=1[CH:13]1[CH2:15][CH2:16][CH:10]2[CH:11]=[CH:12]1
Reactant: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: C1=CC2CCC1c1c[nH]cc12
Temperature: 175 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A light-resistant reaction vessel equipped with a reflux condenser was charged with the ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (1.95 g, 9.6 mmol) obtained in Step 2, 100 ml of ethylene glycol and 2.0 g of potassium hydroxide. The vessel was then purged with nitrogen, and the mixture was stirred for 2 hours at 175° C. The reaction mixture was then cooled to room temperature, and poured into ice water. The resulting solution was extracted with chloroform, the extract was washed with saturated saline and the obtained organic layer was dried over anhydrous sodium sulfate. Concentration of the solution under reduced pressure then gave 4,7-dihydro-4,7-etano-2H-isoindole (0.98 g, yield 70.4%).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([CH:16]([NH2:18])[CH3:17])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(N=[C:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)C1C=CC(CCC2C=CC=CC=2)=CC=1>>[ClH:1].[CH3:17][CH:16]([N:18]=[C:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(OCCCc2ccccc2)cc1

Procedure:
Substituting this amine for the α-methyl-ρ-phenethylbenzylamine of Example IV results in the formation of hexahydro-2-[α-methyl-ρ-(3-phenylpropoxy)benzylimino]azepine hydrochloride, having a M.P. of 202°-5° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([O:1][C:2]1[C:9]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 161.2 %

Procedure:
To a solution of 2,3-dihydroxybenzaldehyde (61, 25 g, 0.18 mol) in N,N-dimethylformamide (150 mL) tetrahydrofuran (250 mL), sodium hydride (7.24 g, 0.18 mol) was added at 0° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 10 minutes. To the reaction mixture was then added benzyl bromide (54 mL, 0.45 mol). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 3 hours, then cooled down to 0° C. Sodium hydride (8 g, 0.2 mol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (128, 46.2 gm, 80%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][C:16]2[N:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:18]=[N:19][C:20]=2[CH3:21])=[CH:10][N:9]=1)=[O:7]>O.C1COCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:17]2[C:16]([CH2:15][O:14][C:11]3[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=3)=[C:20]([CH3:21])[N:19]=[N:18]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cnc(OCc2c(C)nnn2-c2ccc(F)cc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A solution of lithium hydroxide monohydrate (180 mg, 4.25 mmol) in water (7.3 mL) was added dropwise to a suspension of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (730 mg, 2.13 mmol) in THF (7.3 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (700 mg, 100%) as a white solid. MS: m/e=330.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC(C)([O-])C.[K+]>C1(C)C(C)=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C1CNCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
3-Bromopyridine (1.0 g, 6.32 mmol) and piperazine (3.2 g, 37.9 mmol) were dissolved in xylene (10 mL) and the solution was purged with argon for 10 min. Potassium tert-butoxide (0.99 g, 8.86 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h, cooled to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10% MeOH in CH2Cl2) to get 1-(pyridin-3-yl)piperazine (350 mg, yield 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=3.0 Hz, 1H), 7.97-7.95 (dd, J=4.6 Hz, 1.1 Hz, 1H), 7.29-7.26 (m, 1H), 7.20-7.16 (m, 1H), 3.08-3.06 (m, 4H), 2.83-2.81 (m, 4H). MS (ESI) m/z: Calculated for C9H13N3: 163.11. found: 164.0 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]>>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(CBr)c(F)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(F)cc3F)CC1)O2

Procedure:
Compound 124 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-2,4-difluorobenzene and conditions outlined in procedure V. M.p.=104-107° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.65 (m, 2H), 7.5 (t, 1H), 7.35 (q, 1H), 6.85 (m, 2H), 3.65 (s, 2H), 2.9 (s, 2H), 2.8 (d, 2H), 2.5 (t, 2H), 2.15 (d, 2H), 1.85 (t, 2H); LCMS: 428 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cu](C#N)[C:10]#[N:11].C(OCC)(=O)C>CN(C=O)C>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[N:11]
Reactant: O=Cc1cc(Br)cs1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1csc(C=O)c1
Yield: 64.1 %

