Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20].CO>O>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Typically, N-acetyl-D-phenylalanine is allowed to contact DL-phenylalanine methyl ester in a suitable solvent, e.g. methanol or water, to produce a crystalline salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester. That salt is separated from the filtrate and decomposed with aqueous hydrochloric acid to afford N-acetyl-D-phenylalanine as a precipitate and L-phenylalanine methyl ester hydrochloride in solution. After filtering, the solvent in the filtrate is removed to afford the hydrochloride salt of L-phenylalanine methyl ester. Alternatively, the salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester is dissolved in aqueous potassium carbonate and extracted with ether. The D-amide remains in the aqueous phase and the L-ester remains in the organic phase. After phase separation, the ethereal solution is acidified with hydrochloric acid-isopropanol to precipitate the hydrochloride salt of L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BH4-].[Na+]>CO>[OH:19][CH2:18][C:16]1[S:17][C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: COc1cc(-c2ccc(C=O)s2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc(CO)s2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(3,4,5-Trimethoxyphenyl)thiophene-2-carboaldehyde (662 mg) was dissolved in methanol (50 mL), and to the solution sodium borohydride (180 mg) was gradually added under ice cooling. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound.
Reaction SMILES: S1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:20]([O-:23])([O-])=[O:21].[Na+].[Na+]>C(Cl)(Cl)Cl>[S:20]1(=[O:23])(=[O:21])[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1
Reactant: O=S([O-])[O-]
Reactant: N#CC1CCSCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#CC1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A chloroform solution of tetrahydro-2H-thiopyran-4-carbonitrile was dropwise added to a chloroform solution of 77% m-chloroperbenzoic acid at 0° C., followed by stirring at room temperature for 3 hours. An excess amount of an aqueous saturated sodium sulfite solution was added, followed by work-up to obtain tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:24][CH3:25])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2[OH:23])(=[O:3])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:24][CH3:25])[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:26])[CH:13]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2=[O:23])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(N(CC)CCOC(C)=O)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C)c2ccc(N(CC)CCOC(C)=O)cc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 124.4 %

Procedure:
To a flask containing ethyl 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate (0.17 g) in DMF (5 mL) is added potassium carbonate (0.21 g) and iodomethane (0.05 mL). The reaction is tightly capped and heated to 90° C. After 3 hours, the reaction is cooled to room temperature, diluted with dichloromethane, filtered and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 4% to 8% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.22 g of the title compound as a orange solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH3:17])[C:9]=1[F:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([O:15][C:10]1[C:9]([F:18])=[C:8]([NH2:7])[C:13]([F:14])=[CH:12][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(F)c(NC(=O)OC(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of (3-ethoxy-2,6-difluoro-phenyl)-carbamic acid tert-butyl ester (135 g, 0.525 mol) in a mixture of dichloromethane and 10 equivalents trifluoroacetic acid (598 g, 5.25 mol) was stirred at room temperature for 1 hour and concentrated in vacuo. The pH of the residue was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer is extracted with ethyl acetate (3×250 mL). The organic extracts were combined, washed with a saturated aqueous solution of sodium chloride (2×), dried and concentrated in vacuo. Chromatography of the yellow residual liquid down silica gel using 25:1 hexane:ethyl acetate gave 65 g (66%) of the title compound as oil.
Reaction SMILES: [CH:1](=[C:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[Na].C(OC)(=O)[CH2:14][C:15]([CH3:17])=[O:16]>CO>[CH2:2]([CH:1]1[CH:6]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:17][C:15](=[O:16])[CH2:14]1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC=C1CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: CC(C)CC1CC(=O)C=C2CCCC21
Yield: 52 %

Procedure:
The procedure of Example 1 is repeated with 85 g (0.56 mol) of isopentylidene cyclopentanone, 1.61 g (0.07 g-atom) of sodium, 76.5 g (0.66 mol) of methyl acetoacetate and 300 ml of methanol. Upon distillation there are obtained 56 g (bp 97°-100° C. at 0.5 mm) of 5-isobutylbicyclo [4.3.0]-non-1-en-3-one having the structure: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:25]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][N:26]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:26]2[CH2:27][CH:28]3[CH2:31][CH:25]2[CH2:30][NH:29]3)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCN2CC3CC2CN3)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.2 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid, 1,1-dimethylethyl ester (0.108 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.067 g).
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([OH:16])=O)[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1)[CH3:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([NH:17][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([C:27]#[N:28])([CH3:29])[CH3:30])=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2ncn(CC(=O)O)c12
Reactant: CC(N)c1ccc(C(C)(C)C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)c1cccc2ncn(CC(=O)NC(C)c3ccc(C(C)(C)C#N)cc3)c12

