Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=C([Li])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:11]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:13])[F:1])[CH:5]=2)[OH:12])[CH:18]=[CH:19][CH:20]=1
Reactant: [Li]c1cccc(Br)c1
Reactant: CC(=O)c1cccc(OC(F)F)c1
Product: OC(c1cccc(Br)c1)c1cccc(OC(F)F)c1

Procedure:
In an analogous reaction sequence to that described for Building Block C, the reaction of 1-(3-difluoromethoxy-phenyl)-ethanone with 3-bromophenyllithium yielded the (3-bromo-phenyl)-(3-difluoromethoxy-phenyl)-methanol which was used as crude material in the following elimination reaction with a catalytic amount of p-toluenesulfonic acid to yield the 1-bromo-3-[1-(3-difluoromethoxy-phenyl)-vinyl]-benzene (yield: 68% of theory) as a light yellow oil. TLC: Rf: 0.66 (silica gel; heptane:ethyl acetate=4:1, UV, 254 nm).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:13][C:12]([CH2:14][O:15][N:16]=[C:17]([CH:19]2[C:24](=[O:25])[CH2:23][CH:22]([CH:26]3[CH2:31][CH2:30][CH2:29][S:28][CH2:27]3)[CH2:21][C:20]2=[O:32])[CH3:18])=[CH:11][CH:10]=1.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([O:25][C:24]1[CH2:23][CH:22]([CH:26]2[CH2:31][CH2:30][CH2:29][S:28][CH2:27]2)[CH2:21][C:20](=[O:32])[C:19]=1[C:17](=[N:16][O:15][CH2:14][C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)[CH3:18])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: CC(=NOCc1ccc(Cl)s1)C1C(=O)CC(C2CCCSC2)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
In this example, 0.52 g (5.1 mmol) of triethylamine was admixed to a solution containing 1.46 g (3.7 mmol) of 2-[1-[(5-chlorothien-2-yl)methoxyimino]ethyl]-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohexane-1,3-dione in 30 ml of methylene chloride at room temperature (about 20°-25° C.) followed by the dropwise addition of 0.35 g (4.4 mmol) of acetyl chloride. The mixture was stirred at room temperature overnight (about 14 hours) and then washed with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica gel to afford 1.0 g of the title compound as a yellow oil; IR (neat) 1775 cm-1 ; 1H NMR spectrum (90 MHz CDCl3) δ1.00-2.60 (m, 14H), 1.93 (s, 3H), 2.00 (s, 3H), 5.07 (s, 2H) 6.73 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH2:20]([NH:22][C:23](=S)[NH:24][NH2:25])[CH3:21]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:23]([NH:22][CH2:20][CH3:21])=[N:24][N:25]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCNC(=S)NN
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(CC)C(C)=O)c3)nn12

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl) phenyl]acetamide and 6.0 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was then worked up and the product chromatographed as described in Example 70. Recrystalization of the product from dichloromethane-hexane afforded 2.1 g yellow flakes mp 171°-172° C.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[O-]CC.[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=O)=[CH:13][C:12]=1[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[O:29])=[N:23]1>C(O)C>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)=[CH:13][C:12]=1[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C:30]2[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=2[F:36])=[N:23]1
Reactant: COC(=O)c1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reactant: CC(N)=NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(-c2ccc(Cl)c(Cn3ccc(NC(=O)c4c(F)cccc4F)n3)c2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of acetamide oxime (89 mg, 1.20 mmol, GFS chemicals) in ethanol (2 ml) was added 4A activated molecular sieves (418 mg) (pre-dried in the oven overnight) and then 21% sodium ethoxide in ethanol (0.2 ml, 0.536 mmol, Alfa Aesar). To the reaction mixture was added methyl 4-chloro-3-[(3-{[(2,6-difluorophenyl)carbonyl]amino}-1H-pyrazol-1-yl)methyl]benzoate (for a preparation see Intermediate 23)(105 mg, 0.259 mmol). The reaction was heated to reflux (100° C.) and stirred for 3 h under nitrogen. The reaction mixture was evaporated in vacuo and the residue dissolved in methanol (0.5 ml) and filtered through a hydrophobic frit. The residue was dissolved with DMSO (0.5 ml) and the sample was purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white gum (6.1 mg);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][C:16]=1[N+:24]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Zn].CO.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14][C:15]1[C:16]([NH2:24])=[CH:17][CH:18]=[CH:19][C:20]=1[NH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSc1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CSc1c(N)cccc1N)C(=O)O
