Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@H:3]([OH:5])[CH3:4].[H-].[Na+].BrC[C:12]1[CH:13]=[C:14]([B:18]([OH:20])[OH:19])[CH:15]=[CH:16][CH:17]=1.O>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[C@H:3]([O:5][C:12]1[CH:13]=[C:14]([B:18]([OH:20])[OH:19])[CH:15]=[CH:16][CH:17]=1)[CH3:4]
Reactant: C[C@@H](O)C(F)(F)F
Reactant: OB(O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Oc1cccc(B(O)O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 135 %

Procedure:
A solution of (R)-1,1,1-trifluoropropan-2-ol (212 mg) in N,N-dimethylformamide (1.5 ml) was cooled to 0° C., sodium hydride (74 mg, 60 wt. % oil dispersion) and 3-(bromomethyl)phenyl boronic acid (100 mg) were sequentially added thereto, and the mixture was stirred at room temperature for 2 hours. To this reaction mixture were added water and an 1M aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the titled compound (147 mg).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.O[C:26]1[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:8]2[CH2:9][CH2:10][C@H:6]([O:5][C:26]3[CH:27]=[CH:28][C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][CH:31]=3)[C:7]2=[O:24])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
(R)-tert-Butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 0.20 g, 0.55 mmol) was added to a mixture of methyl 5-hydroxypicolinate (0.10 g, 0.66 mmol), and potassium carbonate (0.099 g, 0.72 mmol) in DMF (1.6 mL). The mixture was stirred at 60° C. overnight and then cooled to ambient temperature. The mixture was partitioned between saturated aqueous NH4Cl (40 mL) and EtOAc (100 mL). The organic phase was washed successively with water (40 mL), water (40 mL) and brine (40 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with EtOAc) to afford (S)-methyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.19 g, 0.45 mmol, 81%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:33])[CH3:32])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Li+].[OH-]>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([CH3:29])[C:17]=3[CH3:30])=[C:12]([CH:31]([CH3:32])[CH3:33])[S:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)nsc2C(C)C)c(C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-c2nsc(C(C)C)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl)propanoate (73.1 mg, 0.16 mmol, 1.00 equiv), LiOH (73 mg, 3.05 mmol, 19.42 equiv), tetrahydrofuran/H2O (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting solution was concentrated. The pH value of the residue was adjusted to 3 with 1M hydrogen chloride. The resulting solution was extracted with 3×40 mL of dichloromethane and the organic layers combined and concentrated. The crude product was purified by Prep-HPLC with the following conditions (1#-Waters 2767-5): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water and CH3CN (30% CH3CN up to 90% in 10 min, up to 100% in 2 min, down to 30% in 2 min; Detector, UV 220&254 nm. This resulted in 3.4 mg (5%) of 3-(4-[[3-(4-ethylphenyl)-5-(propan-2-yl)-1,2-thiazol-4-yl]methoxy]-2,3-dimethylphenyl) propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.94 (s, 2H), 3.44-3.53 (m, 1H), 2.92 (t, J=8.1 Hz, 2H), 2.68 (m, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.24 (s, 3H), 2.10 (s, 3H), 2.14 (s, 6H), 1.25 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H31NO3S, 438.2 (M+H). found 438.2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=2)[N:1]=1
Reactant: CN=C=S
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: CCO
Product: COc1cc2nc(S)n(C)c(=O)c2cc1OC

Procedure:
A solution of 2-amino-4,5-dimethoxybenzoic acid (20.0 g) and methyl isothiocyanate (7.23 g) in ethanol was refluxed for 30 minutes. The precipitate was collected by filtration to provide the title compound as colorless needles. Yield 11.77 g (47%) 1H-NMR (CDCl3) δ: 3.67(3H,s), 3.85(3H,s), 3.89(3H,s), 6.93(1H,s), 7.31(1H,s).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22]C=C[N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:39][N:40]1C=CC(C(O)=O)=N1>>[F:1][CH:2]([F:38])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][N:40]([CH3:39])[N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccn(C)n4)nc3cc2Oc2cccnc2OC(F)F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 203 or in accordance with the method or by combining it with an ordinary method but using 4-(2-difluoromethoxy-pyridin-3-yloxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 247 and 1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:24]=[S:25])=[C:4]([F:16])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1c2c(Cl)cc(F)c(N=C=S)c2CS1(=O)=O