Procedure:
2-(7-acetyl-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide is synthesized according to example 5 by mixing 7-acetyl-1H-benzimidazol-1-ylacetic acid (90.0 mg, 0.413 mmol) prepared according to scheme 4, 2-[4-(1-aminoethyl)phenyl]-2-methylpropanenitrile (77.6 mg, 0.413 mmol) prepared according to scheme 6 and Et3N (125 mg, 1.24 mmol, 0.173 mL) and HATU (157 mg, 0.413 mmol) in dry MeCN (10.0 mL). The product is purified by reverse phase HPLC: Gilson prep pumps; Flow rate: 30 ml/min; Column: Synergi Polar (4μ) 21.2×50 mm; Mobile phase: A=water (0.05% TFA) B=MeCN (49.5 mg, 0.128 mmol, 31.0%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=7.03 Hz, 3H) 1.66 (s, 6H) 2.38 (s, 3H) 4.74-4.87 (m, J=7.23, 7.23 Hz, 1H) 5.14 (s, 2H) 7.26 (t, J=7.81 Hz, 1H) 7.35 (d, J=8.40 Hz, 2H) 7.45 (d, J=8.40 Hz, 2H) 7.71 (d, J=7.62 Hz, 1H) 7.85 (d, J=8.01 Hz, 1H) 8.21 (s, 1H) 8.65 (d, J=7.81 Hz, 1H); MS [M+H] calcd.: 389.19. found: 389.09.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
Under a nitrogen atmosphere, 4.5 mL (0.043 mole) of t-butylamine was added to a solution of 7.7 grams (0.035 mole) of 4-bromobenzoyl chloride in 75 mL of tetrahydrofuran. To this was added dropwise 6.7 mL (0.048 mole) of triethylamine. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 18 hours, after which it was poured into 50 mL of water, and the organic layer was separated. The aqueous layer was extracted with one 50 mL portion of diethyl ether. The combined organic layer and extract were washed with two 25 mL portions of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.4 grams of N-t-butyl-4-bromobenzamide, mp 126-128° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH2:44][OH:45])([CH3:43])[C:24]1=[O:46])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@:25]([CH3:43])([CH:44]=[O:45])[C:24]1=[O:46])[CH2:21][CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one (210 mg, 0.311 mmol; Example 248, Step B) in CH2Cl2 (8 mL) at 0° C. was added NaHCO3 (131 mg, 1.56 mmol) and Dess Martin periodinane (158 mg, 0.373 mmol) in one portion. The reaction was stirred at rt for 2 hours. The reaction was diluted with CH2Cl2 (30 mL) and treated with Na2S2O3 (15 mL, saturated aqueous solution) and NaHCO3 (15 mL, saturated aqueous solution) at rt for 2 hours. The separated aqueous layer was extracted with CH2Cl2 (2×50 mL) and the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo to give the title compound. Mass Spectrum (ESI) m/z=672.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)cc1
Product: CN(C)Cc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 61.4 %

Procedure:
Following general procedure D, 6-bromo-N-(4-((dimethylamino)methyl)phenyl)-3-(methylsulfonyl)quinolin-4-amine (43 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (53 mg, 0.183 mmol) to afford the desired product (31.7 mg, 61%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.00 (s, 1H), 8.06-7.97 (m, 2H), 7.74 (s, 3H), 7.46-7.38 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.13 (s, 2H), 3.86 (s, 2H), 3.27 (s, 3H), 2.45 (s, 6H). ESI MS m/z 516 [C25H23Cl2N3O2S+H]+; HPLC 94.5% (AUC), tR=11.57 min.
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])[CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([N:21]3[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[O:10])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCCC1CCC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (28% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.85, 7.73, 7.57, 7.34, 6.99, 4.05, 3.89-3.65, 3.45, 3.33, 2.27, 1.99, 1.76, 1.58-1.39. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.8, 159.9, 145.4, 134.2, 132.4, 129.5, 127.2, 126.9, 126.7, 112.7, 46.4, 44.6, 44.5, 41.2, 39.4, 35.7, 34.1, 28.3, 27.2, 18.4. MS (ES+) m/z 475.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][NH:9]C(OCC1C=CC=CC=1)=O)([CH3:6])=[O:5])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][P:4]([CH2:7][CH2:8][NH2:9])([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(C)(=O)CCN
Yield: 89.2 %

