Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]([OH:14])=[O:13])[NH2:11])=[C:6]([CH3:15])[CH:5]=1)([OH:3])=[O:2].N[C@@H](C(O)=O)CCCCN>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[C:6]([CH3:15])[CH:5]=1)([OH:3])=[O:2]
Reactant: Cc1cc(C(=O)O)ccc1C(N)C(=O)O
Agent: NCCCC[C@@H](N)C(=O)O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1[C@H](N)C(=O)O

Procedure:
Racemic 2-(4-carboxy-2-methylphenyl)glycine (9.2 g, 44 mmol) and D-lysine (6.43 g, 44 mmol) were dissolved in warm water (60 ml). The solution was filtered to remove trace insolubles and then diluted with methanol (200 ml) and diethyl ether (20 ml). An initial precipitate was removed by filtration and the filtrate allowed to stand. After 6 hours the supernatant was decanted from solid and the solid washed with methanol. The solid was then re-crystallised twice from water-methanol and the resulting crystals washed with water-methanol (1:1), methanol and diethyl ether. The white crystals were dried in vacuo, dissolved in water and chromatographed on ion exchange (Dowex 50×8-100 resin). The column was eluted with water, and 10% pyridine in water, fractions collected from the pyridine-water elution were combined and evaporated to dryness. The product was partially dissolved in water and freeze-dried [α]D26 at 147° C. (C=0.26) in aqueous hydrochloric acid (5M).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH3:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC1CCN(C(C)=O)CC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1CCC(NCCc2ccccc2)CC1
Yield: 65 %

Procedure:
A mixture containing 0.5 mol of the compound obtained in Stage A of Example 19, 0.5M benzyl chloride and 1M sodium carbonate in 650 ml of ethanol is refluxed for one night. The precipitate formed is filtered off, the solvent is evaporated, the evaporation residue is taken up in 1N hydrochloric acid and extracted with diethyl ether, and the ethereal extract is rendered basic with sodium hydroxide solution and extracted with ethyl acetate to obtain the desired compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:3]([CH3:12])[CH:4]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)c(C)c1
Temperature: 140 °C
Yield: 40.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (5.0 g, 4.33 mmol) was added to a stirred solution of methyl 4-bromo-3-methylbenzoate (9.93 g, 43.3 mmol), tert-butyl acrylate (50 ml, 341.3 mmol) and sodium acetate (35.8 g, 436.4 mmol) in DMA (350 ml). The mixture was heated at 140° C. for 5 h, filtered through Celite® filter agent and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc, washed with 0.3M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane to 20% EtOAc:80% hexane) to yield the title compound (4.81 g, 40%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[N:21][CH:20]=1.NC1N=CC=CN=1.[ClH:51]>C1COCC1.CO.C(O)(=O)C>[ClH:51].[Br:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)(=[O:31])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[N:21][CH:20]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cncc2c1
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: Nc1ncccn1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cncc2c1
Reaction time: 0.25 h
Yield: 24.29 %

Procedure:
To a flask containing ice cold suspension of pyrimidin-4-amine (0.402 g, 4.23 mmol) in THF (5.42 ml) was added lithium bis(trimethylsilyl)amide (1M in THF) (1.550 ml, 1.550 mmol) drop wise over 10 min. The mixture was stirred for 15 min providing a white suspension. A solution of perfluorophenyl 4-bromoisoquinoline-7-sulfonate (0.640 g, 1.409 mmol) in THF (5.0 ml) was added drop wise and the resulting mixture stirred for 1 hr. To the solution was added acetic acid (500 μl) and the solution dried under reduced pressure. The crude material was purified with a 40 g HP Silicycle column (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 25%) to elute starting material, then MeOH in DCM (0 to 20%) providing product which had coeluted with aminopyrimidine. The mixture was purified with a 10 g PE-AX column (Biotage AB, Uppsala, Sweden) washing with MeOH, then about 3% HCl in MeOH to provide 4-bromo-N-(pyrimidin-4-yl)isoquinoline-7-sulfonamide (Intermediate OOOO) (0.125 g, 0.342 mmol, 24.29% yield) as a white solid (possibly HCl salt). m/z (ESI) 365.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][S:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9]O[CH2:7][CH2:6]1)=[O:4].[CH3:16]OC(C1(CI)CCCCC1)=O>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9][CH2:16][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CSC(C)=O)CCOCC1
Reactant: COC(=O)C1(CI)CCCCC1
Product: COC(=O)C1(CSC(C)=O)CCCCC1
Yield: 92 %

