Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:20])[CH:26]=3)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(-c1cccc(O)c1)c(=O)n2C1CCCC1
Temperature: 120 °C
Yield: 79 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.31 mmol), 3-hydroxyphenylboronic acid (50 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 mL). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification. The title compound was obtained in (82.1 mg, 79% yield).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=4[F:45])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+]>C1COCC1>[F:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([F:45])[C:38]=1[C:33]1[N:32]=[C:31]([C:29]([NH:28][C:12]2[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:15]3)=[C:8]3[CH2:7][CH2:6][CH:5]([OH:4])[C:9]3=[N:10][CH:11]=2)=[O:30])[CH:36]=[CH:35][C:34]=1[F:37]
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
A mixture of 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (174 mg, 0.28 mmol), MeOH (0.7 mL), THF (0.7 mL) and 1.0 M aq. NaOH (1.1 mL, 1.1 mmol) was stirred at room temperature for 20 min. The organic solvents were removed under reduced pressure. The aqueous layer was diluted with EtOAc and NH4Cl (aq.), extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (151 mg, 93%). LCMS calc. for C30H33F3N5O4 (M+H)+: m/z=584.2. Found: 584.2.
Reaction SMILES: [Na].[NH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]=[C:3]1[NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([O-])=[O:15]>CO.CCOCC>[OH:17][C:12]1[N:11]=[C:3]2[NH:2][C:6]3([CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:5][N:4]2[C:14](=[O:15])[CH:13]=1
Reactant: NC1=NCC2(CCCC2)N1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(O)nc2n1CC1(CCCC1)N2
Temperature: 100 °C
Yield: 74 %

Procedure:
2.37 g of sodium are added in a fractionated way to 10 mL of MeOH. After total dissolution, 5.68 g of 1,3-diazaspiro[4.4]non-2-en-2-amine solubilized beforehand in 5 mL of MeOH, and then 25.38 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The oil obtained is taken up in ether. The precipitate is filtered and the residue is then taken up in 10 mL of H2O and acidified with conc. HCl until pH 3-4. The formed precipitate is filtered, washed with ether and dried in the oven in vacuo. 3.97 g (yield=74%) of 7′-hydroxyspiro[cyclopentane-1,2′-imidazo[1,2-a]pyrimidin]-5′-one are obtained as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2ccc(-c3ccc(Cl)cc3)nc12
Temperature: 70 °C
Yield: 100.5 %

Procedure:
A mixture of ethyl 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.12 g, 0.4 mmol) and 0.5 N sodium hydroxide solution (4 mL) in methanol (4 mL) was heated to 70° C. for 2 h. The mixture was cooled, diluted with water (8 mL) and concentrated in vacuo. The aqueous solution was acidified to pH 2 by the addition of 3N HCl. The precipitate was isolated by filtration, washed with water, and dried to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.11 g, 100%). Off-white solid. MS (ISN) 272.3 [(M−H)−]; mp 309-311° C.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7]([C:22]2[CH:33]=[CH:32][C:25]([CH2:26][N:27]3[CH:31]=[N:30][N:29]=[N:28]3)=[CH:24][CH:23]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: Brc1ccc(Cn2cnnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 61.5 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (401.0 mg, 1.256 mmol, see Example 1(c) above), 1-(4-bromobenzyl)-1H-tetrazole (199.4 mg, 0.834 mmol, see step (a) above), toluene (20 mL), ethanol (3.0 mL), NaOH (1.0M, 5.0 mL, 5.0 mmol) and Pd(PPh3)4 (29.0 mg, 0.25 mmol) were mixed under N2. The mixture was warmed to reflux for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using CHCl3:MeOH (40:1) as eluent to give 222.4 mg of the sub-title compound (yield: 62%).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][C@@H:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=3)[C:21](OC)=[O:22])[CH:14]=2)[CH2:9]1)(=[O:6])=[O:5])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][C:20]1[CH:19]=[C:18]([CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=1)[CH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])[CH2:16]2
Reactant: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 39.9 %