Procedure:
4-Bromo-2-thiophenecarboaldehyde (5.00 g) was dissolved in DMF (40 ml), and copper cyanide (3.52 g) was added thereto. After heating under reflux for 3 hours, the mixture was cooled as it was to room temperature and ethyl acetate was added thereto. The mixture was washed with an aqueous ammonia, water, 0.1N aqueous hydrochloric acid and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), and then recrystallized from ethyl acetate-hexane, to give the title compound as pale yellowish white crystals (2.30 g, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:25]#[N:26])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C
Product: Cc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,4-dimethylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 91%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[C@H:9]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH2:8][C@H:7](O)[CH2:6]1.COCCN(S(F)(F)[F:27])CCOC.C(=O)([O-])O.[Na+]>ClCCl>[F:27][C@H:7]1[CH2:8][C@H:9]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[C@@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]1
Reactant: COCO[C@@H]1C[C@@H](O)C[C@H]1c1ccnn1C
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCO[C@H]1C[C@@H](F)C[C@@H]1c1ccnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of the (1S*,3R*,4S*)-3-(methoxymethoxy)-4-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (150 mg, 0.663 mmol) prepared in Example 106b in dichloromethane (2.0 mL), bis(2-methoxyethyl)amino sulfur trifluoride (0.26 mL, 1.33 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, an aqueous sodium hydrogencarbonate solution (10 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=2:3) to yield the title compound (132 mg, 87%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH2:27])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 0.3M solution of methyl 3-cyclohexyl-2-(2-vinylphenyl)1H-indole-6-carboxylate in dry DMF, 60% NaH (1.5 eq) in mineral oil was added at 0° C., after 1 h allyl bromide (1.5 eq) was added and the suspension was stirred at RT for 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (100% as crude); MS (ES+) m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=O)=[CH:12][CH:13]=1)=[O:6].[Cl-].[OH:30][NH3+:31].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:31][OH:30])=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
800 mg of 3,4-dichloro-N1-{6-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 1 and 670 mg of hydroxyammonium chloride (hydroxylamine hydrochloride) were suspended in 40 ml of ethanol and, after adding 5.4 ml of pyridine to the resulting suspension, the mixture was stirred at 60° C. After 30 minutes, the reaction solution was distilled off under reduced pressure. To the resulting residue, 60 ml of ethyl acetate was added and the solution was washed in turn with water and a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After ethyl acetate was distilled off, ether was added to the residue and the deposited crystal was isolated by filtration and then washed with ether to obtain the titled compound (430 mg, white powder).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[CH:25][C:20]3=[CH:19][N:18]=2)[N:2]=1.[H][H]>[Pd].CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][C:20]3=[CH:19][N:18]=2)[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2cnccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2n1CCNC2
Yield: 34.7 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(imidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (100 mg, 0.178 mmol) and MeOH (5 mL) were added 10% Pd—C (100 mg). The resulting mixture was stirred under 12 psi of hydrogen for h. The mixture was filtered and concentrated. The resulting residue was purified on prep-HPLC (ACN/H2O with 0.1% HCOOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (35 mg, 35%). LRMS (M+H+) m/z 566.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[NH:18][C:19]2=[O:28])=[N:14]1.Br[CH2:35][C:36]#[N:37]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[N:18]([CH2:35][C:36]#[N:37])[C:19]2=[O:28])=[N:14]1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Reactant: N#CCBr
Product: CC(C)Cn1c(=O)n(CC#N)c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made by alkylation of 2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione with bromoacetonitrile following conditions in Example 6.d. 504.2 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OC1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 145.2 %

Procedure:
A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.500 mL, 4.71 mmol), Piperidin-4-ol (0.619 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution, diisopropyl ethyl amine (0.463 mL, 6.12 mmol) was added dropwise, and the reaction was allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜50 mL), and brine (2×˜50 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.742 g, 3.34 mmol, 71% yield).