Procedure:
Prepared according to the method for the preparation of 4-acetylsulfanylmethyltetrahydropyran-4-carboxylic acid methyl ester, from 1-iodomethylcyclohexanecarboxylic acid methyl ester (20 g), to yield the title compound as a brown gum (15 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][NH2:11])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NN)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) in THF (25 mL) at room temperature under argon was added H2NNH2 (0.64 g, 20.0 mmol). The reaction mixture was stirred at room temperature under argon overnight. Analysis by HPLC/MS indicated that the reaction was complete. The solvent was evaporated, and the residue was coevaporated with toluene (2×5 mL) then THF (5 mL), and then dried under vacuum. The crude title compound was used directly in the next step. HPLC/MS: retention time=0.77 min.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[Cl:16][C:17]1[CH:18]=[N:19][C:20]([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[N:21][CH:22]=1>>[Cl:16][C:17]1[CH:18]=[N:19][C:20]([CH:23]2[CH2:27][CH2:26][N:25]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:24]2)=[N:21][CH:22]=1
Reactant: Clc1cnc(C2CCNC2)nc1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Product: O=C(OC1C2CC3CC1CC(O)(C3)C2)N1CCC(c2ncc(Cl)cn2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 Step 1 using 1-hydroxy-4-adamantyl chloroformate solution and 5-chloro-2-(pyrrolidin-3-yl)pyrimidine. Two isomers were separated by prep HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].NCC(O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: NCC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloro-1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalene-3-carboxylate (0.165 g, 0.54 mmol) was dissolved in 1,4-dioxane (30 mL), and glycine tert-butyl ester hydrochloride (0.090 g, 0.54 mmol) and TEA (TEA) (0.11 mL, 0.81 mmol) were added. The reaction was stirred overnight at 70° C. The reaction was stirred for 18 hours. Another 0.5 equivalents of glycine and one equivalent of TEA were added, and the reaction was stirred at 105° C. for 1 hour. The solvent was then removed, and the crude residue was dissolved in EtOAc and washed with water (3×25 mL), dried with MgSO4, and concentrated. The crude product was purified by silica flash chromatography using the 10-50% EtOAc/hexanes. MS m/e=392 (M+H)+.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:8]1[CH:9]=[CH:10][C:2]2[C:1]([C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:17][CH:16]=3)([C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:17][CH:16]=3)[O:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1ccccc1
Product: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21

Procedure:
Phenolphthalein is synthesized by standard methods involving a condensation reaction with phthalic anhydride and phenol under appropriate reaction conditions. Substituted phenolpthalein derivatives are obtained from the correspondingly substituted phthalic anhydride and in a similar manner.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>CN1CCCC1=O>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CN1Cc2ccnc(Cl)c2C1=O
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nccc3c2C(=O)N(C)C3)c(OC)c1

Procedure:
A solution of 4-chloro-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 310E, 1.5 g, 8.2 mmol) in N-Methylpyrrolidinone (20 mL) was charged with 2,4-dimethoxy benzylamine (2.5 mL, 16 mmol) and irradiated in the microwave for 40 min at 160° C. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (20 mL). The aqueous layer was back-extracted with EtOAc (3×10 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a red solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using Heptane/EtOAc (70:30→0:100) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an orange solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.10 (d, J=5.30 Hz, 1H), 7.11 (d, J=8.34 Hz, 1H), 7.01-7.07 (m, 1H), 6.72 (d, J=5.31 Hz, 1H), 6.57 (d, J=2.27 Hz, 1H), 6.44 (dd, J=2.53, 8.34 Hz, 1H), 4.53 (d, J=6.06 Hz, 2H), 4.37 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 2.98 (s, 3H). MS (ES+): m/z 314.14 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1>>[Cl:22][C:21]1[C:16]([O:14][C:10]2[CH:9]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=[CH:12][CH:11]=2)=[N:17][CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Product: CN1CCN(c2cccc(Oc3ncc([N+](=O)[O-])cc3Cl)c2)CC1

