Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.S(C)C>O>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:88])[C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][C@@H:24]([CH2:32][CH2:33][C:34](=[O:87])[NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54](=[O:86])[CH2:55][O:56][C:57]4[CH:62]=[CH:61][C:60]([C:63]5[NH:67][N:66]=[C:65]6[C:68]7[CH:69]=[CH:70][CH:71]=[C:72]([NH:76][C:77]([NH:79][N:80]8[CH2:85][CH2:84][O:83][CH2:82][CH2:81]8)=[O:78])[C:73]=7[C:74](=[O:75])[C:64]=56)=[CH:59][CH:58]=4)[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][CH:20]=3)[N:8]=2)[N:3]=1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CSC
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)O)cc1
Reaction time: 1 h

Procedure:
Compound 30 (0.45 g, 0.37 mmol) was treated with 20 ml of a cleavage cocktail (10:10:1:1 TFA:CH2Cl2: Me2S: H2O). After one hour, the solvent was removed and the residue purified by RPHPLC. Fractions containing the product were combined, concentrated to a small volume and lyophilized to yield a yellow solid (0.23 g, 0.18 mmol, 49%, compound 32).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29])[CH3:32]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCNCC
Product: CCN(CC)C(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 68 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and diethylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.3 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) to provide the title compound as colorless powder (2.79 g, 68%). 1 H-NMR (CDCl3) 6: 3.41(3H,s), 3.63(3H,s), 5.59(2H,s), 7.38-7.50(4H,m), 7.65(1H,s), 7.68-7.81(4H,m).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([OH:14])=O)=[CH:8][N:7]=[C:6]1[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.C(Cl)(=O)C(Cl)=O.[C:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[OH:33][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:27]=1[C:12]([C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[N:7][CH:8]=1)=[O:14]
Reactant: COCCn1c(-c2ccsc2)ncc(C(=O)O)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccsc2)ncc(C(=O)C2=C(O)CCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1,6-dihydro-1-(2-methoxyethyl)-6-oxo-2-(3-thienyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 10, Step C) (0.5 g, 1.8 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.45 g, 3.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude oil was redissolved in 10 mL of dichloromethane and treated with 1,3-cyclohexanedione (0.22 g, 2.0 mmol) and triethylamine (0.18 g, 1.8 mmol). The reaction mixture was stirred for 30 min then treated with a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.015 g, 0.18 mmol) and triethylamine (0.182 g, 1.8 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.160 g of the title compound (also known as 2-[[1,6-dihydro-1-(2-methoxyethyl)-6-oxo-2-(3-thienyl)-5-pyrimidinyl]carbonyl]-1,3-cyclohexanedione), a compound of the invention, as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1=O
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 4-hydroxy-9-cis-retinoic acid (16 mg, 0.05 mmole) in CH2Cl2 (1.5 ml) was added Dess-Martin reagent [see Dess and Martin in J. Org. Chem. 48:4155 (1983)] (42 mg, 0.1 mmole) in one portion at 25° C. After stirring for 5 minutes, the mixture was diluted with 10 ml of ether and to this was added saturated aqueous NaHCO3 (5 ml) containing Na2SO3 (55 mg). The mixture was stirred for 20 minutes to dissolve the solid and the layers separated. The ether layer was washed with H2O (2×5 ml), brine (5 ml) and dried (MgSO4). The solvent was recovered under reduced pressure and residue was subjected to flash column chromatography (silica, 60% ether in Hexane) to give 4-keto-9-cis-retinoic acid (14 mg. 90%), characterized as follows: TLC rf=0.6 (silica, 80% ether in hexane); 1HNMR (400 mHz, CDCl3) δ 7.05 (dd, J=16, 12 Hz, 1H, olefinic), 6.82 (d, J=16 Hz, 1H, olefinic), 6.32 (d, J=16 Hz, 1H, olefinic), 6.30 (d, J=16 Hz, 1H, olefinic), 6.20 (d, J=12 Hz, 1H, olefinic), 5.80 (s, 1H, olefinic), 2.5 (t, J=7 Hz, 2H, CH2—CO), 2.31 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.9 (s, 3H, CH3), 1.89 (m, 2H, CH2), 1.20 (s, 6H, 2×CH3).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>[OH-].[Na+]>[CH2:18]([O:17][C:15]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 0 °C
