Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:12]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].CCN(C(C)C)C(C)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].Cl>ClCCCl>[CH3:18][C:14]1([CH3:17])[C:15](=[O:16])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:9])[CH3:10])=[C:2]([NH:1][C:38](=[O:39])[CH2:37][Cl:36])[CH:3]=2)[C:12](=[O:26])[N:13]1[CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1N
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1.37 mg (3.89 mmol) 3-(3-amino-4-isopropyl-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione and 528 mg (4.08 mmol) Hünig's base were dissolved in 50 ml 1,2-dichloroethane. The mixture was cooled to −20° C. and treated with a solution of 439 mg (3.89 mmol) chloroacetylchlorid in 20 ml 1,2-dichloroethane. After stirring 1 h at 0° C., 25 ml ethanolic hydrochloric acid were added and the mixture evaporated to dryness. The raw material, containing huening's base hydrochloride was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16](=[O:29])[C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:30][CH3:31].[CH3:32][Si](Cl)(C)C>CO>[CH3:32][O:14][C:13](=[O:15])[CH2:12][NH:11][C:8]1[O:9][C:10]2[C:2]([OH:1])=[C:3]([O:30][CH3:31])[CH:4]=[CH:5][C:6]=2[C:7]=1[C:16](=[O:29])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cc(C(=O)c2c(NCC(=O)O)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Solvent: CO
Product: COC(=O)CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
[7-hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-ylamino]acetic acid (30 mg, 0.07 mmol) was dissolved in dry methanol (5 mL) and trimethylsilyl chloride (100 μL) was added to it. The reaction was stirred at room temperature for 6 hours (monitored by tlc). Solvent was distilled under vacuum and the crude was purified over silica gel plate to afford the title compound as yellow solid (23 mg, 79%); 1H NMR (300 MHz, CDCl3) δ 9.11(b, 1H, NH), 6.97(s, 2H, benzoyl Hs), 6.62(d, 1H, J=8.56 Hz), 6.51(d, 1H, J=8.49 Hz), 4.42(d, 1H, J=6.09 Hz), 3.91(s, 3H, OMe), 3.86(s, 3H, OMe), 3.84(s, 6H, 2×OMe), 3.81(s, 3H, OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:29])=O.C1[CH2:36][O:35][CH2:34]C1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:23])([F:25])[F:24])[CH:16]=2)(=[O:13])=[O:14])[CH2:34][O:35][CH3:36])[C:5]([C:8]([Cl:29])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (100 mg, 0.24 mmol), oxalyl chloride (2 N in DCM, 0.24 mL, 0.48 mmol), TEA (0.064 mL) in THF (1 mL) was stirred at RT for 2 hours and then evaporated to dryness to give 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[C:9]([CH:10]=O)[C:8]([O:13][CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][C@@H:16]1[C@H:21]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]2[CH2:35][CH2:36][C@H:17]1[C@@H:18]([C:37]([NH2:39])=[O:38])[CH2:19]2.C(Cl)[Cl:41]>>[ClH:41].[ClH:41].[C:29]1([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:21]2[N:20]3[CH2:35][CH2:36][C@@H:17]([C@@H:18]([C:37]([NH2:39])=[O:38])[CH2:19]3)[C@@H:16]2[NH:15][CH2:10][C:9]2[CH:12]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[O:13][CH3:14])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)[C@H]1CN2CC[C@@H]1[C@H](N)[C@@H]2C(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: COc1ccc(S(C)(=O)=O)cc1C=O
Product: COc1ccc(S(C)(=O)=O)cc1CN[C@H]1[C@H]2CCN(C[C@@H]2C(N)=O)[C@H]1C(c1ccccc1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A mixture of 5-methylsulfonyl-o-anisaldehyde (364 mg,1.7 mmol), (3R,4S,5S,6S)-5-amino-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide (500 mg, 1.50 mmol) and NaBH(Oac)3 (636 mg, 3.0 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 hr. The reaction mixture was extracted with CH2Cl2 (300 ml), washed with NaHCO3 aqueous solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography. The resulted product was diluted with HCl/methanol (15 ml), stirred for 30 min and the white precipitate (appeared during the reaction) was collected by filtration to afford a titled compound (589 mg, 58.2%) as a white crystalline.