Procedure:
To (S)-methyl 3-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (0.044 mmol, 20 mg) at 0° C. in THF (1 mL) under an argon atmosphere was added Lithium aluminium hydride in THF (0.044 mmol, 0.044 mL) dropwise. The reaction was left to stir for 1.5 hrs at 0° C. The reaction was quenched with water before the addition of 5N HCl (aq) to adjust the pH to 5. The mixture was filtered through a celite cartridge before washing with EtOAc. The EtOAc layer was washed with water (×1) before drying the EtOAc over MgSO4. The solvent was removed in vacuo before purifying the crude (1:1 EtOAc/Heptane, 4 g silica cartridge) to give the title compound (7.5 mg, 40%). MS (ESI): m/z [M+Na]+ 450.0
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.O.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:14][C:7]1[N:6]=[C:5]([NH:3][CH2:1][CH3:2])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCN
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
An ice-cold solution of EtNH2 (49.8 g, 1.10 mol) in toluene (200 mL) was added over 15 min to an ice-cold solution of 2,6-dichloro-3-nitropyridine (100.0 g, 0.52 mol) in toluene (225 mL). The mixture was stirred at 0° C. for 45 min. Water (500 mL) and EtOAc (500 mL) were added and the phases were separated. The organic layer was successively washed with water (200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residual solid was recrystallised from MeOH to give the title compound (83.7 g, 80% yield) as yellow needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]3[O:31][C:32](=[O:35])[NH:33][N:34]=3)[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:45]([CH3:47])[CH3:46].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:29]([CH3:36])([C:30]3[O:31][C:32](=[O:35])[N:33]([CH:45]([CH3:47])[CH3:46])[N:34]=3)[C:28](=[O:37])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:25])([F:26])[C:21]([F:22])([F:23])[F:24])[N:9]=2)[N:7]=1
Reactant: CC1(c2n[nH]c(=O)o2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1nc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5cc(Cl)ccc45)nc(N)c32)oc1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the intermediate from Step A above (120 mg, 0.22 mmol) and finely powdered potassium carbonate (36.9 mg, 0.264 mmol) in DMF (3 mL), was added 2-iodopropane (35.9 mg, 0.21 mmol) and the reaction was stirred for 7 hours at room temperature. Water (4 mL) and ethyl acetate (15 mL) were then added to the reaction mixture. The water layer was extracted with ethyl acetate (3×). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to give the indicated compound as a white solid. Chiral separation using SFC on a Chiralcel OJ column provided both enantiomers of the title compound. 1H NMR (500 MHz, CDCl3) δ 1.31 (d, J=6.4 Hz, 3H); 1.33 (d, J=6.4 Hz, 3H); 1.77 (s, 3H); 2.84 (t, J=7.8 Hz, 2H); 4.36 (t, J=6.6 Hz, 1H); 4.78 (t, J=7.6 Hz, 2H); 5.34 (s, 2H); 7.27 (d, J=8.7 Hz, 1H); 7.49 (s, 1H); 8.51 (d, J=8.7 Hz, 1H). m/z=587.13 (M+H).
Reaction SMILES: [CH:1]1([O:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:56][C:49]1[N:50]=[C:51]([NH:12][O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: NOC1CCCc2ccccc21
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NOC4CCCc5ccccc54)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 15 %

Procedure:
The title compound was prepared according to method B as described in examples 4 and 5 by reacting O-[1,2,3,4-tetrahydronaphth-1-yl)hydroxylamine (prepared by the procedure described in example 6) (0.35 g, 2.0 mmol) with 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g, 1.58 mmol) and debenzoylating the purified product using methanolic ammonia to provide the title 2-chloro-N-(1,2,3,4-tetrahydronaphth-1-yloxy)adenosine (0.10 g, 15%) (after column chromatography) as a colourless foam (a mixture of diastereoisomers), 1H NMR (DMSO-d6)γ 1.65 - 2.85 (6H, m,--CH2CH2CH2 --), 3.53-3.61 (1H, m, H-5'a), 3.64-3.70 (1H, m, H-5'b), 3.94 (1H, br d, H-4'), 4.16 (1H, br d, H-3'), 4.53 (1H, q, H-2'), 5.07 (2H, m, 5'-OH and OCH--), 5.26, 5.53 (2H, 2d, 2'- and 3'-OH), 5.88 (1H, d, H-1'), 7.13-7.30 (3H, m, Ar-H), 7.88-7.96 (1H, m, Ar-H), 8.52 (1H, s, H-8), 11.60 (1H, br s, N-H). HPLC retention time 20.71 and 20.95 min (gradient elution over 25 min.; 25-45% acetonitrile/0.1M.
Reaction SMILES: C1(C2C=CC=CC=2CO)C2C(=CC=CC=2)C=CC=1.[Mg].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)=[O:34]>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:34]
Reactant: Brc1ccccc1
Reactant: O=C(c1ccccn1)c1ccccn1
Agent: OCc1ccccc1-c1cccc2ccccc12
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccccn1)c1ccccn1

