Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=O)[CH:3]=1.[CH2:16]([NH:18][C:19](=[O:32])[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)[CH3:17]>>[CH2:16]([NH:18][C:19](=[O:32])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:27][CH2:28][N:29]([CH2:14][C:4]3[CH:3]=[C:2]([OH:1])[C:7]4[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=4[CH:5]=3)[CH2:30][CH2:31]2)=[CH:24][CH:25]=1)[CH3:17]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc(O)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 359A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 3H) 1.37 (d, J=6.82 Hz, 3H) 2.90-3.13 (m, 4H) 3.13-3.24 (m, 2H) 3.33 (br. s., 2H) 3.92 (d, J=12.63 Hz, 2H) 4.16 (br. s., 2H) 4.57 (q, J=6.65 Hz, 1H) 6.43 (d, J=1.77 Hz, 1H) 6.57 (d, J=1.52 Hz, 1H) 6.94 (d, J=8.84 Hz, 2H) 7.70 (d, J=8.84 Hz, 2H) 8.18 (t, J=5.43 Hz, 1H) 9.66 (d, J=9.35 Hz, 1H) 10.75 (s, 1H). ESI-MS: m/z 425.4 (M+H)+.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][O:10][C:11](=[O:33])[CH2:12][C:13]1[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:18]=1.ICCC.[Cl-].[NH4+]>C1COCC1.O.CCOC(C)=O>[CH3:9][O:10][C:11](=[O:33])[CH:12]([C:13]1[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)cc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCI
Solvent: O
Product: CCCC(C(=O)OC)c1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
A solution of LDA (0.18 mL of 1.8 M in THF, 0.31 mmol) was added dropwise to a stirred solution of (4,4″-dichloro-[1,1′;3′,1″]terphenyl-5′-yl)-acetic acid methyl ester (100 mg, 0.26 mmol) in THF (10 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. before iodopropane (0.035 mL, 0.31 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. A saturated aqueous solution of ammonium chloride (10 mL) was carefully added and the residue was partitionned between EtOAc and water. The aqueous layers were extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) yield 70 mg (66%) 1H NMR (CDCl3) δ 7.60 (t, 1H), 7.55 (d, 4H), 7.48 (d, 2H), 7.42 (d, 4H), 3.65-3.72 (m, 4H), 2.11-2.23 (m, 1H), 1.78-1.89 (m, 1H), 1.28-1.40 (m, 4H), 0.94 (t, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCCNCC2)nn1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-[1,4]diazepan-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (60% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]SC1C(C2C=NC=CC=2)=NNC=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH2:18][N:19]([CH3:23])[CH2:20][CH2:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(#Cc1c[nH]nc1-c1cccnc1)CCCC1CCCCC1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CN1CCC=C(c2n[nH]cc2C#CCCCC2CCCCC2)C1
Yield: 90 %

Procedure:
Compound 44E was converted to compound 45E, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 90% (amorphous). LCMS (method A); Rt: 2.28 min, ([M+H]+=312). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.76-6.71 (bs, 1H), 3.41-3.37 (m, 2H), 2.59 (bt, J=7 Hz, 2H), 2.45-2.35 (m, 7H), 1.75-1.55 (m, 6H), 1.35-1.10 (m, 7H), 0.94-0.8 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=O.C(O)(=O)C.[CH:19](N)=[NH:20]>C(OCCO)C>[C:11]([C:7]1[S:6][C:5]2[C:3]([OH:2])=[N:20][CH:19]=[N:10][C:9]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: N=CN
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Solvent: CCOCCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2ncnc(O)c2s1
Yield: 99.3 %

Procedure:
3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.00 g, 4.69 mmol, 1 eq.), formamidine acetate (1.46 g, 4.69 mmol, 3 eq.) and 2-ethoxyethanol (10 mL) were refluxed under nitrogen for 4 hours. Purified over silica gel in 3:1 to 1:1 Hexanes/ethyl acetate to 100% ethyl acetate to obtain 970 mg of yellow solids as product. LCMS detects (M+H)+=209.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].C1(C)C=CC=CC=1.Cl[CH2:20][C:21](=[O:23])[CH3:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:20][C:21](=[O:23])[CH3:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 88.5 %