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:28]([NH:32][C:33]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1)=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: CCCCN=C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCNC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate, 0.061 ml (0.548 mmol) of butyl isocyanate and 5 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. The residue is digested in 5 ml of boiling methanol, cooled to 5° C. and filtered, yielding 3-[4-(n-butylamino-carbonylamino-methyl)-phenylamino]-4-(3-chloro-phenyl-amino)-1H-pyrazolo[3,4-d]pyrimidine; m.p. 217-218° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.Cl.Cl.[F:25][C:26]([F:37])([F:36])[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:35][CH:32]3[CH2:33][CH2:34][CH:29]([O:28][CH2:27][C:26]([F:25])([F:36])[F:37])[CH2:30][CH2:31]3)[N:10]=2)[CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reactant: NC1CCC(OCC(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: NC(=O)c1cnc(NC2CCC(OCC(F)(F)F)CC2)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 22.36 %

Procedure:
To a stirring solution of 4-((1R,3S)-3-hydroxycyclohexyl-amino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (440 mg, 1.400 mmol; synthesis described herein) and bis-4-(2,2,2-trifluoroethoxy)-cyclohexanamine trihydrochloride (529 mg, 2.099 mmol) in DMSO (6.964 mL) was added DIEA (0.978 mL, 5.60 mmol). The resulting mixture was allowed to stir overnight at 100° C. The crude reaction mixture was concentrated, purified by silica gel chromatography (0-10% methanol/dichloromethane), and then purified by reversed-phase silica gel chromatography (methanol/water with 0.1% formic acid modifier). The product containing fractions were neutralized and concentrated to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-(2,2,2-trifluoroethoxy)cyclohexyl-amino)pyrimidine-5-carboxamide (135 mg, 0.313 mmol, 22.36% yield) as a mixture of 2 stereoisomers. MS (ESI) m/z 432.2 [M+H]+. This mixture was separated using chiral super-fluid chromatography (AD-H column) to afford 87.8 mg (0.203 mmol) of a single, faster eluting, stereoisomer (PEAK 1) and 24.2 mg (0.056 mmol) of a second single, slower eluting, stereoisomer (PEAK 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C>[C:20]([O:19][CH:12]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: COC=Cc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Product: COC=Cc1ccc(C(OC(C)=O)c2ccccc2)cc1

Procedure:
By the method of example 48, 1-bromo-4-(2-methoxyethenyl)benzene is lithiated and added to benzaldehyde. The crude product is acetylated with acetic anhydride in the presence of DMAP, providing alpha-(4-(2-methoxyethenyl)phenyl)benzyl acetate as a colorless oil. This ester (1.76 g) is treated with methanesulfonic acid (0.5 ml) in methanol (25 ml) at 50° for 16 hr. The acetoxy group and the enol ether are both solvolyzed in this reaction. The mixture is cooled, poured into saturated aqueous sodium bicarbonate, and extracted with three portions of ether, which are dried and evaporated to leave 1-(2,2-dimethoxyethyl)-4-((methoxy)(phenyl)methyl)benzene as a colorless oil (1.62 g). The methoxy group is hydrogenolyzed by dissolving this material in ethyl acetate (100 ml), and shaking with 10% Pd/C under 50 psi hydrogen for 60 hr. Filtration and evaporation provide 1-(2,2-dimethoxyethyl)-4-(phenylmethyl)benzene as a colorless oil (1.46 g). By the method of example 1(B&C), this is converted into the title compound, which is obtained as a pale yellow solid, mp 148°-150° after recrystallization from hexaneethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[C:15]([C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][C:26]2[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH:32][C:27]1[C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:19]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:20][CH:21]=2)=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:9])([O-:3])=[O:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1[N+](=O)[O-]
Yield: 0.1 %

Procedure:
Using the procedure described in Example 102, Part A, 3-nitro-4-methoxybenzoic acid (2.8 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.9 mmol) yielded 0.70 mg (84%) of the title compound.
