Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([F:16])([F:15])[F:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:14][C:13]([F:15])([F:16])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
To a stirred solution of 338 (294 mg, 1.209 mmol) in THF (10 mL) at 0° C. under nitrogen was added sequentially NMM (159.5 μL, 1.451 mmol) neat via syringe and ethyl chloroformate (138.7 μL, 1.451 mmol) neat by syringe. After 45 min the resulting suspension was filtered through GF/F filter paper with THF and the filtrate was isolated and stirred at 0° C. under nitrogen. A solution of NaBH4 (45.74 mg, 1.209 mmol) in H2O (2 mL) was added and the cooling bath was removed. After about 15 min, the reaction was concentrated and the residue was resuspended in Et2O (30 mL) and H2O (30 mL) with stirring. After stirring for 5 min the layers were separated and the organic phase washed brine (1×30 mL). The organic phase was (MgSO4), filtered and concentrated to afford 240 mg (86%) of tert-butyl 1,1,1-trifluoro-3-hydroxypropan-2-ylcarbamate (340) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[ClH:31].F[C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.C(#N)C.CN(C=O)C>C(Cl)Cl>[ClH:31].[N:10]([CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[C:29](=[O:30])[N:4]2[C:5]=1[C:13]([O:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:14])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: Fc1ncc[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Yield: 38 %

Procedure:
A mixture of diphenylmethyl 7-amino-3-azidomethylceph-3-em-4-carboxylate (1.2 g.), 2-fluoroimidazole hydrochloride (367 mg.) and acetonitrile (4 ml.) was stirred at 85°. When a complete solution was achieved DMF (1 ml.) was added. After 2 hours the solvent was evaporated and the residue, after drying overnight, was purified by chromatography on fine mesh silica (ratio 40:1 w/w) at 0° using methylene chloride/MeOH/HOAc 100:0:0 to 92:4:4 v/v/v as eluant. The oil obtained was dissolved in the minimum of methylene chloride and precipitated with ether. After drying there was obtained diphenylmethyl 3-azidomethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate hydrochloride (38%) as a white powder having the following n.m.r. in solent A: 3.65 (d, 1H); 3.8 (d, 1H); 3.95 (d, 1H); 4.3 (d, 1H); 5.3 (d, 1H); 5.85 (d, 1H); 6.9 (s, 2H); 7.0 (s, 1H); 7.5-7.7 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[Si]([C:17]#[N:18])(C)(C)C.[OH:19]S(O)(=O)=O.CC(O)=O>C1(C)C=CC=CC=1.[Zn+2].[I-].[I-].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:17]([NH2:18])=[O:19])=[CH:7][CH2:6][CH2:5]2
Reactant: C[Si](C)(C)C#N
Reactant: O=S(=O)(O)O
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)C1=CCCc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.46 g, 24.3 mmol) and ZnI2 (50 mg) in toluene (50 mL) was added TMSCN (4.82 mL, 48.6 mmol), and the solution stirred at 60° C. overnight. The reaction was cooled to rt, and H2SO4 (5.6 mL) was added. Then AcOH (34 mL), H2SO4 (25 mL) and H2O (4 mL) were added to the reaction, and it was heated to 105° C. for 3 h. The mixture was cooled and poured over ice-water (250 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4.88 g (80%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.25-2.33 (2H, m), 2.72 (2H, t, J=8.0 Hz), 6.51 (1H, t, J=4.6 Hz), 7.20 (1H, br s), 7.35-7.40 (3H, m), 7.65 (1H, br s). [M+H] calc'd for C11H10BrNO, 252, 254. found 252, 254.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]#[N:16].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([N:21]1[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]1)=[NH:16]
Reactant: N#CNc1ccccc1-c1ccccc1F
Reactant: OC1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: N=C(Nc1ccccc1-c1ccccc1F)N1CCC(O)CC1

Procedure:
A mixture of 2'-fluoro-2-biphenylylcyanamide (2.5 g) and 4-hydroxypiperidine (1.4 g) in ethanol (30 ml) was heated at reflux on a steam bath for 2 hours gave a yellow foamy solid which was reacted with fumaric acid (1.3 g) in methanol (10 ml) to give N-(2'-fluoro-2-biphenylyl)-4-hydroxypiperidine-1-carboxamidine fumarate as a colourless solid (m.p. 214°-215° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3S(C)(=O)=O)[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>C(N)CCCCC.C(#N)C.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[NH:13][CH2:11][CH2:8][CH2:7][CH2:6][CH2:5][CH3:1])[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(S(C)(=O)=O)nc4ccccc43)CC2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCCCCCN
Product: CCCCCCNc1nc2ccccc2n1C1CCN(C(=O)c2ccc(CCCC)cc2)CC1
Yield: 101.8 %

Procedure:
In a sealed glass tube, (4-butyl-phenyl)-[4-(2-methanesulfonyl-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (9 mg) and hexyl amine (3 drops) were heated at 120-150° C. for 18 h. The crude product was taken into 1 ml 1:1 acetonitrile/water and purified via preparative liquid chromatography to give (4-butyl-phenyl)-[4-(2-hexylamino-benzoimidazol-1-yl)-piperidin-1-yl]-methanone (4.8 mg).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]=1[CH3:38])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]=1[CH3:38])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2.33 h
Yield: 43.6 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (49 μl, 383 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (5 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-N-propyl-1,3-benzoxazole-2-carboxamide (I-284) (112 mg, 319 μmol) and triethylamine (58 μl, 415 μmol), followed by stirring at the same temperature for 140 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol==10:1, v/v) to obtain the entitled compound (62 mg, 44%) as an amorphous substance.
Reaction SMILES: [SH:1][C:2]1C=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[N:12]=1.C(OCC)(=O)C.C[N:26](C=O)C>O>[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:1][C:2]2[N:26]=[CH:6][CH:5]=[CH:4][N:3]=2)[N:12]=1)#[N:18]
Reactant: Sc1ccccn1
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Sc2ncccn2)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
2-Mercaptopyridine (0.89 g, 7.94 mmol) and sodium hydride (60% in oil, 0.35 g, 8.66 mmol) were dissolved in DMF (30 ml), and 2-chloro-6-cyanopyridine (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at 70° C. for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (1.32 g, 85%).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1>N1C=CC=CC=1>[C:11]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[S:7]([NH:17][C:18]2[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=2)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(Cl)nn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)nn1)c1ccccc1-c1ccccc1
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
A solution of 2-biphenylsulphonyl chloride (0.31 g), 3-amino-6-chloropyridazine (0.5 g) in pyridine (5 ml) was stirred for 18 hours. Volatile material was removed by evaporation and 1M sodium hydroxide solution (4 ml) and methanol (10 ml) were added. The reaction mixture was stirred on a steam bath for 20 minutes and, after cooling, volatile material was again removed by evaporation. The residue was dissolved in water (100 ml) and acidified with concentrated hydrochloric acid to pH 1-2 and extracted with ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated to give a solid. The solid was recrystallised twice from isopropanol to give 2-phenyl-N-(6-chloro-3-pyridazinyl)benzenesulphonamide (0.08 g), m.p. 196°-198° C.; mass spectrum (+ve FAB, methanol/dichloromethane/NBA): 346 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.N1CCOCC1.C(N1C[CH2:45][N:44]2[CH2:47][CH2:48][N:49]([CH2:50][CH2:51]CC)P1N(CCCC)CC2)CCC.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:49]5[CH2:48][CH2:47][N:44]([CH3:45])[CH2:51][CH2:50]5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CCCCN1CCN2CCN(CCCC)P1N(CCCC)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: C1COCCN1
Product: CN1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (49 mg, 0.3 mmol), morpholine (130 mg, 1.44 mmol), 2,8,9-tributyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (99 mg, 0.29 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 1 h under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 115 mg of 110 (yield=31%). 1H NMR (CDCl3, 400 MHz): δ8.12-8.10 (m, 1H), 7.58-7.52 (m, 1H), 7.15-7.05 (m, 4H), 6.55 (d, J=9.2 Hz, 1H), 4.25-4.23 (m, 2H), 3.75-3.63 (m, 5H), 3.12-3.10 (m, 2H), 2.93-2.91 (m, 4H), 2.62-2.57 (m, 3H). LC-MS (ESI): m/z=480 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:16]3[C:5]=1[CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][C:11]=2[Cl:17])([O-])=O.[H][H]>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:16]3[C:5]=1[CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][C:11]=2[Cl:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)c2c(Cl)ccc3c2c1CC3
