Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]([CH2:18][CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>O>[CH2:21]([C:3]([N:2]([CH3:20])[CH3:1])([CH2:18][CH3:19])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
In a 2.5 1 sulfonation flask, 900 ml of a solution (1 mol) of 2-dimethylamino-1 -(4-morpholino-phenyl)butan-1 -one according to b) above are heated again to 50° C. 179.7 g (1.05 mol) of benzyl bromide are then added dropwise over 20 minutes. The mixture is stirred for 3 to 4 hours at 50° C. until the thin layer chromatogram shows that there is no educt left. The temperature is raised to 60° C. and then 80 g (2 mol) of sodium hydroxide powder are added in increments over 45 minutes. The mixture is then stirred for another 1 to 2 hours at 50° C. until the thin layer chromatogram shows that there is no educt left. The reaction mixture is charged with 150 ml of water and stirred. The water phase is separated and the organic phase is concentrated on a vacuum rotary evaporator. 378.3 g of the yellowish crude product of 2-benzyl-2-dimethylamino-1 -(4-morpholinophenyl)butan-1 -one having a melting point from 102° C. to 110° C. remain in the flask. The crude product is dissolved hot in 600 ml of ethanol, cooled, crystallised, filtered and then washed with cold ethanol. The crystals are dried. They melt at 114° C. to 115° C., and gas chromatogram as well as thin layer chromatogram show them to be pure. The yield is 299.0 g of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)butan-1-one. A further 22.4 g of pure product can be isolated from the mother liquor. The 1H-NMR spectrum of the pure product corresponds to that of the indicated structure.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[OH-].[Na+]>O.ClC(Cl)Cl>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:1]1[CH2:3][CH2:2]1)=[O:13]
Reactant: O=C(Cl)c1ccccc1O
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1O)N1CC1
Temperature: -5 °C

Procedure:
To 690 parts of a solution of aziridine in water 0.875M are added 42 parts of sodium hydrogen carbonate while cooling in an ice-salt bath at -5° C. While stirring vigorously, there is added dropwise, during a 30 minutes period, a solution of 78.8 parts of 2-hydroxybenzoyl chloride in 150 parts of trichloromethane at a temperature below 5° C. The reaction mixture is allowed to reach 25° C while stirring, and a diluted sodium hydroxide solution is added to pH 8. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 56 parts of 1-(2-hydroxybenzoyl)aziridine as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.C(O)(C)(C)C.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 80 °C

Procedure:
To a mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Combi-Blocks Inc, Cat#: SS-3744; 342 mg, 1.55 mmol) and tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52) (521 mg, 1.30 mmol) in tert-butanol (10 mL, 105 mmol) was added DIEA (0.57 mL, 3.25 mmol). The reaction mixture was heated at 80° C. in an oil bath for 21 h. The resulting brown suspension was concentrated under reduced pressure and the crude solid was suspended in Et2O (ca. 20 mL) and filtered affording the crude material of tert-butyl (3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (1a) as a green solid. m/z (ESI, +ve ion) 558.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (1H, s), 8.73 (1H, s), 8.14 (1H, s), 7.89 (1H, d, J=9.4 Hz), 7.57 (1H, d, J=8.4 Hz), 7.42 (3H, t, J=8.0 Hz), 7.28 (1H, d, J=8.8 Hz), 6.87 (1H, d, J=8.6 Hz), 6.53 (1H, d, J=2.3 Hz), 6.43 (1H, d, J=9.4 Hz), 6.05 (1H, br. s.), 3.73-3.82 (3H, m), 3.06 (4H, br. s.), 2.36-2.47 (4H, 2.15-2.26 (3H, s), 1.45 (9H, s).
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:29][NH:30][CH3:31].CN(C=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[C:9]([CH2:10][N:30]([CH3:31])[CH3:29])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH2:27])=[O:26])=[O:14])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(C)(C)C
Reaction time: 1 h

Procedure:
2-[2-(3-Tert-butyl-4-formylpyrazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.13 mmol) and dimethylamine hydrochloride (20 mg, 0.23 mmol) were mixed with DMF (0.3 mL) and acetic acid (0.3 mL). Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added and the mixture stirred for 1 h. The reaction was quenched with MeOH and water and directly purified by preparative reverse phase HPLC. The clean product was passed down an SCX cartridge and the volatiles were blown off under a nitrogen atmosphere (2.1 mg, 5 μmol, 4%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+].O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 41.7 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then, mcpba (70.2% purity; 8.95 g (36.4 mmol)) was added gradually so that the internal temperature did not exceed −15° C. 10% Aqueous sodium hydroxide solution (70.8 ml) was then added, and after stirring and still standing the water layer was separated. The separated water layer was washed with dichloromethane (48 ml) twice. After addition of a 2N-ammonium acetate aqueous solution, the water layer was extracted with dichloromethane (48 ml) twice. The dichloromethane layer was washed with water (48 ml) twice, concentrated under a reduced pressure, crystallized with dichloromethane (28 ml) and ethyl acetate (184 ml), and filtered to obtain 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (10.9 g) (HPLC purity 99.7%, yield 41.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Yield: 53.1 %