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-3-(2,6-dinitro-phenylsulfanyl)-propionic acid (1.7 g, 4.4 mmol) in 3:1 v/v MeOH/H2O (80 mL) containing NH4Cl (7.0 g, 130 mmol) was added Zn dust (5.7 g, 87.2 mmol) and the resulting mixture was stirred for 1 h. The mixture was filtered through a pad of Celite, the filtrate volume was reduced in vacuuo and acidified to pH 4 with 1.0 M HCl. The mixture was extracted with EtOAc, the combined extracts washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give (R)-2-tert-butoxycarbonylamino-3-(2,6-diamino-phenylsulfanyl)-propionic acid (1.0 g) which was used without purification.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.[ClH:30]>CO>[ClH:30].[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 25 °C

Procedure:
(3aRS,7aRS)-2-benzyl-7,7-diphenyl-4-perhydroisoindolone (150 g), methanol (1,500 cc) and 1N hydrochloric acid (450 cc) are added to 10% palladiumon-charcoal (15 g); the reaction mixture is hydrogenated, with stirring, at ambient temperature and under atmospheric pressure. After a reaction time of 5 hours, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized from ethanol (200 cc); the crystals obtained are drained, washed with ethanol (50 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (110 g) melting at 270° C. with decomposition is obtained.
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([F:18])[CH:4]([P:6](C(OCC)OCC)(=[O:10])[O:7]CC)[CH3:5].B.C1COCC1.Cl>C1COCC1>[NH2:1][CH2:2][CH:3]([F:18])[CH:4]([PH:6](=[O:7])[OH:10])[CH3:5]
Reactant: CCOC(OCC)P(=O)(OCC)C(C)C(F)C(N)=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C(F)CN)[PH](=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
To an ice bath cooled solution of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxymethyl)phosphinate (1.6 g, 5.3 mmol) in THF (15 ml) was added 1 M BH3-THF (12.3 mL, 12.3 mmol) while under an argon atmosphere. After 10 minutes, the solution was heated to reflux for 3 h. The solution was cooled to room temperature and 6 N HCl (100 mL) was added dropwise. The THF was removed by rotovap and another portion of 6 N HCl (100 mL) was added. The mixture was refluxed for 3 h. The solution was cooled, evaporated, co-evaporated with water and then with etanol. The residue was purified ion exchange chromatography (DOWEX® 50WX-8-200, H+ form, 3.5×4.0 cm). The ion exchange resin was prewashed with 2:1 methanol/water. The crude product dissolved in 1:1 methanol/water was loaded onto the column and washed with 1:1 methanol/water. The eluent was changed to 3:1 methanol/concentrated ammonium hydroxide. The appropriate fractions were combined and evaporated to give 150 mg (15%) of a diastereomeric mixture of (3-amino-2-fluoro-1-methylpropyl)phosphinic acid as an oil. Data: 1H NMR (400 MHz, D2O) δ6.2-7.8 (m, 1H), 4.8-5.2 (m, 1H), 3.2-3.5 (m, 2H), 1.8-2.2 (m, 1H), 1.0-1.2 (m, 3H); MS: m/z=156 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24](O)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:24](=[O:28])[C@@H:25]([OH:26])[CH3:27])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(O)C(=O)O
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (600 mg) was reacted with lactic acid via General Procedure B to give (S)-1-(4-((2-chloro-4morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[C:13]4[N:14]=[C:15]([C:21]5[N:22]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:23]=[CH:24][N:25]=5)[S:16][C:17]=4[CH2:18][CH2:19][O:20][C:11]=3[CH:10]=2)[CH:6]=[N:5]1.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:33]1[CH2:36][CH:35]([NH:37][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([C:9]3[CH:32]=[CH:31][C:12]4[C:13]5[N:14]=[C:15]([C:21]6[N:22]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:23]=[CH:24][N:25]=6)[S:16][C:17]=5[CH2:18][CH2:19][O:20][C:11]=4[CH:10]=3)[CH:6]=[N:5]2)[CH2:34]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCCl)c3)ccc1-2
Reactant: NC1COC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCNC4COC4)c3)ccc1-2