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([CH3:51])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:40][C:20]3[N:21]([CH2:31][C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])[CH:22]=[C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[C:24](=[O:25])[C:19]=3[C:18]=2[CH2:41][N:42]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH3:43])=[CH:13][CH:12]=1)=[O:9])(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][CH2:6][C@@H:7]([CH3:51])[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:40][C:20]3[N:21]([CH2:31][C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])[CH:22]=[C:23]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[C:24](=[O:25])[C:19]=3[C:18]=2[CH2:41][N:42]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH3:43])=[CH:15][CH:16]=1)=[O:9]
Reactant: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc(NC(=O)[C@H](C)COC(C)(C)C)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc(NC(=O)[C@H](C)CO)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
The compound obtained in Example 9 (11.11 g) was dissolved trifluoroacetic acid (5 ml) under ice cooling conditions, and then after stirring for 1 hour, the solution was allowed to warm to room temperature and stirred for further 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and then the residue was dissolved in methanol (20 ml) and again cooled with ice, and then a 5 N solution of sodium hydroxide was added to reach pH 9.0. The reaction mixture was stirred for 30 minutes and further stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure at low temperature, and then the obtained residue was chromatographed on silica gel. The light yellow amorphous crystals obtained (0.83 g, 82%) were recrystallized from ether to yield light yellow powdery crystals (0.69 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])=[CH2:9])=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].[N-:32]=[N+]=[N-].[Na+].CN(C)C=O.[BH4-].[Na+]>C(OCC)(=O)C.O1CCCC1>[NH2:32][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])=[CH2:9])=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1C(=O)Nc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1ccc(N)c([N+](=O)[O-])c1)c1ccccc1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 2-[1-(4-chloro-3-nitrophenyl)ethenyl]-N-[3-(trifluoromethyl)phenyl]benzamide (0.72 g, 1.6 mmol), sodium azide (3.1 g, 4.8 mmol) and N,N-dimethylformamide (2 mL) was stirred 60° C. for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to give an oily residue. This residue was dissolved in tetrahydrofuran, cooled to 0° C. then sodium borohydride (0.11 g, 2.7 mmol) was added and stirring was continued for 30 minutes at room temperature. The reaction mixture was quenched with methanol (2 mL), concentrated then diluted with ethyl acetate (50 mL). The organic solution was washed with water (30 mL) then brine solution (30 mL) then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluting with 15-50% ethyl acetate-hexane) to give 2-[1-(4-amino-3-nitrophenyl)ethenyl]-N-[3-(trifluoromethyl)phenyl]benzamide (0.35 g, 0.8 mmol, 50% yield). MS (EI) for C22H16F3N3O3: 428 (MH+).
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21]([F:26])[C:22](Cl)=[N:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.[CH2:34]([OH:36])[CH3:35].CN([CH:40]=[O:41])C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[F:26][C:21]1[C:22]([C:40]([O:36][CH2:34][CH3:35])=[O:41])=[N:23][CH:24]=[C:19]([OH:18])[CH:20]=1
Reactant: CN(C)C=O
Reactant: CCO
Reactant: CC(C)(C)[Si](Oc1cnc(Cl)c(F)c1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1ncc(O)cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-((tert-butyl(diphenyl)silyl)oxy)-2-chloro-3-fluoropyridine (29.5 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (5.59 g), triethylamine (10.7 mL), ethanol (300 mL) and DMF (300 mL) was stirred overnight at 80° C. under a carbon monoxide atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (30.8 g) as a mixture with DMF.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:2][CH2:3]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of methyl 3-(piperazin-1-ylmethyl)benzoate (2.47 g, 10.542 mmol), 4-nitrobenzoic acid (1.77 g, 10.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.03 g, 15.813 mmol), triethylamine (2.94 mL, 21.084 mmol) and acetonitrile (40 mL) were stirred together, at ambient temperature, for 4 hours before being concentrated under vacuum. The residue was dissolved in ethyl acetate, filtered, washed with water (×2) and treated with strong cation exchange column chromatography to afford the title compound (3.12 g). MS (ESI) m/z 384.3 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[C:14](=O)[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(C(=O)Cc1cccs1)[C@@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCc1cccs1)[C@@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A5-1 when using 45 mg (0.13 mmol) (R)-N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide ((R)-A4-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using a mixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v) dimethylethylamine.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]([NH:16][C:17](=[NH:22])[CH2:18][CH2:19][S:20][CH3:21])(=[O:15])(=[O:14])[NH2:13]>C(Cl)(Cl)Cl.CO>[S:12]([NH:16][C:17](=[NH:22])[CH2:18][CH2:19][S:20]([CH3:21])=[O:9])(=[O:14])(=[O:15])[NH2:13]