Procedure:
To a solution of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine 2,2-dioxide (0.5 g, 1.88 mmol) and triethylamine (0.6 mL) in anhydrous tetrahydrofuran (THF, 10 mL), thiophosgene (0.238 g, 1.1 eq) in THF (2 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated at reflux for 2 days. The solvents were removed in vacuo to give the title compound of Step A which was used in Step B.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]3[CH2:22][CH:5]3[C:6](=[O:21])[N:7](CC3C=CC(OC)=CC=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[Br:1][C:2]1[C:3]2[CH:4]3[CH2:22][CH:5]3[C:6](=[O:21])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(CN2C(=O)C3CC3c3c(Br)cccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1Nc2cccc(Br)c2C2CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a suspension of 7-bromo-3-(4-methoxybenzyl)-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one (0.300 g, 0.837 mmol) in 9:1 acetonitrile/water (5.5 mL) was added CAN (0.459 g, 0.837 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and adjusted pH to 7-9 by using saturated Na2CO3. The resulting mixture was extracted with EtOAc. The combined organic layer was concentrated and purified by flash chromatography (0 to 50% ethyl acetate:hexanes) to afford the title compound (0.18 g, 95% yield) as a pale yellow solid. LCMS, [M+H]+=237.9. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 2.84 (td, J=8.1, 5.2 Hz, 1H), 2.22-2.13 (m, 1H), 1.76 (td, J=9.2, 4.7 Hz, 1H), 0.75 (dd, J=10.0, 5.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[CH2:17](Br)[CH3:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][N:12]([CH2:17][CH3:18])[CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: CCBr
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Product: CCN1CC[C@@H]2CC(=O)c3cc(F)ccc3[C@@H]2C1

Procedure:
In an analogous manner to that described in Example 49 b), from cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with ethyl bromide there was obtained cis-8-fluoro-2-ethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][CH3:18].[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([NH:19][C:13]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitro-1H-indole-2-carboxylic acid (6.95 g, 33.7 mmol) in N,N-dimethylformamide (DMF)/pyridine (1/1, 150 ml) N,N′-carbonyl-diimidazole (5.47 g, 33.71 mmol) was added. The mixture was stirred at 80° C. for 1 h. At 0° C. propylamine (9.96 g, 168.56 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 16 h. The solution was diluted with water (2 I). After addition of sodium chloride the product precipitated. After filtration the residue was washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)(O)[O-].[Na+].Br[CH2:17][C:18](Br)=[O:19]>C(Cl)(Cl)Cl>[O:19]=[C:18]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:17]1
Reactant: O=C(Br)CBr
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The title compound was prepared similarly to literature procedure (Caliendo, G; et. al.; Bioorg. Med Chem. Lett., 2002, 10, 2663), but in one step. Commercially available 3-amino-4-hydroxybenzonitrile (2.5 g, 18.6 mmol) was dissolved in chloroform (300 mL) and saturated sodium bicarbonate (90 mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. The reaction was stirred overnight at room temperature. The layers were separated and the aqueous layer was filtered to yield the desired product as a tan solid, 2.3 g (69%).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C.O>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1
Temperature: 70 °C

Procedure:
To a stirring solution of 4-(2-Hydroxy-3,4-dimethoxy-phenyl)-indan-1-one (Compound 303) (100 mg, 0.352 mmol) in acetonitrile (15 mL), were added potassium carbonate (145 mg, 1.056 mmol) and 3-(bromomethyl)-3-(methoxymethyl)oxetane (102 mg, 0.528 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afforded the title compound as a colorless liquid.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:14])=O.CN(C=O)C>>[Cl:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CCOCCO
Solvent: CN(C)C=O
Product: CCOC(=O)CCOCCCl