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.416 mmol) and 3-oxetanamine (0.608 g, 2.08 mmol) in 5 mL of DMF was added potassium carbonate (0.287 g, 2.08 mmol) and potassium iodide (0.069 g, 0.416 mmol). The reaction mixture was heated at 50° C. for approximately 4 hours. The heated was increased to 70 C and the reaction was continued another 15 hours to give the desired product as determined by LCMS. The crude material was purified by RP-HPLC to cleanly give 461. MS: (ESI+)=518.3
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH2:15][Cl:16].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:16][CH2:15][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:8]([CH:9]=[O:10])[C:7]=1[OH:12]
Reactant: COCCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
While cooling a mixture of 12.0 g of 5-nitrosalicylaldehyde and 100 ml of chloromethyl methyl ether in an ice bath, 43.9 g of anhydrous aluminum chloride was added in small portions to the mixture, followed by stirring at room temperature for 10 minutes and thereafter by refluxing with heating for 22 hours. The reaction mixture was then cooled in an ice bath, and 200 ml of water was added to the mixture with full stirring, whereby white crystals were separated out. The white crystals were collected and dissolved in hot hexane, and the solution was filtered. The mother liquor was thereafter cooled, giving 14.9 g of 3-chloromethyl-5-nitrosalicylaldehyde in the form of white needlelike crystals (yield 72%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[N:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCn1cccn1
Product: N#Cc1c(OCCn2cccn2)cccc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
Prepared as in Example 215c from 2-(1H-pyrazol-1-yl)ethanol and 2,6-dinitrobenzonitrile in 89.2% yield. MS 259 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:24])([O-:19])=[O:18]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc([N+](=O)[O-])c3)c2)CC1
Yield: 20.7 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-nitrobenzoyl chloride (128 mg, 0.687 mmol), 17.4 mg (21%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](Cl)=[S:19])=[CH:13][CH:12]=1.C(OCC)C>O>[O:17]([C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:18]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:19]
Reactant: SCc1ccccc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: S=C(Oc1ccccc1)SCc1ccccc1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Benzyl mercaptan (1.24 g, 10 mmol) was added to an aqueous (20 mL) solution of NaOH (0.8 g, 20 mmol) at room temperature and stirred for 15 minutes. Phenyl thionochloroformate (2.07 g, 12 mmol) was next added dropwise to this solution at the same temperature and stirred for a further 2 hours. Diethyl ether (20 mL) and water (50 mL) was added and the organic layer separated. The aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic fractions were dried with Na2SO4, filtered, the solvent removed and the crude product chromatographed (using silica gel, 2% ethyl acetate in petroleum spirits) to afford the title compound (1.95 g, 75%) as a yellow oil. 1H-nmr (CDCl3) δ 4.43 (2H), 7.10-7.50 (10H). 13C-nmr (CDCl3) δ 41.7, 122.1, 126.7, 127.8, 128.8, 129.3, 129.6, 135.1, 154.0, 213.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.O>[CH2:26]([NH:33][C:2]1[N:3]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:24])[F:25])[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccccc2)nc(N2CCOCC2)n1
Yield: 66.8 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and benzylamine (67 mg, 0.625 mmol) in dioxane (5 mL) was heated to reflux for 5 min and cooled. The mixture was diluted with water to give a white precipitate, which was recrystallised from EtOH to give 73 mg (67% yield) of N-benzyl-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 185-188° C.; 1H NMR (CDCl3) (rotamers) δ 8.41 and 8.28 (2d, J=7.4 and 7.7 Hz, 1H), 7.89 (m, 1H), 7.64 and 7.50 (2t, JHF=53.8 and 53.7 Hz, 1H), 7.43-7.29 (m, 7H), 5.62 (m, exchangeable with D2O, 1H), 4.72 and 4.68 (2d, J=6.0 and 5.9 Hz, 2H), 3.89 (m, 4H), 3.78 (m, 4H); Anal. Calc. for C22H21F2N7O: C, 60.4; H, 4.8; N, 22.4. Found: C, 60.6; H, 4.8; N, 22.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[OH-].[NH4+:26]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([CH:14]([NH2:26])[CH3:16])([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(N)C1(O)CCN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of 2-methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acid benzyl ester (Example A9, 0.31 g, 1.25 mmol) in methanol (10 mL) and ammonium hydroxide (7 mL) is heated in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture is dissolved ethyl acetate, washed with water, dried over Na2SO4 and evaporated to afford the title compound (0.340 g). 