Reactant: CSCCC(=N)NS(N)(=O)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)CCC(=N)NS(N)(=O)=O
Reaction time: 2 h

Procedure:
A solution of commercial 80% pure m-chloroperbenzoic acid (5.4 g, 25 mmol) in chloroform (40 ml) was added dropwise to a solution of N-sulfamyl-3-(methylthio)propionamidine (4.94 g, 25 mmol) in methanol (50 ml) at room temperature. After stirring for two hours, the product was collected by filtration, analytically pure, to give 4.44 g, mp 141°-144°.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC1CCCO1.[CH2:13]([NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:51])[C@@H:27]([OH:50])[C@@H:28]([NH:36][C:37]([C:39]1[C:40]([CH3:49])=[C:41]([O:45]C(=O)C)[CH:42]=[CH:43][CH:44]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])[CH:14]=[CH2:15]>CO>[CH2:13]([NH:16][C:17]([C@@H:19]1[C:23]([CH3:25])([CH3:24])[S:22][CH2:21][N:20]1[C:26](=[O:51])[C@@H:27]([OH:50])[C@@H:28]([NH:36][C:37](=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[C:40]=1[CH3:49])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(OC(C)=O)c2C)CSC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC1CCCO1
Product: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(O)c2C)CSC1(C)C
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
MeOH (330 mL) and K2CO3 (66.9 g; 484 mmol) were sequentially added to a 2-methyltetrahydrofuran solution of crude acetic acid 3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester (theoretical amount: 405 g; 731 mmol) in a 3-L flask at room temperature. Two and a half hours later, additional K2CO3 (20 g; 144 mmol) was added. Three hours later the reaction mixture was vacuum-filtered on a pad of Celite, using 4:1 2-methyltetrahydrofuran/MeOH (330 mL) for rinsing over the solids and washing the filter cake. The filtrate was transferred to a 6-L separatory funnel, using 4:1 2-methyltetrahydrofuran/MeOH (80 mL) for rinsing. The solution was diluted with i-PrOAc (1.66 L) and was then washed with a solution of NaCl (83.0 g) in H2O (1.60 L). The organic fraction was washed with 0.5 N HCl (1.66 L) and then with a saturated aqueous NaCl solution (400 mL). The resulting organic fraction was transferred to a 4-L Erlenmeyer flask and MgSO4 (120 g) was added. After stirring for 10 min, the mixture was vacuum-filtered directly into a 5-L distillation flask, using 2:1 i-PrOAc/2-methyltetrahydrofuran (600 mL) for rinsing the separatory funnel and Erlenmeyer flask and washing the MgSO4. The 2-methyltetrahydrofuran was displaced by distillation at one atmosphere with the simultaneous addition of i-PrOAc in five portions (a total of 3.60 L was used), while maintaining a minimum pot volume of ˜2.50 L. The resulting crystallizing mixture was cooled to 75° C. and was held at this temperature for 30 min. The suspension was then allowed to slowly cool to room temperature overnight. The suspension was vacuum-filtered, using i-PrOAc (600 mL) for transferring and washing the crystals. After drying in a vacuum oven at 40° C., 204 g (54% from (2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid) of crystalline (4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide was obtained. This material was recrystallized as described below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[OH:17][CH:18]([CH2:28][OH:29])[CH2:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(OCC(O)CO)cc1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([O:10][C:11](=[O:14])[CH2:12]Br)([CH3:9])([CH3:8])[CH3:7]>COC(C)(C)C>[C:6]([O:10][C:11](=[O:14])[CH2:12][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)CBr
Solvent: COC(C)(C)C
Product: CCCCNCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
N-Butylamine (5 mL, 51 mmol) was dissolved in t-butyl methyl ether (100 mL), and bromoacetic acid t-butyl ester (3.7 mL, 25 mmol) was then added to the solution. The obtained mixture was stirred at room temperature overnight. The generated precipitate was filtered, and the filtrate was then concentrated under reduced pressure, so as to obtain the title compound (4.67 g, yield: 100%) in the form of a colorless oily substance.