Procedure:
With the same method as for Compound 13, a Grignard reagent was prepared from magnesium (Wako Pure Chemical Industries, Ltd.) and bromobenzene (Wako Pure Chemical Industries, Ltd.), and di-2-pyridyl ketone (Aldrich) was allowed to react with the reagent, to thereby obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.CCN(CC)CC.[NH2:27][CH2:28][C:29]#[N:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:30][CH2:29][C:28]#[N:27])=[O:12])[C:4]=2[CH:3]=1
Reactant: N#CCN
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 80.6 %

Procedure:
By the method of Example 18, the title compound of Example 2 (5.24 g, 17.8 mmol) in 100 mL of CH2Cl2 with molecular sieves #5A (10 g) and Et3N (2.5 mL, 18.0 mmol) was reacted with aminoacetonitrile (1.0 g, 17.8 mmol) to produce 4.5 g of the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([OH:19])[CH2:13][N:12]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]([C@H:11]1[C@@H:16]2[O:17][C:32]([CH3:37])([CH3:33])[O:18][C@@H:15]2[C@@H:14]([OH:19])[CH2:13][N:12]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]2C(=O)OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@H]3OC(C)(C)O[C@H]3[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3585 %

Procedure:
The above compound (4) (7.4 g) was dissolved in DMF (80 mL) and DMP (17.6 g) and p-toluenesulfonic acid monohydrate (70 mg) were added, and then the mixture was stirred overnight at room temperature and further stirred at 60° C. for 1.5 hours. To the reaction solution was added ethyl acetate (150 mL) and, after washing with an aqueous saturated sodium hydrogencarbonate solution and saturated saline (×3), the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (ethyl acetate:cyclohexane=1:3→1:2→1:1) to obtain the titled compound (6.3 g) as a syrup.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([F:23])[CH:17]=3)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].C(O)(=O)C.[ClH:29].CO>C1COCC1.[Zn]>[ClH:29].[NH2:1][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([F:23])[CH:17]=3)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one (141 mg, 0.44 mmol) in 4 ml THF are added zinc dust (143 mg, 2.19 mmol) and acetic acid (250 μl, 4.37 mmol) and the mixture is stirred for 18 hours at room temperature. The suspension is diluted with THF and acidified with a small amount of 25% hydrochloric acid to obtain a clear solution. More THF and methanol are added. The mixture is filtered and the filtrate is evaporated. The residue is triturated with water, the solids are filtered off, washed with water and dried under vacuum to afford 3-[4-(1-amino-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one hydrochloride as white solid;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=2)[CH:5]=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][O:10]2)[C:7]=1[NH2:8].[CH2:24]([NH:26][C:27]([NH:29][C:30](SC)=NC(=O)NCC)=[O:28])[CH3:25]>O1CCOCC1.OS(O)(=O)=O>[CH2:24]([NH:26][C:27]([NH:29][C:30]1[NH:8][C:7]2[C:6]([CH:9]3[CH2:13][CH2:12][CH2:11][O:10]3)=[CH:5][C:4]([C:14]3[CH:19]=[N:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[N:16][CH:15]=3)=[CH:3][C:2]=2[N:1]=1)=[O:28])[CH3:25]
Reactant: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2)cn1
Reactant: CCNC(=O)N=C(NC(=O)NCC)SC
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(C3CCCO3)c2[nH]1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a stirring solution of 2-[5-(3,4-diamino-5-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (9) (32.10 g, 102.1 mmol) in 1,4-dioxane (160.5 mL, Sigma-Aldrich 360481) was added pH 3.5 buffer (240.8 mL), prepared by dissolving NaOAc trihydrate (34.5 g) in 1N aqueous H2SO4 (240 mL). 1-Ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanyl-carbonimidoyl)urea (10) (28.46 g, 122.5 mmol, CB Research and Development) was added to the reaction mixture and stirred at reflux overnight (HPLC showed 99% consumption of starting diamine). The reaction mixture was cooled to room temperature and poured portion-wise (frothing) into a stirring solution of aqueous saturated NaHCO3 (480 mL) and water (120 mL) giving pH 8-9. This was stirred for 30 minutes, the solid was collected by filtration, washed copiously with water to neutral pH, and then more sparingly with EtOH. The solid was dried under reduced pressure giving (11) as an off-white solid (34.48 g, 82% yield; 99.4% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 411.41 (1.73 min). 1H NMR (300 MHz, MeOD) δ 9.02 (s, 2H), 7.62 (s, 1H), 7.37 (s, 1H), 5.31 (s, 1H), 4.23 (dd, J=14.5, 7.3 Hz, 1H), 4.01 (dd, J=15.0, 7.1 Hz, 1H), 3.38-3.28 (m, 2H), 2.58-2.46 (m, 1H), 2.16-2.05 (m, 2H), 2.02-1.88 (m, 1H), 1.63 (s, 6H), 1.22 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH:17]([NH2:20])([CH3:19])[CH3:18].C1CCCCC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH:17]([CH3:19])[CH3:18])[C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(C)N
Reactant: CC(=O)c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)nc1NC(C)C

