Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
To a solution containing 30 g of the naphthol compound obtained in Step (1) above, 250 ml to acetonitrile and 45 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and poured into 1 l of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:21]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:21])=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(=O)c1ccc(F)cc1
Yield: 84 %

Procedure:
To a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid (3.0 g, 14.3 mmol) in dry MeOH (50 ml) was added concentrated sulfuric acid (50 mg) and the mixture refluxed under nitrogen for 16 h. The bulk of the MeOH was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 100 ml) and extracted with ethyl acetate (3×50 ml). The organic extract was washed with water (1×100 ml), brine (1×100 ml), dried (Na2SO4) and evaporated to give methyl 5-(4-fluorophenyl)-5-oxopentanoate (2.69 g, 84%) as a white crystalline solid.
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27](N)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]>>[C:14]([C:16]1([NH:25][C:26](=[O:34])[CH:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)#[N:15]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: N=C1NC(=O)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared from 3-imino-2,3-dihydro-isoindol-1-one and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 15. MS, m/z 424.5=M+1.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[CH:9].[CH2:16]([C:18]([C:29]1[CH:34]=[CH:33][C:32](OS(C(F)(F)F)(=O)=O)=[C:31]([CH3:43])[CH:30]=1)([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)[CH2:19][CH3:20])[CH3:17].C(OCC)(=O)C>C(#N)C.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>[CH2:16]([C:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:29]1[CH:34]=[CH:33][C:32]([C:9]#[C:8][C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:31]([CH3:43])[CH:30]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: C#CC1(O)CCCC1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Triethylamine (5.2 mL, 37.3 mmol), 1-ethynylcyclopentanol (2 g, 18.2 mmol), cuprous iodide (0.24 g, 1.26 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.44 g, 1.25 mmol) were added to a solution of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl ester (Example 1-(1); 5.2 g, 12.5 mmol) in acetonitrile (52 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred at 110° C. for four hours. Ethyl acetate was added to the residue. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (3 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24]2)[CH:10]([OH:14])[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>>[CH:35]1([NH:38][C:11](=[O:13])[CH:10]([OH:14])[CH:9]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:24]2)[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:37][CH2:36]1
Reactant: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NC1CC1
Product: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)NC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-(3-fluorophenyl)-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylamine; ESI-MS [M+H]+: 500.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21][CH3:22])=[CH:15][C:14]=3[F:23])=[O:9])=[CH:4][CH:3]=1.CN(C=[O:30])C.ClC1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21]([CH3:22])=[O:30])=[CH:15][C:14]=3[F:23])=[O:9])=[CH:24][CH:25]=1
Reactant: CSc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reactant: CN(C)C=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.17 h

Procedure:
A suspension of 150 mg of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide from Example No. 170 and 0.75 mL of DMF in 15 mL of chloroform is treated with 79 mg of m-chloroperbenzoic acid. After stirring for 10 min the mixture is treated with 10 mL of a concentrated aqeous solution of sodium bisulfite. After stirring an addtional 5 min the phases are separated and the organic layer is washed with 15 mL of a saturated aqueous solution of sodium bicarbonate. The organic layer is dried (MgSO4) and the solvent was evaporated at reduced pressure. The residual solid is washed with a small volume of diethyl ether and dried to give 95 mg of a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23](O)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].CCN(S(F)(F)[F:37])CC.O>C1(C)C=CC=CC=1>[CH3:3][C:2]([Si:5]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([F:37])[C:24]([CH3:26])([CH3:25])[CH3:27])[CH:9]=1)([CH3:29])[CH3:30])([CH3:1])[CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(F)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 66.30B (0.400 g, 0.925 mmol) in toluene (10 mL) at −78° C. was added DAST (0.209 g, 1.29 mmol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then warmed to 23° C. and stirred for an additional 2 hours. Water was added to quench the reaction mixture. The reaction was then extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30C as a colorless oil (0.400 g, 99% yield).
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: CNC
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran is treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction is partitioned between water and ethyl acetate. The organic phase is washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][C:7]1(O)[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)[CH3:2]
Reactant: CCOCCCC1(O)c2ccccc2C=Cc2ccc(I)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOCCCC1c2ccccc2C=Cc2ccc(I)cc21
Reaction time: 0.25 h

Procedure:
5-(3-Ethoxypropyl)-3-iodo-5H-dibenzo[a,d]cyclohepten-5-ol (8.35 g., 0.020 mole) is mixed thoroughly with 7.6 g. (0.20 mole) of sodium borohydride and the mixture added carefully in portions to 130 ml. of trifluoroacetic acid stirred vigorously in an ice bath. A moderate stream of nitrogen is passed over the mixture throughout the addition, which is carried out in an efficient fume hood, and upon completion of the addition, the mixture is stirred for 15 minutes and concentrated in vacuo. The residue is treated with ice water, and the resulting gum separated by decantation. This residue is dissolved in toluene, extracted three times with 1 N NaOH, washed once with water, and dried over sodium sulfate. The solution is evaporated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1cccc(F)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cccc(F)c1F
Temperature: 55 °C
Yield: 92.6 %