Procedure:
A solution of 4-methyl-3-nitrobenzonitrile (30 g), N-bromosuccinimide (37 g) and azobisisobutyronitrile (3.1 g) in carbon tetrachloride (300 ml) was refluxed under heating for 8 hr. To the reaction mixture was added water (100 ml) and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:4) and recrystallized from ethyl acetate-hexane to give the title compound (23.7 g) as pale-yellow crystals, m.p.=85-89° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33][CH2:32]2>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH2:27][C@@H:23]5[CH2:24][CH2:25][CH2:26][O:22]5)[CH:30]=4)[C:35]3=[O:34])=[CH:15][C:14]=2[F:20])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1

Procedure:
[(R)-1-(4-Amino-2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was reacted with 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochroman-1-one by method AC. The product with the molecular weight of 525.63 (C29H36FN3O5) was obtained in this way; MS (ESI): 526 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].[Cl:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1.O>CN(C=O)C>[Cl:7][C:8]1[C:13]([CH2:14][O:6][CH2:3][C:4]#[CH:5])=[CH:12][C:11]([C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[C:10]([F:28])[CH:9]=1
Reactant: C#CCO
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(CBr)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.04 g (1.10 mmol) of sodium hydride was suspended in 5 ml of DMF, and 0.06 g (1.10 mmol) of propargyl alcohol was dropwise added thereto at room temperature, followed by stirring for 30 minutes. Then, 0.40 g (1.00 mmol) of 3-(4-chloro-2-fluoro-5-bromomethylphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 5 ml of DMF, and dropwise added thereto, followed by stirring for 2 hours. The reaction mixture was poured into water and extracted with ethyl ether. The extract was dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.34 g (yield: 91%) of the desired product. Melting point: 99-101C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:3][C:4]3[C:9]([N:1]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2nc3cccnc3s2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Oc2nc3cccnc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
To a solution of [4-([1,3]thiazolo[5,4-b]pyridin-2-yloxy)phenyl]methanol (140 mg, 0.542 mmol) in CH2Cl2 (3.6 mL) was added SOCl2 (43 μL, 0.596 mmol, 1.1 equiv.). The solution was allowed to stir under N2 at rt for 4 h. The reaction mixture was then concentrated to afford the desired product as a cream-colored solid (157 mg, 92%). MS (ESI): mass calcd. for C13H9ClN2OS, 276.0; m/z found, 277.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.47 (dd, J=4.4, 1.5, 1H), 8.11 (dd, J=8.2, 1.5, 1H), 7.65-7.57 (m, 2H), 7.56-7.47 (m, 3H), 4.85 (s, 2H).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 411.89 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]2[NH:14][C:15](=[O:16])[NH:17][C:18]2=[O:19])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: O=C1CNC(=O)N1
Reactant: COc1cc(C=O)cc(OC)c1O
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1O
Yield: 75.7 %