Procedure:
1-(2,4-dichloro-pyrimidin-5-yl)-ethanone (10 g, 0.052 mol), sodium hydrogen carbonate (19.35 g, 0.058 mol) and isopropylamine (5 mL, 0.058 mol) are taken up in 35 mL THF and 200 mL cyclohexane and stirred for 2 h at 20° C. The reaction solution is filtered through silica gel, the solvent is eliminated in vacuo and 1-(2-chloro-4-isopropylaminopyrimidin-5-yl)-ethanone (HPLC-MS: tRet.=1.73 min, MS(M+H)+=214/216; method FECB3) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16]S(C)(=O)=O)[CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Yield: 69.6 %

Procedure:
5-(4-fluorophenyl)-4-benzyloxy-2-mesyloxyethylbenzene (2.5 g, 6.24 mmol) was dissolved in methanol (80 mL). To this was added sodium hydroxide (300 mg, 7.5 mmol) dissolved in water (20 mL). The solution was heated to reflux and heating maintained for 24 hours, when an additional equivalent of sodium hydroxide was added, and reflux maintained for an additional 16 hours. The mixture was cooled, acidified with 1N HCl, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an orange solid which was triturated with hexane to yield 5-(4-fluorophenyl)-4-benzyloxy-2-hydroxyethylbenzene (1.4 g) as an off-white powder. NMR (DMSO-d6): 1.11, t, (3H); 2.50, q (2H); 3.34, s (3H); 5.02, s (2H); 6.60, d (1H); 6.98, s (1H); 7.16, t (2H); 7.35, m (5H); 7.50, dd (2H); 9.44, s (1H). Mass Spec 5 (GCMS) 322 (M).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:45]2[N:44]=[CH:43][N:42]([CH3:46])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:45]3[N:44]=[CH:43][N:42]([CH3:46])[C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: Cn1cnc2c(CCl)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2ncn3C)cc1

Procedure:
Analogously to Method D, 0.800 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.317 g of 4-chloromethyl-1-methyl-1H-benzimidazole are reacted. The title compound is obtained as a yellow resin. Rf=0.30 (15:1 dichloromethane-methanol); Rt=4.74.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4]1\[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]\1=[O:10]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1
Reactant: CO/C=C1\CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Pd]
Solvent: CO
Product: COCC1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 6 h

Procedure:
1,1-dimethylethyl (3E)-3-[(methyloxy)methylidene]-4-oxo-1-piperidinecarboxylate D30 (1.5 g) was dissolved in methanol (30 ml), and then 5% Pd/C (1 g) was added. The reaction mixture was hydrogenated at atmospheric pressure for 6 hours. Then the Pd/C was removed by filtration and the solution was evaporated in vacuo to afford the desired product D31 as a pale yellow oil in 1.2 g. LCMS [M-56+H] 188.1@1.53 min (5 min run)