Procedure:
To a oven dried round bottom flask with stir bar was added 2,3-difluorobenzaldehyde (0.5 g, 3.52 mmol), (R)-2-methylpropane-2-sulfinamide (0.469 g, 3.87 mmol) and DCE (7.04 mL). To this mixture was then added Copper (II) Sulfate (0.842 g, 5.28 mmol). Reaction mixture heated in a preheated oil bath to 55° C. for 24 hours. The reaction mixture was filtered through a celite pad washing solids with DCE. Combined filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(2,3-difluorobenzylidene)-2-methylpropane-2-sulfinamide (0.8007 g, 3.26 mmol, 93% yield). LCMS m/z 246.1 (M+H)+, Rt 0.91 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[S:10][CH:11]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:12][C:13]([OH:15])=[O:14]>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[N:1]3[C:9]4[C:4]([N:3]=[C:2]3[S:10][C:11]=2[CH2:12][C:13]([OH:15])=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=4)=[CH:18][CH:19]=1
Reactant: O=C(O)CC(Sc1nc2ncccc2[nH]1)C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1sc2nc3ncccc3n2c1-c1ccc(Cl)cc1
Yield: 57.6 %

Procedure:
17 g (0.047 m) of 3-(imidazo[4,5-b]pyridine-2-ylthio)-3-(4-chlorobenzoyl)propionic acid, prepared according to Example 2, is dissolved in 200 ml trifluoroacetic acid, and the solution is heated to gentle reflux overnight. The solution is cooled and filtered, the solvent is removed in vacuo and the residual solid triturated with ether and the solid collected. The resulting trifluoroacetate is disproportionated in hot acetonitrile to give 9.3 g of title compound, m.p. 250°-252° C.
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[NH:13][C:14]2[S:15][C:16]([S:19]([CH3:21])=[O:20])=[CH:17][N:18]=2)=[CH:8][CH:7]=1)(=O)C>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:13][C:14]2[S:15][C:16]([S:19]([CH3:21])=[O:20])=[CH:17][N:18]=2)=[O:22])=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1ccc(C(=O)Nc2ncc(S(C)=O)s2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)c1cnc(NC(=O)c2ccc(O)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 M hydrochloric acid (45.0 mL) is added to a suspension of 7 (0.439 g, 1.32 mmol) in tetrahydrofuran (20.0 mL), and the suspension is warmed to reflux. The reaction became homogeneous upon heating. After refluxing for 4 hours, the reaction is allowed to cool to room temperature, and stood at room temperature overnight before the reaction is filtered. The filter pad is washed with water then dried in vacuo at 70° C. to give 9 as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][OH:21])=[CH:24][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([F:20])[CH:3]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cn1cc(C(=O)/C=C/c2ccc(Cl)cc2F)ccc1=O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Product: Cn1cc(C(=O)CC(c2ccc(CO)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 203, step 1, (E)-5-(3-(4-chloro-2-fluorophenyl)acryloyl)-1-methylpyridin-2(1H)-one (example 314, step 2) was reacted with 4-(hydroxymethyl)phenyl-boronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium (I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless foam, MS (ESI+): m/z=400.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:22](=O)[CH3:23]>C(O)(=O)C.CO.[Pd]>[CH2:22]([C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=1[OH:1])[CH3:23]
Reactant: CCCCCCCCCCCCCCc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCCCCCCCCc1ccc(CC)c(O)c1
Reaction time: 18 h

Procedure:
A 15.6 g portion of 1-(2-hydroxy-4-tetradecylphenyl)-ethanone was heated in a mixture of 120 ml of acetic acid and 30 ml of methanol until solution was complete. A 4 g portion of 5% palladium on carbon was added and the mixture was hydrogenated in a Parr apparatus for 18 hours. The mixture was then filtered through diatomaceous earth and the solvents removed under reduced pressure, giving 14.5 g of the desired compound, mp 59°-60° C.
Reaction SMILES: [CH2:1]([N:8]([CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)CCC>[CH2:1]([O:15][C:14](=[O:16])[CH2:13][CH:12]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]#[N:11])[CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(CC(=O)O)N(CC#N)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)CC(C)N(CC#N)Cc1ccccc1
Yield: 41 %