Procedure:
To a 100 ml volume three-necked flask, sodium p-toluenesulfinate (20-a) (9.25 g), tetrabutylammonium bromide (1.65 g), toluene (29 g), and chloroacetone (21-a) (5.0 g) were added, and stirred at 65° C. for 1.25 hours. To the mixture, water (10 g) was added, and stirred for 4 hours. After the mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted with toluene 2 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (chloroform: ethyl acetate=20:1) to give 9.749 g of 1-(4-methylphenylsulfonyl)-2-propanone (7-2-4).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.Cl.[NH2:58][CH:59]([C:65]([F:68])([F:67])[F:66])[CH2:60][C:61]([O:63][CH3:64])=[O:62]>CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:58][CH:59]([C:65]([F:66])([F:67])[F:68])[CH2:60][C:61]([O:63][CH3:64])=[O:62])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CC(N)C(F)(F)F
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CC(NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
750 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A (2.36 mmol, 1 equivalent) were initially charged in 15 ml of DMF, and 2.24 g of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU, 5.89 mmol, 2.5 equivalents) and 1.03 ml of N,N-diisopropylethylamine (0.76 g, 5.89 mmol, 2.5 equivalents) were added. The mixture was stirred at 60° C. for 20 min, 0.98 g of methyl 3-amino-4,4,4-trifluorobutanoate hydrochloride (Example 22A, 4.71 mmol, 2 equivalents) was added and the mixture was stirred at 60° C. overnight. The mixture was then added to 120 ml of water and stirred at RT for 30 min. The precipitated solid was filtered off, washed with 6 ml of diethyl ether and dried under reduced pressure. The residue was then concentrated on a silica gel column (mobile phases: dichloromethane/ethyl acetate 10:1). This gave 0.32 g (29% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:12][C:13](=[O:15])[O:18][C:17](=[O:19])[CH2:16]2)=[CH:6][CH:7]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)CC(CCCc1ccc(O)cc1)CC(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CCCC2CC(=O)OC(=O)C2)cc1

Procedure:
3-[3-(4-Hydroxyphenyl)propyl]glutaric acid (533 mg) is reacted with acetic anhydride as described in Example 1C to afford 3-[3-[4-(acetyloxy)phenyl]propyl]glutaric anhydride, melting point 55°-57° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)(=O)C.O=[Pt]=O>[CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCCC(=O)O)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)C1CCC(CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 107.9 %

Procedure:
A suspension of compound 77 (1.0 g, 4.8 mmol) and 0.1 g of PtO2 in 50 mL of acetic acid was stirred under a H2 atmosphere (50 psi) at ambient temperature for 6 hours. After filtering and evaporating off the solvent, 1.1 g crude product was obtained. The compound was used directly in the next step without further purification. LC-MS m/z 211 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10](=[N:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:9])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Yield: 42.2 %

Procedure:
While a solution of 2.43 g 5-bromo-2-fluorophenylamine (compound in Production Example 335), 2.6 g benzophenone and 122 mg 4-toluenesulfonic acid in 50 ml toluene was azeotropically dehydrated, the mixture was heated for 6 hours under reflux. The reaction mixture was diluted with ethyl acetate and washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.91 g of the title compound (colorless oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH:9](CC(N)=O)[NH:8][CH2:7][CH2:6]2.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1c(C)c2c(c(C)c1OC)C(CC(N)=O)NCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(C)c1OC)CNCC2
Yield: 36.8 %