Procedure:
(2-Benzyloxycarbonylamino-ethyl)-methyl-phosphinic acid ethyl ester (1.3 g, 4.56 mmol) and 10% Pd/C (485 mg) were combined in a flask and EtOH (46 mL) was added. The reaction flask atmosphere was exchanged for H2 and the reaction was run at room temperature until complete, as determined by TLC (eluent: 100% EtOAc). The reaction was then filtered through Supercell NF and the filtrate was concentrated to yield (2-amino-ethyl)-methyl-phosphinic acid ethyl ester (615 mg, 90%) as a yellow oil in which white crystals began to form under high vacuum.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A solution of 0.19 g methyl 4-({3-cyclohexyl-5-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-1-yl}methyl)benzoate from Step C Example 1 in 6 mL ethanol and 2.5 mL water was treated with 2.4 equivalents of 5 N NaOH solution till the hydrolysis was complete based on HPLC. After evaporating ethanol under reduced pressure, the residue was acidified with 20% molar excess of 2 N HCl to precipitate the acid product. Extract the reaction mixture with 2×35 mL EtOAc. Wash the combined organic layer with saturated brine, dry over anhydrous Na2SO4, and evaporate to give the title compound as a white solid. It can be recrystallized from 5:3 MeCN and water to give fine crystalline needles. 1H NMR (CDCl3, 500 MHz) δ 7.89 (d, J=8.3 Hz, 2H), 7.39˜7.42 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.3 Hz, 2H), 6.30 (s, 1H), 5.38 (s, 2H), 2.67 (tt, J=3.5 & 11.5 Hz, 1H), 1.97˜2.01 (m, 2H), 1.80˜1.85 (m, 2H), 1.71˜1.75 (m, 1H), 1.38˜1.53 (m, 4H), 1.26˜1.33 (m, 1H). LC-MS: 2.47 min. (M+H=445.3).
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:38](=[O:63])[C:39]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:40]([CH3:52])[N:41]([CH:43]([C:45]2[CH:50]=[CH:49][C:48](Br)=[CH:47][N:46]=2)[CH3:44])[CH:42]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:38](=[O:63])[C:39]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:40]([CH3:52])[N:41]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([C:1]#[N:2])=[CH:47][N:46]=2)[CH3:44])[CH:42]=1)=[O:36])[CH3:33]
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O

Procedure:
Example 19c is prepared as described for Example 15, substituting preparation 15b with preparation 19b. ESI mass spectrum: [M+H]+=456; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [CH2:1]([O:5][CH:6]=[CH2:7])[CH:2]([CH3:4])[CH3:3].[CH:8]([CH:10]=[CH2:11])=[O:9]>C(C1C=CC(C)=C(O)C=1C(C)(C)C)(C)(C)C>[CH2:1]([O:5][CH:6]1[CH2:7][CH2:11][CH:10]=[CH:8][O:9]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=COCC(C)C
Reactant: C=CC=O
Agent: Cc1ccc(C(C)(C)C)c(C(C)(C)C)c1O
Product: CC(C)COC1CCC=CO1
Reaction time: 16 h
Yield: 88 %

Procedure:
In a 50 L-volume autoclave made of stainless-steel, 16.22 kg of isobutylvinylether (IBVE), 6.97 kg of acrolein (ACR) and 0.08 kg of di-t-butylhydroxytoluene (BHT) were placed and the inside of the reactor was purged with nitrogen. The pressure was increased to 3 MPa with nitrogen and reaction was performed at 135° C. for 16 hours. The yield of 3,4-dihydro-2-isobutoxy-2H-pyran (DHIBP) was 94% (with ACR used as standard). The reaction solution was subjected to distillation, to thereby obtain 17.1 kg of DHIBP (20 kPa/120° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[CH3:27][Mg]Br.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([OH:12])[CH3:27])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
4.0 g (10.2 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of tetrahydrofuran, and 12.3 ml of methyl magnesium bromide (1.0M tetrahydrofuran solution) was dropwise added thereto at -65° C. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.3 g (yield: 55.3%) of the desired product as pale yellow crystals. Melting point: 154-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:42])([CH3:41])[C:39]#[N:40])=[CH:34][CH:33]=1>C(Cl)Cl>[C:39]([C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:37][CH:36]=1)([CH3:42])[CH3:41])#[N:40]
Reactant: CC(C)(C#N)c1ccc(CN)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3ccc(F)c(F)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
(6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (42 mg, 0.2 mmol) prepared according to scheme 2 is dissolved in CH2Cl2 (2 mL). Triethylamine (83 μL, 0.6 mmol) is added, followed by pivaloyl chloride (25 μL, 0.2 mmol). After 30 minutes, 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (35 mg, 0.2 mmol) prepared according to scheme 18 is added dissolved in 1 mL of CH2Cl2. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 40% to 60% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (17 mg, 0.05 mmol, 25%). MS (ESI) (M+1) 383.3. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.65 (s, 6H) 2.30 (s, 3H) 4.29 (d, J=5.47 Hz, 2H) 5.09 (s, 2H) 7.19-7.31 (m, 3H) 7.32-7.35 (m, 1H) 7.47 (dd, J=8.98, 3.91 Hz, 1H) 8.22 (s, 1H) 8.66-8.74 (m, 1H).