Procedure:
3-(4-Methylpiperazin-1-yl)phenol was reacted with 2,3-dichloro-5-nitro pyridine (as obtained in preparation 1), to obtain 1-(3-(3-chloro-5-nitropyridin-2-yloxy)phenyl)-4-methylpiperazine which was further converted to the title compound as per the procedure described in preparation 2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](C=O)=[CH:13][CH:12]=1)[CH3:2].CO[CH:22]([O:25][CH3:26])[O:23][CH3:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:22]([O:23][CH3:24])[O:25][CH3:26])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCOc1ccc(C=O)cc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3 (424 g, 1.60 mol), trimethylorthoformate (0.37 L, 3.40 mol) and p-toluenesulfonic acid monohydrate (15 g, 79 mmol) in MeOH (1 L) was stirred for 5 h at room temperature. Triethylamine (11 mL, 79 mmol) was added, the resulting solution was concentrated in vacuo, diluted with EtOAc (2 L) and subsequently washed with H2O (2×1 L) and saturated aqueous NaCl (1×1 L). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield an amber liquid (4, 481 g, 1.55 mol, 97%) with no need for further purification: 1H-NMR (400 MHz, CDCl3) δ=7.33 (d, J=8.7, 2H), 6.97 (d, J=8.7, 2H), 5.33 (s, 1H), 4.11 (q, J=7.1, 2H), 3.95 (t, J=6.4, 2H), 3.29 (s, 6H), 2.32 (t, J=7.4, 2H), 1.79 (m, 2H), 1.69 (m, 2H), 1.49 (m, 2H), 1.24 (t, J=7.1, 3H); 13C-NMR (400 MHz, CDCl3) δ=173.7, 159.3, 130.4, 128.0 (2C), 114.2 (2C), 103.2, 67.8, 60.4, 52.7 (2C), 34.4, 29.1, 25.8, 24.8, 14.4; IR(film) ν=2937, 1723, 1610, 1513, 1241, 1171, 1104, 1046, 980, 828 cm−1; HRMS (MALDI-FTMS) not detectable due to instability; detected: m/z 287.1254 (287.1252 calculated for parent aldehyde 3 C17H27O5Na, (M+Na)+).
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:26])[C:24]=2[CH3:25])[CH2:3]1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:25][C:24]1[C:23](=[O:26])[O:22][CH2:21][C:20]=1[N:4]1[CH2:3][C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:5]1=[O:19]
Reactant: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=C(N2CC(=O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reaction time: 1.5 h

Procedure:
To tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (see example I-37A and I-37B, Step C, racemate prior to chiral HPLC separation) (200 mg, 0.546 mmol) in DCM (2.8 mL) was added sodium bicarbonate (68.8 mg, 0.819 mmol) and Dess-Martin periodinane (347 mg, 0.819 mmol). The reaction mixture was vigorously stirred for 1.5 h, then quenched with 10% Na2S2O3 and NaHCO3 aqueous solutions, and stirred for 20 min. The aqueous layer was extracted with DCM, and the organic layers were washed with brine, dried, and concentrated to give tert-butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1,4-dioxo-2,8-diazaspiro[4.5]decane-8-carboxylate. LC/MS: [(M+1)]+=365
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[O:7][C:5]1=O)[CH:2]=[CH2:3].[Na].[N:12]1C=C[CH:15]=[CH:14][CH:13]=1>C(OCC)C>[CH2:13]([N:12]1[C:8](=[O:10])[CH2:9][CH:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:7])[CH:14]=[CH2:15]
Reactant: c1ccncc1
Reactant: C=CCC1CC(=O)OC1=O
Agent: [Na]
Solvent: CCOCC
Product: C=CCC1CC(=O)N(CC=C)C1=O
Reaction time: 2 h
Yield: 89.9 %