1H NMR (200 MHz, CDCl3): δ 7.33-7.26 (m, 5H), 5.28 (bs, 2H), 5.07 (s, 2H), 3.56-3.16 (m, 5H), 2.03-1.76 (m, 2H), 1.15 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: Nc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 4-aminophenylboronic acid (274 mg, 2 mmol) to give 5-{-4-[2-(4′-amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1Br.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>C1COCC1>[Br:6][C:7]1[CH:11]=[CH:10][CH2:9][C:8]=1[Sn:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C[Sn](C)(C)Cl
Reactant: BrC1=C(Br)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)C1=C(Br)C=CC1
Temperature: -75 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium, 1.6M in hexanes, (58 mL, 92.0 mmol) in THF (50 mL) was cooled under nitrogen to −75° C. 1,2-Dibromocyclopentene (10.00 g, 44.3 mmol) in dry THF (10 mL) was added dropwise over ˜10 minutes. The mixture was stirred at −75° C. for a further 20 minutes and then allowed to reach 0° C. The reaction mixture was then re-cooled to −75° C. and trimethyltin chloride (8.85 g, 44.3 mmol) in THF (30 mL) was added, under nitrogen, over ˜10 minutes. After stirring at −75° C. for 30 minutes the reaction was allowed to reach room temperature and then stirred for 2 hours. The reaction mixture was then evaporated down to an oil and partitioned between brine and dichloromethane (100/200 mL). After shaking thoroughly, the organic layer was dried (magnesium sulphate), filtered and evaporated to give an oil. (13.15 g, ˜80% pure).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:37]([O:39][CH3:40])=[O:38])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)Cl
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679 mmol), N,N-diisopropylethylamine (59.1 μL, 0.3440 mmol) and DMF (1.00 mL) was treated with methyl chloroformate (5.25 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolation of the title compound. 1H NMR (400 MHz, CD3OD) ppm: 8.32 (br. s., 1H), 7.58-7.66 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.14-7.22 (m, 1H), 7.00-7.12 (m, 2H), 6.73 (s, 1H), 4.26 (d, 2H, J=12.9 Hz), 3.71 (s, 3H), 3.33-3.37 (m, 3H), 2.9-3.17 (m, 2H), 1.85-2.06 (m, 4H); MS (ES+): m/z 391.06 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[NH:10][N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.[NH2:18][CH2:19][C@@H:20]([OH:22])[CH3:21]>C1COCC1>[CH:13]1([C:12]2[C:3]3[C:4](=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=3[NH:18][CH2:19][C@H:20]([OH:22])[CH3:21])[NH:10][N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CSc1nc(Cl)c2c(C3CCCC3)n[nH]c2n1
Reactant: C[C@H](O)CN
Solvent: C1CCOC1
Product: CSc1nc(NC[C@@H](C)O)c2c(C3CCCC3)n[nH]c2n1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
4-Chloro-3-cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 1.860 mmol) was dissolved in 25 mL dry THF, and (S)-1-Amino-propan-2-ol (1.758 mL, 22.32 mmol) was added. The reaction mixture was heated to reflux for three hours, then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water, washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 0.56 g of (R)-1-(3-Cyclopentyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-propan-2-ol. Mass Spec. M+H=309.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]4[NH:28][N:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Nc2nc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(-c2nc3c(c(Nc4ccc(Cc5nnn[nH]5)cc4)n2)CCC3)s1
Temperature: 110 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
In an 4-mL was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile (20 mg, 0.055 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) and tetrabutylammonium fluoride trihydrate (25 mg, 0.07 mmol). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml) was added. The precipitate was collected by filtration and washed with water (5 ml) followed dichloromethane (5 ml). The solid thus obtained was further triturated with dichloromethane (4 ml) to give the title compound (11 mg, 45% yield, HCl salt, it is regioisomers). MW/HCl=446.36. 1H NMR (DMSO-D6, 360 MHz) δ 7.76 (m, 3H), 7.30 (d, J=7.9 Hz, 2H), 7.23 (d, J=3.6 Hz, 1H), 4.29 (s, 2H), 2.92 (t, J=6.8 Hz, 2H), 2.86 (t, J=6.8 Hz, 2H), 2.11 (t, J=6.8 Hz, 2H). MS: ESI+, m/z 410 [M+H]+. LCMS: 97%.