Yield: 88 %

Procedure:
To a stirred solution of tyrosine (10 g) in 4N aq. sodium hydroxide (30 mL) cooled in an ice bath was slowly added allyl chloroformate (6.4 mL) in a period of 20 minutes. Ten minutes after completion of the addition the ice bath was removed and 4N aq. sodium hydroxide (30 mL) and H2O (5mL) were added. After two hours at RT MeOH (60 mL) was added. After an additional two hours the reaction mixture was extracted with Et2O. The aq. mixture was cooled in an ice bath, acidified to pH 2-3 using 36-38% hydrochloric acid and extracted with EtOAc. De organic extract was dried (Na2SO4) and concentrated under reduced pressure to give Alloc-Tyr-OH (38) as an oil (14.5 g, 88%). Rf 0.35 (DCM/MeOH/AcOH, 89/10/1, v/v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[NH:8][C:9]([Cl:13])=[C:10]([Cl:12])[CH:11]=1)=[O:6].[OH-].[Na+].N1C=CC=C1.[I:25]I.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[NH:8][C:9]([Cl:13])=[C:10]([Cl:12])[C:11]=1[I:25])=[O:6]
Reactant: II
Reactant: COc1ccccc1C(=O)c1cc(Cl)c(Cl)[nH]1
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: c1cc[nH]c1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C(=O)c1[nH]c(Cl)c(Cl)c1I
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Added to 1.08 g of 2-(2-methoxybenzoyl)-4,5-dichloropyrrole were 16 ml of a 1:1 mixture of dioxane and water and 4 ml of a 1 N aqueous solution of sodium hydroxide to dissolve the pyrrole derivative, followed by the addition of 12 ml of an aqueous solution containing 1.2 g of iodine and 1.44 g of sodium iodide. The resultant mixture was stirred at room temperature for 15 hours. Thereafter, 40 ml of a 1 N aqueous solution of sodium thiosulfate was added, followed by stirring for 1 hour. Crystals thus deposited were collected by filtration, washed with water and then dried to obtain 1.24 g of 2-(2-methoxybenzoyl)-3-iodo-4,5-dichloropyrrole (Compound No. 1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]=[C:20]([CH3:30])[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:24]3[CH:23]=[C:22]([CH2:21][C:20](=[O:19])[CH3:30])[O:26][N:25]=3)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)Cc1cc(C(=O)O)no1
Product: CC(=O)Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 5-(2-oxopropyl)isoxazole-3-carboxylic acid (169 mg, 0.997 mmol). The product was purified with flash chromatography using a gradient of methanol in DCM affording 101 mg (32%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.54 (s, 3H), 3.96 (s, 2H), 4.20-4.49 (m, 2H), 4.53-4.64 (m, 1H), 6.63 (d, 1H), 6.65-6.69 (m, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.79-7.90 (m, 2H), 8.04 (d, 1H).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([NH2:22])[CH:18]=2)=[CH:13][CH:12]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29])[CH3:24]>C1COCC1.C(OCC)(=O)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][C:28]([NH:22][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:29])[CH3:24]
Reactant: CCOC(=O)CC(=O)O
Reactant: Nc1cc(-c2ccc(F)cc2)on1
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Yield: 832.3 %

Procedure:
Diisopropyl carbodiimide (0.07 mL, 0.45 mmol) and 5-(4-fluoro-phenyl)-isoxazol-3-ylamine (67 mg, 0.037 mmol) were added to a stirred solution of malonic acid monoethyl ester (50 mg, 0.37 mmol) in THF (1 mL) and stirring was continued at reflux temperature for 4 hrs. The mixture was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with water, followed by brine solution. The organic layer collected was dried over Na2SO4 and concentrated under reduced pressure to afford 90 mg (81.8% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=O.C(C1C=C(C=C(C)C=1O)C#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[C:5]#[N:19]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cc(C=O)cc(Cl)c1O
Product: COc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 3-chloro-4-hydroxy-5-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.82 min; 1H NMR (CDCl3): δ3.98 (s, 3H), 6.36 (s, 1H), 7.04 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([CH3:50])([CH3:49])[CH2:6][C:7]([O:9][CH:10]([CH2:30][O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:8])=[O:3].[CH:51]1[C:56]([Cl:57])=[CH:55][C:54]([OH:58])=[C:53]([O:59][C:60]2[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=2[Cl:66])[CH:52]=1.N1C=CC=CC=1>C(Cl)Cl>[C:32]([O:31][CH2:30][CH:10]([CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:9][C:7]([CH2:6][C:5]([CH3:49])([CH3:50])[CH2:4][C:2]([O:58][C:54]1[CH:55]=[C:56]([Cl:57])[CH:51]=[CH:52][C:53]=1[O:59][C:60]1[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=1[Cl:66])=[O:3])=[O:8])(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Cl
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
A mixture of 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl 4-chloroformyl-3,3-dimethylbutyrate (F) (1.5 g.), triclosan (0.4 g.) and pyridine (0.17 ml.) in methylene chloride (35 ml.) was stirred at 0°-5° C. for 3 hours and then allowed to attain ambient temperature during 45 hours. The methylene chloride was evaporated and replaced by ether (50 ml.). The mixture obtained was washed successively with water (3×20 ml.), 2M hydrochloric acid (25 ml.), saturated sodium hydrogen carbonate solution (2×20 ml.) and water (2×20 ml.), and then dried (MgSO4) and evaporated. The oil obtained crystallised on treatment with ethanol to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 4-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxycarbonyl]-3,3-dimethylbutyrate as white crystals (0.3 g.), (m.p. just below 20° C.); NMR (CDCl3): 0.7-1.0 (6H, m, CH3CH2), 1.12 (6H, s, CCH3), 1.15-1.7 (52H,m, CH2), 2.17 (4H, m, CH2CH2CO), 2.44 (2H,s, CH2CO2CH), 2.60 (2H, s, aromatic O.CO CH2), 3.9-4.4 (4H, m, CH2O), 5.1-5.4 (1H, m, CH2CO2CH), 6.9-7.5 (6H, m, aromatic H)ppm.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:4]1[N:3]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:2]([CH3:1])=[N:6][C:5]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccccc2C#N)c(C)n1
Solvent: CC#N
Product: Cc1nc(C)n(-c2ccccc2C#N)c1Br

Procedure:
Compound 6 (5.18 grams, 26.0 mmol) was dissolved in acetonitrile (150 mL). To this was added N-bromosuccinimide (4.67 grams, 26.0 mmol). This was stirred at reflux for 1 hour before being evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was evaporated in vacuo to give the title compound as a yellow solid. NMR confirmed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:40])([F:39])[C:14]([CH2:34][NH:35][CH2:36][CH2:37]C)([OH:33])[CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:35]([CH2:36][CH3:37])[CH2:34][C:14]([CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:13]([F:12])([F:40])[F:39])=[O:5]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Prepared similarly to Example 48 from 2-chloro-6-fluorobenzoylchloride and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[C:19]1([CH3:32])[CH:24]=[CH:23][C:22]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:29]2[CH2:30][CH2:31][CH:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:32])=[CH:20][CH:21]=3)[CH2:27][CH2:28]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C(C)C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