Procedure:
6,7-Dimethoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline acetamide (396 mg) was dissolved in 1,4-dioxane (10 ml). NaOH (10 ml, 2M aq.) was added and the mixture was refluxed for 21 h. Organic solvents were evaporated and the aq. residue was extracted with dichloromethane (4×20 ml). Combined organics were dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography using EtOAc/MeOH/Et3N (20/2/1→16/4/1) as eluent to give 116 mg (42%) of 6,7-dimethoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline as a clear, oily residue.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)S[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(C2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3N=2)C=CC=CC=1>>[C:14]1([NH:13][C:12]2[CH:7]=[CH:8][C:9]([NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:24]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
phenothiazine, 2-phenyl-benzimidazole
Reaction SMILES: O.[CH2:2]([NH2:6])[CH2:3][CH2:4][CH3:5].[C:7](OC)(=[O:10])[C:8]#[CH:9].[Na+].[Cl-]>C(O)(=O)C>[CH2:2]([NH:6][C:7](=[O:10])[C:8]#[CH:9])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CC(=O)NCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 30 mL of water and 7.3 g (100 mmol) n-Butylamine is added dropwise 8.4 g (100 mmol) methyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (12.0 g, yield 96%, purity 96% by GC).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:17])[CH2:15][OH:16])=[CH:10][CH:9]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Cl-].[NH4+]>O1CCCC1>[OH:16][CH2:15][C@@H:14]([NH:17][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N[C@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
Following the literature procedure (Panek, J., J. Org. Chem., 1998, 63, 2382), triethylamine (6.2 ml, 44.5 mmole) was added to a solution of (S)-phenylglycinol (5 g, 36.45 mmole) in anhydrous tetrahydrofuran (150 ml) under argon at 0° C. After stirring for 15 min, tert-butyl bromoacetate (5.9 ml, 39.96 mmole) was added slowly to this cooled solution. The resulting mixture was warmed to room temperature, and stirred for 15 h. Saturated ammonium chloride aqueous solution was added, and the aqueous layer was extracted with diethyl ether (3 times). The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The resulting solid was recrystallized from a diethyl ether/n-hexane mixture to give tert-butyl (S)-(2-Hydroxy-1-phenyl-ethylamino)-acetate as a white solid (3 g, 33%).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=O)CC)(=[O:11])[CH2:9][CH3:10].CN([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]N=1)C.C(C(CC)C=O)C>CCCCCC.O>[C:8]([O:12][CH:13]=[C:24]([CH2:25][CH3:20])[CH2:23][CH3:22])(=[O:11])[CH2:9][CH3:10]
Reactant: CN(C)c1ccccn1
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(C=O)CC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: CCC(=O)OC=C(CC)CC
Temperature: 70 °C

Procedure:
A reaction vessel was charged sequentially with Et3N (12.8 L), propionic anhydride (14.48 L), dimethylaminopyridine (94 gm) and 2-ethylbutyraldehyde (7.5 L). The mixture was stirred and heated under gentle reflux (120°-135° C.) for 5 hours in a nitrogen atmosphere. The reaction was then cooled to 70° C. and H2O (13.5 L) was added slowly. On complete addition, the mixture was heated at reflux for 45 minutes and then cooled to room temperature before hexane (7.5 L) was added. The aqueous layer was separated and re-extracted with hexane (5 L) and the combined organic layers were washed with saturated NaHCO3 (2×7.5 L) before being evaporated in vacuo at 40° C. The residue (10 Kg) so obtained was fractionally distilled (b.p. 75°-80° C., 30-40 mm Hg) to give the required product (7.712 Kg) as a mobile liquid.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[C:37]([S:40]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:42])=[O:41])[S:38][CH:39]=1)([O-:34])=[O:33]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1csc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
The 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol hydrochloride (306 mg, 0.84 mmol, Example 91, Step 1) was dissolved in CH2Cl2 (20 mL) and the solution was chilled to 0° C. To this solution was added triethylamine (292 μL, 2.10 mmol) followed by 4-nitrothiophene-2-sulfonyl chloride (210 mg, 0.923 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. Afterwards, the mixture was filtered and concentrated, the filtrate was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 2-(4-(4-((4-nitro-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (86 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+](=[CH2:19])=[N-].CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+]>O1CCCC1.C(OCC)C.C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:19][CH:12]2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc(OC(C)=O)cc1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CC1c1ccc(OC(C)=O)cc1
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of methyl (2E)-3-[4-(acetyloxy)phenyl]acrylate (2.20 g, 10.0 mmol) in tetrahydrofuran (200 mL) was stirred under ice-cooling, and a solution of diazomethane, prepared from N-methyl-N′-nitro-N-nitrosoguanidine (50% water-containing product, 7.50 g, 51.0 mmol) and aqueous potassium hydroxide (6.28 g, 112 mmol) solution (10.5 mL), in diethyl ether (75 mL) and palladium(II) acetate (0.150 g, 0.668 mmol) were alternately added thereto over 10 min in small portions. The reaction mixture was stirred for 2 hr under ice-cooling, and acetic acid (3 drops) was added. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (2.26 g, yield 97%) as a colorless oil.
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)(=[O:6])[O:3][CH2:4][CH3:5]>C(O)C.[Pd]>[CH3:1][P:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])(=[O:6])[O:3][CH2:4][CH3:5]
Reactant: CCOP(C)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOP(C)(=O)c1ccccc1N