Procedure:
2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspended in 5 ml (68.5 mmol) thionyl chloride and 20 μl (0.27 mmol) DMF are added. The reaction mixture is refluxed for 4 hours and then evaporated down i. vac. The product is further reacted without any more purification.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccc4)cccc3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (0.8 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) in acetonitrile (100 mL). The mixture was stirred for 30 minutes, and benzoyl chloride (0.4 g, 3.2 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was stirred with 2N HCl (30 mL) and CH2Cl2 (80 mL). The solid was collected to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.5 g, 68%) as a white solid: mp 228-230° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.48 (d, J=17.3 Hz, 1H), 4.53 (d, J=22.1 Hz, 1H), 4.55 (s, 2H), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.44-7.65 (m, 6H, Ar), 7.87 (d, J=7.1 Hz, 2H, Ar), 9.11 (t, J=5.7 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.61, 31.20, 46.30, 51.60, 121.67, 127.25, 128.35, 130.67, 131.36, 131.63, 134.07, 134.74, 140.16, 166.37, 168.10, 171.04, 172.88; Anal. calcd. for C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.58; H, 5.08; N, 11.12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Cl:11]
Reactant: CO
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 5-amino-2-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-amino-2-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[OH:9][C@:10]([CH3:46])([CH2:44][OH:45])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([S:5]([O:45][CH2:44][C@:10]([OH:9])([CH3:46])[C:11](=[O:43])[C@@H:12]([NH:20][C:21](=[O:42])[C@@H:22]([NH:26][C:27](=[O:41])[C@@H:28]([NH:32][C:33]([C:35]1[S:39][C:38]([CH3:40])=[N:37][CH:36]=1)=[O:34])[CH2:29][O:30][CH3:31])[CH2:23][O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](COC)NC(=O)[C@H](COC)NC(=O)c1cnc(C)s1

Procedure:
Prepared according to procedures described above, by reacting butanesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C29H42N4O10S2 m/z: 671 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=2[CH3:26])[C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O.CO.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(N)cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stifling, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH2:10][OH:11])[CH:2]1[O:21][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc([N+](=O)[O-])c(CO)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1CO

Procedure:
5-allyloxy-2-nitrobenzyl alcohol (7.3 g, 35 mmol) and m-chloroperoxybenzoic acid (77 wt. %, 9.4 g, 42 mmol) were dissolved in dichloromethane and refluxed until the allyl peaks disappeared from the 1H-NMR spectrum (approximately 48 hours). The reaction was then washed with aqueous sodium carbonate twice, water three times and then dried over sodium sulfate. The solvent was partially removed by rotary evaporation and then poured into hexanes to precipitate the product. The resulting solid was collected by suction filtration and was used in the next step without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:6]1[S:5][CH:9]=[CH:8][CH:7]=1)=[O:16]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCl)c1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
16 g (0.120 mol) of aluminium chloride are introduced portionwise over 15 min into a solution, maintained at about +5°, of 20.2 g (0.240 mol) of thiophene and 15.5 g (0.100 mol) of 5-chlorovaleryl chloride and the mixture is stirred for 5 h at room temperature. After removal of the supernatant by means of separating the phases by settling, the reaction medium is taken up in 120 ml of 3N hydrochloric acid solution and extracted with chloroform.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:2]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 16.1 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 5.0 g of 2-(indol-3-yl)-ethanol, 14.4 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 7.73 ml of tributylphosphine, 7.83 g of 1,1'-(azodicarbonyl)dipiperidine and 150 ml of anhydrous benzene were used, to give 3.03 g of the title compound, melting at 81.0-82.5° C.
Reaction SMILES: [C:1]1([C:6]([CH:8]([CH3:12])[C:9](O)=[S:10])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][C:15]([OH:17])=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O>[C:1]1([C:6]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[S:10])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(=O)O
Reactant: CC(C(=O)c1cccs1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: CC(C(=O)c1cccs1)C(=S)NCC(=O)O
Yield: 55.2 %

Procedure:
To a solution of 21.6 g (0.1 mole) of 2-(2-thenoyl) thiopropionic acid and 7.5 g (0.1 mole) of glycine in 100 ml of dimethylsulfoxide, 20.6 g of N,N'-dicyclohexyl-carbodiimide are added, under stirring, between 15° to 20° C. Stirring is continued for half an hour more, most of the solvent is evaporated under vacuum, 200 ml of water are added and the solution is taken to pH 9 with NaOH. Dicyclohexylurea is eliminated by filtration, then it is acidified with HCl. 14.2 g (yield 52%) of N-[2-(2-thenoyl)thiopropionyl]-glycine are obtained. The product is unitary in TLC.