To a mixture of (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (499 mg) described in Preparation Example 18, 4-(p-tolyloxy)piperidine (383 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (829 mg) were added chloroform (3 mL) and methanol (3 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (196 mg).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](Cl)=[N:8][C:7]=1[O:16][CH2:17][CH:18]([F:20])[F:19]>C1COCC1>[CH3:3][O:4][C:5](=[O:21])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([NH:2][CH3:1])=[N:8][C:7]=1[O:16][CH2:17][CH:18]([F:20])[F:19]
Reactant: CN
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Solvent: C1CCOC1
Product: CNc1nc(OCC(F)F)c(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
Methylamine (2 M in THF; 32.0 mL, 64.0 mmol) is added at 10° C. to 6-chloro-2-(2,2-difluoro-ethoxy)-5-nitro-nicotinic acid methyl ester (9.1 g, 30.7 mmol) in THF (50 mL). After 1 h at rt the reaction mixture is concentrated, treated with water and filtered. The filtercake is washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+].Cl>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:20]=[O:21])[C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: O=N[O-]
Reactant: CCCn1c(N)cc(=O)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reaction time: 0.17 h
Yield: 146.3 %

Procedure:
1,3-Di-n-propyl-6-aminouracil (30 g) was suspended in 1 L of water with 41 ml of 20% acetic acid and overhead stirring. Sodium nitrite (9.03 g) in 41 ml of water was added in portions, keeping the solution acidic with 12 ml concentrated hydrochloric acid. A purple precipitate formed. Addition was complete in 10 minutes and the suspension was allowed to stir for 2 hours. The solution was then filtered, and the filtrate was rinsed with water and dried under vacuum to yield 46 g of 1,3-di-n-propyl-5-nitroso-6-aminouracil.
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][O:37][CH3:38])=[C:9]([C@:11]([NH:28][S@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])([C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:17]=[C:16]([F:26])[C:15]=2[Cl:27])[CH2:12][OH:13])[CH:10]=1.Br[CH2:40][C:41]#[N:42].[Cl-].[NH4+]>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][O:37][CH3:38])=[C:9]([C@:11]([NH:28][S@:29]([C:31]([CH3:32])([CH3:33])[CH3:34])=[O:30])([C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:17]=[C:16]([F:26])[C:15]=2[Cl:27])[CH2:12][O:13][CH2:40][C:41]#[N:42])[CH:10]=1
Reactant: N#CCBr
Reactant: COCOc1ccc(Br)cc1[C@](CO)(N[S@@](=O)C(C)(C)C)c1cc(N2CCOCC2)nc(F)c1Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1[C@](COCC#N)(N[S@@](=O)C(C)(C)C)c1cc(N2CCOCC2)nc(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.7 %

Procedure:
Lithium hydroxide hydrate (0.402 g, 9.58 mmol) was added to a solution of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-hydroxyethyl)-2-methylpropane-2-sulfinamide (1.9 g, 3.19 mmol) in THF (25 mL) at RT, followed by bromoacetonitrile (0.445 mL, 6.39 mmol). The reaction mixture was allowed to stir at RT for 12 h. The reaction mixture was treated with aqueous saturated ammonium chloride, and the mixture was extracted with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and then concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to afford 1.51 g of (S)—N—((S)-1-(5-bromo-2-(methoxymethoxy)phenyl)-1-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-(cyanomethoxy)ethyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chloroacetyl chloride (0.37 ml, 4.6 mmol) was added to a solution of indoline (0.47 ml, 4.19 mmol) and triethylamine (TEA; 0.70 ml, 5.03 mmol) in dichloromethane (DCM; 15 ml). The mixture was stirred for 3 hrs at room temperature (RT) and then quenched with water (5 ml). The phases were separated and the aqueous layer was extracted with DCM (3×5 ml). The combined organic layers were dried over MgSO4 and concentrated to a dark brown residue, 1 g (quantitative), which was used for the next step without further purification.