Procedure:
A solution of 4.6 g of 3-(N-benzyl-N-cyanomethylamino)butyric acid in 100 ml of n-butanol is combined with 0.5 ml of concentrated sulfuric acid and the mixture is heated for 4 hours on a water trap under reflux. The reaction mixture is allowed to cool, concentrated to dryness, and the residue dissolved in diethyl ether. The ether solution is washed with 10% sodium bicarbonate solution and saturated sodium chloride solution, dried, and evaporated to dryness. The oily residue is distilled in a bulb tube at 85°-105° C. and 0.01 torr, thus obtaining 1.17 g of 3-(N-benzyl-N-cyanomethylamino)butyric acid n-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH2:19]([N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]=3[CH:10]=2)[CH2:31][CH2:32]1)[CH3:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CN(Cc1ccccc1)C1CCNCC1
Product: CN(Cc1ccccc1)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde was reacted with benzyl-methyl-piperidin-4-yl-amine (hydrochloride salt) using the general reductive amination procedure to yield benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-methyl-amine, which was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester in General Procedure A. Purification on silica yielded 396. NMR (CDCl3); 1.65-1.73 (2H, m), 1.79-1.83 (2H, m), 2.05-2.09 (2H, m), 2.20 (3H, s), 2.45-2.47 (1H, m); 3.02 (2H, d), 3.60 (2H, s), 3.78 (2H, s), 3.85-3.89 (4H, m), 3.92-3.96 (4H, m), 5.23 (2H, s, br.), 7.12 (1H, s), 7.23-7.24 (1H, m), 7.31-7.33 (4H, m), 9.30 (2H, s). MS ESI m/z 531 (MH+, 100%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[CH2:21][CH:22]([CH3:30])[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH:22]([CH3:30])[CH2:21][O:1][C:2]2[C:11]3[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:13])[C:3]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:25][CH2:26]1
Reactant: CC(CCl)CN1CCOCC1
Reactant: O=c1oc2c(O)cccc2c(O)c1-c1ccccc1
Product: CC(COc1c(-c2ccccc2)c(=O)oc2c(O)cccc12)CN1CCOCC1
Yield: 60.7 %

Procedure:
Prepared according to the method of Example 30 by alkylation of 4,8-dihydroxy-3-phenyl-coumarin by 1-chloro-2-methyl-3-morpholino-propane. After recrystallisation from isopropanol, a white solid is obtained with the melting point of 136° C. Yield 60.7%.
Reaction SMILES: [NH2:1][C@H:2]([C:9](O)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C1(N)CCCCC1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C@H:35]([C:43]([O:45][CH3:46])=[O:44])[C@@H:36]([CH3:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].Cl.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:1][C@H:2]([C:9]([NH:34][C@H:35]([C:43]([O:45][CH3:46])=[O:44])[C@@H:36]([CH3:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: NC1CCCCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)COC(C)(C)C)[C@@H](C)OC(C)(C)C
Temperature: -10 °C
Reaction time: 8 h

Procedure:
19.3 g (38.6 mmols) of DPC-Ser(tBu)-OH.cyclohexylamine salt are taken up in 500 ml of chloroform and extracted at 0°C by shaking three times with 25 ml of 1 N citric acid and five times with 40 ml of half-saturated sodium chloride solution. The solution is dried over sodium sulphate and then evaporated and the resulting foam is taken up in 250 ml of ethyl acetate. 5.36 ml (38.6 mmols) of triethylamine are added and the solution is cooled to -10°C and mixed with 5.13 ml (38.6 mmols) of isobutyl chlorocarbonate whilst stirring. The mixture is stirred for 10 minutes at -10°C and a solution of 7.3 g (38.6 mmols) of H-Thr(tBu)-OMe in 100 ml of ethyl acetate, cooled to -12°C, is then added dropwise in such a way that the reaction temperature never exceeds -10°C. After completion of the addition the mixture is stirred for a further hour at - 10°C and is then left to stand overnight at room temperature. The solution is freed of the triethylamine hydrochloride which has separated out by filtering it and is washed at 0°C, three times with 20 ml at a time of 1 N citric acid and five times with saturated sodium chloride solution, dried and evaporated. Crude product (oil); 22.07 g. To purify it, 1 g is chromatographed on a silica gel column (2.5 cm, 30 cm). Using petroleum ether-ethyl acetate (1:1), 787 mg of pure product are eluted after a first run of 110 ml.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][CH2:49][CH:50]1[CH2:53][O:52][CH2:51]1)=[N:40]2>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:45]([C:43]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][C:39]([NH:48][CH2:49][CH:50]4[CH2:51][O:52][CH2:53]4)=[N:40]3)=[C:35]([F:34])[CH:44]=2)=[O:46])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Reactant: O=C(O)c1cc(F)c2cnc(NCC3COC3)nc2c1
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCC4COC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-2-[(oxetan-3-ylmethyl)-amino]-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-63) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87f.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH:10]=1>[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CCC=C3c1ccc(Cl)cc1Cl
Agent: [Pd]
Product: CCN(CC)c1cccc2nc3n(c12)CCCC3c1ccc(Cl)cc1Cl
Yield: 46.7 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-N,N-diethyl-1,2-dihydropyrido[1,2-a]benzimidazol-9-amine (53.0 mg, 0.137 mmol) was stirred in the presence of 1.9% palladium on fibroin (10 mg) under hydrogen atmosphere at room temperature for 7 days. The catalyst was removed and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow oil (24.8 mg, 0.0640 mmol, 47%).