Procedure:
Prepared according to the procedure described in Example 90 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), and μ-alanine (1.4 g, 16 mmoles), to afford the pure product (6.0 g), mp 296°-297° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J5) (205 mg, 0.79 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (302 mg, 0.97 mmol) according to the general procedure M. Obtained as a pink foam (340 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.[CH3:11][C:12]([CH2:16]O)([CH2:14][OH:15])[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:9][C:8]1([CH:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:15][CH2:14][C:12]([CH3:16])([CH3:13])[CH2:11][O:10]1
Reactant: CC(=O)C1CCC(O)CC1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(C)(C2CCC(O)CC2)OC1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 1-(4-hydroxy-cyclohexyl)-ethanone (2.24 g, 1 eq.), toluene (160 mL), neopentylglycol (1.96 g, 1.2 eq.) and pTsOH (150 mg, 0.05 eq.) in a flask equipped with Dean-Stark apparatus was heated to reflux overnight. The mixture was cooled down to room temperature and contentrated. The crude product was purified by silic gel column chromatography (25% to 50% EtOAc/hexanes) to give 4-(2,5,5-trimethyl-[1,3]dioxan-2-yl)-cyclohexanol (2.23 g, 62%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=O)(C)(C)C.[Cl:45]CCl.[ClH:48].O>C(OCC)(=O)C>[ClH:45].[ClH:48].[NH2:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Reactant: ClCCl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg of N-[N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-leucyl]-L-valyl]-L-phenylalanine, methyl ester (slower isomer) (see example 6C) in 3 ml of ethyl acetate and 1.5 ml of dichloromethane was cooled in an ice bath under nitrogen, and then treated with anhydrous hydrogen chloride gas to saturation. Once the reaction was saturated, the ice bath was removed, the reaction was stoppered, and stirred at ambient temperature. After one hour, the reaction was concentrated to dryness in vacuo, resuspended in 5 ml of ethyl acetate, cooled in an ice bath under nitrogen, resaturated with anhydrous hydrogen chloride and stoppered. After 30 minutes, the reaction was concentrated to dryness in vacuo, then recrystallized from methanol/ether at room temperature, and refrigerated overnight to afford 200 mg of the title compound as a hydrate with 0.4 mole of water, melting point 242°-252° C., dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[N:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[N:11][N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1ccc(-c2nnco2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nnco3)cc2)CC1

Procedure:
Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.
Reaction SMILES: [N+]([CH:4](C1C=CC=CC=1)[C:5](NC1C=CC=CC=1)=[O:6])([O-])=O.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.B.O>O1CCCC1>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([OH:20])[CH:22]=2)[C:5](=[O:6])[CH3:4])=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=C(Nc1ccccc1)C(c1ccccc1)[N+](=O)[O-]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1cccc(O)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(CCc1ccc([N+](=O)[O-])cc1)c1cccc(O)c1

Procedure:
10 g (0.4 mol) of the nitrophenylacetanilide prepared in 1a) was placed in a flask and borane in tetrahydrofuran (THF) (1 M, 250 ml) was added carefully. The resulting solution was heated under reflux and water (12 ml) in THF (100 ml) was added dropwise over 1 hour. A further 50 ml of water was added and the mixture was heated for 15 mins. The THF was evaporated under reduced pressure and methanol (100 ml) was added to dissolve the oil. Thin layer chromatography (tlc)(silica H, 20% methanol in chloroform) gave a Rf much higher than the starting acetanilide.
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:18]=2)=[CH:13][C:12]=1[O:32][CH3:33]>N1C=CC=CC=1.ClCCl>[NH2:26][C:24]1[C:25]2[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[C:12]([O:32][CH3:33])[CH:13]=3)=[CH:18][N:19]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)OCC(C)(C)C
Reaction time: 0.17 h

Procedure:
Neopentylchloroformate (28 uL, 0.186 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in pyridine (1 mL) and dichloromethane (1 mL) under nitrogen at 0° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was taken into ethyl acetate. The organic layer was washed, dried and evaporated. The solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give neopentyl N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate. 1H NMR (CDCl3) δ 1.00 (s 9H), 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 5.22 (m, 3H), 6.22 (s, 1H), 7.01 (s, 1H), 7.08 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.17 (br. d, 1H), 8.32 (s, 1H); LC/MS (MH+=438).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[C:9]1([C:7]2[CH:8]=[C:3]([OH:2])[N:4]=[N:5][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Temperature: 150 °C

Procedure:
A mixture of 3-methoxy-5-phenyl-6-(4-([4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl)phenyl)pyridazine (2-3) TFA (36.8 mg, 0.059 mmol) and pyridine hydrochloride (591 mg, 5.1 mmol) was heated at 150° C. for 5 min. This solid was dissolved in water, the solution made basic with NaHCO3, and the product extracted into methylene chloride/methanol (5%). This solution was dried, filtered and the solvents evaporated. This residue was digested in acetonitrile to give 5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazin-3-ol (2-4) as a tan solid freebase. NMR (CDCl3/CD3OD): δ8.66 (1H, br d, J=4.5 Hz), 8.40 (1H, br d, J=7 Hz), 8.29 (1H, br m), 7.67 (2H, br m), 7.55 (2H, d, J=7.5 Hz), 7.42 (1H, s), 7.35 (1H, t, J=7.5 Hz), 7.11-7.30 (4H, m), 7.08 (2H, d, J=9 Hz), 6.98 (1H, s), 4.21 (2H, s), 3.47 (2H, d, J=10 Hz), 3.26 (1H, m), 3.00 (2H, m), 2.43 (2H, br d, J=11 Hz), 2.13 (2H, m); m/e (m+1): 489.2.