Procedure:
A solution of ethyl P-methyl-2-nitrophenylphosphinate (10 mmol) in ethanol (40 ml) containing 10% palladium on carbon (200 mg) is hydrogenated at atmospheric pressure. After cessation of hydrogen uptake, the mixture is filtered and evaporated to dryness to give ethyl P-methyl-2-aminophenylphosphinate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[CH:4][C:3]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)c(Cl)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Benzyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (20.8 g, 54.7 mmol) and N-chlorosuccinimide (8.04 g, 60.2 mmol) were dissolved in N,N-dimethylformamide (339 mL) and allowed to stir overnight. The reaction was diluted with water, extracted with diethyl ether, washed with saturated aqueous sodium chloride then dried over MgSO4, filtered and the solvent evaporated. The mixture was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give an orange oil (13.7 g, 62%). 1H NMR (400 MHz, CDCl3): δ 7.34 (m, 5H), 6.95 (s, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.0 Hz, 2H), 5.18 (d, J=12.1 Hz, 1H), 5.10 (d, J=12.3 Hz, 1H), 4.98 (d, J=8.2 Hz, 1H), 4.71 (d, J=5.3 Hz, 1H), 4.54 (m, 1H), 3.97 (m, 2H), 2.96 (m, 2H), 1.43 (s, 9H); LCMS found for C21H25ClN2NaO4 (M+Na)+: m/z=427.0.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](C)[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.[C:36](O)(C(F)(F)F)=O>C(Cl)Cl>[O:34]=[C:22]1[CH2:23][C:24]([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([CH3:36])[CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1
Solvent: ClCCl
Product: Cc1cccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methyl-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K15) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (145 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.O[CH:13]([CH3:20])[C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16].[Cl-].[Na+]>ClCCl.ClC.CCCCCC>[Br:1][CH2:19][C:14](=[CH:13][CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C(=O)OC)C(C)O
Agent: CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC=C(CBr)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
8.0 g (46 mmoles) of N-bromosuccinimide were dissolved in 60 ml of dry dichloromethane and were cooled to 0° C. To the mixture were added drop by drop 4 ml (50 mmoles) of dimethyl sulphide dissolved in 40 ml of chloromethane. The mixture was stirred for 10 minutes at 0° C. At the end of that time 5.46 (42 mmoles) of a solution of methyl 3-hydroxy-2-methylidene-butanoate in 40 ml of dichloromethane were slowly added to it. The resulting suspension was stirred for 24 hours at room temperature until a transparent solution was obtained. To this mixture was added n-hexane (100 ml) and it was poured into a separating funnel containing 200 ml of a saturated solution of sodium chloride and ice. The organic phase was washed with 100 ml of a saturated solution of sodium chloride. The aqueous phases were extracted with diethyl ether (2×100 ml), they were washed with water (3×100 ml) and they were dried over anhydrous sodium sulphate. They were vacuum concentrated giving 7.45 g (92% yield) of a syrupy liquid of methyl 2-bromomethyl-2-butanoate.