Procedure:
About 140 g (1 mol) of allylsuccinic anhydride and 250 ml of diethyl ether which has been dried over metallic sodium are placed under nitrogen in a round-bottomed flask equipped with a stirrer, dropping funnel and reflux condenser, and then mixed with 75 g (0.95 mol) of pyridine. About 57 g of allylamine in 100 ml of diethyl ether which has been dried over metallic sodium are then added dropwise to the flask with stirring over a period of 2 hours. When the addition is complete, the mixture is refluxed for an additional 1 hour. The resultant mixture is washed in a separating funnel with 5 percent aqueous hydrochloric acid until the pH of the aqueous phase is 6.5. The organic phase is dried over magnesium sulfate. After filtering off the drying agent, the solvent is removed at 15 hPa (abs.). About 153 g of N-allyl-allylsuccinimide, which boils at 130° C. at 0.5 hPa, are obtained from the residue by distillation.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:27])[CH2:26][NH:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:23]([F:27])([F:22])[CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=360.4 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-chlorophenylboronic acid (51 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([Cl:19])[CH:21]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(Cl)c(Cl)c3)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 20.95 g of 3,4-dichlorobenzoyl chloride there is obtained 4-(3,4-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 95°-96°.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:28]1[NH:29][C:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:43][CH3:44])[CH:39]=3)[CH:34]=2)=[CH:31][NH+:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:45][N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CCOC(C)=O>[CH3:44][O:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([C:30]1[NH:29][C:28]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:46][CH3:45])=[O:26])=[N:32][CH:31]=1)[CH:42]=[CH:41]2
Reactant: COc1ccc2cc(-c3c[nH+]c([C@H](CCCCCC(=O)O)NC(=O)OCc4ccccc4)[nH]3)ccc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2ccc3cc(OC)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of E2 in DMF (0.1 M) were added HATU (1.5 eq.) and DIPEA (2.0 eq.) followed after 10 min by methylamine (2.0 M solution in THF, 5 eq.). Reaction mixture was stirred at room temperature for 16 h, then it was diluted with EtOAc, washed with sat. aq. NaHCO3 sol., brine, dried over Na2SO4, filtered and concentrated to give a dark brown residue. The resulting crude was purified by column chromatography (eluent: petroleum ether/EtOAc from 9:1 to 100% EtOAc, then EtOAc/MeOH=95:5) to give the title compound as a colorless oil. MS (ES+) C30H34N4O4: 515 (M+H)+.
Reaction SMILES: CC(C)([S@@]([NH:6][C@:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:10])=O)C.Cl.O1CCOCC1>CO>[NH2:6][C@:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: Cc1cccc(NC(=O)C[C@@](C)(N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(NC(=O)C[C@@](C)(N)c2ccccc2)c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of (R)-3-((S)-1,1-dimethylethylsulfinamido)-3-phenyl-N-m-tolylbutanamide (300 mg, 0.81 mmol) in MeOH (5 mL) was added 4M HCl/dioxane (3 mL, 12 mmol). The solution was stirred for 1 h and concentrated to give (R)-3-amino-3-phenyl-N-m-tolylbutanamide (218 mg, 90%) without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([S:28]([CH2:27][CH2:26][CH3:25])(=[O:30])=[O:29])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: CCCS(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 3-chloropropane-1-sulfonyl chloride
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1.[CH3:53][C:54]([OH:59])([CH3:58])[CH2:55][NH:56][CH3:57]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:56]([CH2:55][C:54]([OH:59])([CH3:58])[CH3:53])[CH3:57])=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1
Reactant: CNCC(C)(C)O
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(CC(C)(C)O)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1

Procedure:
HATU coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with 2-methyl-1-(methylamino)propan-2-ol. White solid. Yield: 110 mg