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Reaction time: 14 h
Yield: 100.4 %

Procedure:
A solution of 5,6-dichloro-3-nitroacenaphthene (3.7 g, 13.8 mmol, from Example C4) in 250 mL of tetrahydrofuran was treated with 1.0 g of Raney-nickel and shaken in a hydrogen atmosphere at 21° C. and a pressure of 52.8 psi for 14 hours. The catalyst was removed by filtration, and the solvent was removed in vacuo to give 3.3 g of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][CH2:21][C@@H:22]3[C:26]([O:28][CH3:29])=[O:27])[C@H:18]3[C@H:9]2[C@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17]3)[CH2:14][C@H:13]([OH:30])[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.C(O)C.C([O-])(O)=O.[Na+].O>[C:43]([O:30][C@@H:13]1[CH2:12][CH2:11][C@@:10]2([CH3:31])[C@@H:15]([CH2:16][CH2:17][C@@H:18]3[C@@H:9]2[C@H:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[C:26]([O:28][CH3:29])=[O:27])[CH2:14]1)(=[O:45])[CH3:44]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3[C@H](NC3CCCCC3)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 11α-cyclohexylamino-3α-hydroxy-5α-androstane-17β-carboxylate (550 mg) in chloroform (5.5 ml) containing dry PTSA (440 mg) was stirred for 20 min then treated with acetic anhydride (1.0 ml) and left for 18 h. The reaction mixture was diluted with ethanol and evaporated to give an oil. The residue is ethanol (10 ml) was diluted with 5% NaHCO3 solution (50 ml) and water (100 ml) and extracted with ether (3×). The extracts were washed with water (1×), dried and evaporated to give an oil. This was crystallised from methanol to give the title compound (249 mg), m.p. 126°-128°, [α]D +12°.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=O)[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:35][NH2:36]>CO>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([NH:36][CH3:35])=[O:32])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: CO
Product: CNC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
70 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate prepared in Example 3 was dissolved in 5 mL of 2M methylamine in methanol in a sealed tube. The mixture was stirred at 50° C. for 24 hours. The solvent was then removed and the residue purified using TLC with a 15:1 dichloromethane:methanol solution to yield (1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]4[CH2:26][N:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:24]4)[CH:15]=3)[C@@:11]([C@H:34]([OH:36])[CH3:35])([CH3:33])[CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:36][C@@H:34]([C@@:11]1([CH3:33])[C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26]3)[CH:15]=2)[CH2:13][N:9]([C:7](=[O:8])[C@@H:5]([OH:6])[CH2:4][OH:3])[CH2:10]1)[CH3:35]
Reactant: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(c2ccccn2)C1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc([C@@H]2CN(C(=O)[C@@H](O)CO)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-{[1-pyridin-2-ylazetidin-3-yl]oxy}phenyl)-3-methylpyrrolidin-3-yl]ethanol (22.1 mg) in tetrahydrofuran (2 mL) is added aqueous 1.0 M HCl (1 mL). Stir overnight at room temperature. Add aqueous 1.0 M HCl (1 mL) and stir for additional 8 hours. Neutralize with aqueous 1.0 M NaOH, extract with ethyl acetate, dry and evaporate to provide the title compound (18.2 mg). MS(ES+)=472 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:20]([N:22](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.CS(C)=O>[C:20]([CH2:2][CH2:3][CH:4]([CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:22]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCC(CCO)CCc1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CCCC(CCC#N)CCc1cccnc1
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (3.0 mmol) of methyl 7-hydroxy-5-[2-(3-pyridyl)ethyl]-heptanoate in 3 ml methylene chloride is cooled to 0° and 0.52 mL (3.7 mmol) triethylamine is added followed by 0.26 mL (3.3 mL) methanesulfonyl chloride. The reaction mixture is stirred at 0° for 30 minutes and then 1.65 g (25 mmol) finely powdered potassium cyanide is added followed by 15 mL dimethyl sulfoxide. After stirring for 30 minutes the cold bath is removed and the mixture is stirred at room temperature for 18 hours. The reaction mixture is poured on to saturated aqueous ammonium chloride solution and then extracted with ethyl acetate (3×70 mL). Combined organic phase is washed with water (4×60 mL), brine (60 mL) and dried (MgSO4), filtered and evaporated to give an oil which is purified by flash chromatography to give both the desired methyl 7-cyano-5-[2-(3 -pyridyl)ethyl]-heptanoate and the mesylate of the starting alcohol. The mesylate is subjected to the cyanide displacement conditions described above to yield additional methyl 7-cyano-5-[2-(3-pyridyl)-ethyl]-heptanoate.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:9][C:10]2[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>ClCCCl>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:53][C:52]4[CH:55]=[CH:56][CH:57]=[C:50]([I:49])[CH:51]=4)[CH2:18][CH2:19]3)[N:13]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:12](=[O:25])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCNCC2
Reactant: O=Cc1cccc(I)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(cyclohexylamino)-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one dihydrochloride (1 g, 2.56 mmol, intermediate I.1.c.1) in DCE (16 mL), was added Hunig's base (0.67 mL, 1.42 mmol), sodium triacetoxyborohydride (0.25 g, 1.18 mmol) and 3-iodo-benzaldehyde (329 mg, 3.83 mmol) in DCE (0.5 mL) dropwise. The reaction mixture was stirred at rt for 18 h, quenched with aq NaHCO3, extracted twice with EtOAc, washed with brine, concentrated in vacuo and purified flash chromatography (silica gel, EtOAc) to provide the desired product LRMS (M+1)=535.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]([C:24]4[CH2:31][C:27]5([CH2:30][CH2:29][CH2:28]5)[O:26][N:25]=4)=[C:16]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:28]1[C:27]2([CH2:31][C:24]([C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:16]=3[NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:25][O:26]2)[CH2:30][CH2:29]1
Reactant: COc1ccc(Cn2ncc3c(NC4CCOCC4)c(C4=NOC5(CCC5)C4)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1nc2[nH]ncc2c(NC2CCOCC2)c1C1=NOC2(CCC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Methoxybenzyl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.8 gm, 4 mmol) (example 9) was dissolved in trifluoroacetic acid (4.56 gm, 40 mmol) and the reaction mixture was stirred for about 4 hours at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and sodium bicarbonate solution was added drop wise. It was extracted with ethyl acetate, organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[OH:15].[CH2:16](Br)[C:17]#[CH:18].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:13])([CH3:14])[CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[O:15][CH2:18][C:17]#[CH:16]
Reactant: COc1cc2c(cc1O)C(C)(C)CC2=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C#CCOc1cc2c(cc1OC)C(=O)CC2(C)C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
6-Methoxy-3,3-dimethyl-5-hydroxy-indan-1-one (2.2 g), 1.5 g of propargyl bromide, and 3.7 g of K2CO3 in 9 ml of 1-methyl pyrrolidone was placed in a 25 ml reaction flask and stirred for one hour. Then, it was stirred further at 100° C. for one hour. The reaction mixture was distributed between water and ethyl acetate. The organic phase was washed with 1N NaOH solution and NaCl solution, dried over Na2SO4 and concentrated to yield 2.7 g of a yellow liquid. UV 310 nm (ε=18′734), MS: 244(M+), 229, 105(100%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 60.1 %

Procedure:
A mixture of 2.00 g (6.6 mmole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (12.08 mmole) of 4-amino-benzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.600 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11).