Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[C:3]1([CH2:2][CH2:1][NH:9][CH2:16]/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNCCc1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of phenethylamine (20 mL, 160 mmol) in anhydrous THF (250 mL) was added NaHCO3 (7 g) followed by methyl 4-bromocrotonate (10 mL, 84 mmol). After stirring for 4 h the reaction was concentrated to approximately half the volume and filtered through a pad of silica gel and eluted with 2% MeOH/CHCl3 to wash off the product. The crude product obtained after evaporation of the filtrate was purified by flash chromatography (silica gel, 2% MeOH/CHCl3) to give the title compound as a slightly yellow liquid (16.5 g, 81%). TLC Rf 0.53 (5% MeOH/CHCl3); 1H NMR (CDCl3) δ 1.2 (1H, s), 2.8 (4H, br s), 3.35 (2H, dd), 3.7 (3H, s), 5.95 (1H, dt), 7.0 (1H, dt), 7.25 (5H, br s)
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10])=[O:5].[OH-].[Na+].CCOC(C)=O>CO.O>[F:1][C:2]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[C:24]([CH2:35][O:36][CH3:37])[CH:23]=3)[O:19][N:18]=2)[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)NCCC(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3ccc(C(=O)NCCC(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of example 117 (1 860 mg; 3.69 mmol) in MeOH (40 mL), sodium hydroxide (3.69 mL; 5 M; 18.5 mmol) in H2O was added. The reaction was stirred at RT for 1 h. EtOAc was added and the organic phase washed 3 times with HCl 1M. The organic phase was dried over MgSO4, filtered off and concentrated to afford the title compound as a white powder (1490.0 mg, 82%). 1H NMR: (DMSO-d6, 300 MHz) δ 8.58 (m, 1H), 8.33 (brs, 1H), 8.18 (dd, J=1.7 Hz, 8 Hz, 1H), 8.03 (dd, J=1.7 Hz, 8 Hz, 1H), 7.95 (d, J=10.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.40-7.22 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 3.49 (m, 2H), 3.25 (s, 3H), 2.53 (m, 2H), 2.04 (s, 3H). LC/MS (Method B): 490.3 (M+H)+ 488.4 (M−H)−. HPLC (Method A) Rt: 4.83 min (purity: 99.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C.[Cl-].[NH4+]>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[C:5]([Br:15])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc([C@@H]2CNC(=O)C2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc([C@@H]2CNC(=O)C2)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Seven and one-half (7.5) g (35.71 mmol) of (4R)-4-(3-amino-4-chlorophenyl)-pyrrolidin-2-one was dissolved in 170 mL chloroform (0.25 M) and 3 mL of acetic acid. To this solution, 6.3 g of solid N-bromosuccinimide was added portion-wise. The reaction was stirred overnight at room temperature. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (50 mL). The aqueous solution was extracted with dichloromethane (2×50 mL), dried over MgSO4 and the solvent evaporated to dryness. Water was added to the oil and the pH adjusted to 9 with 1N NaOH. The solid was filtered, washed consecutively with water, ether, and hexane and dried under a high vacuum to give 9.3 g of the title compound (88% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@H:38]([C:52]4[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:66]([C@:73](N)([C:79]([O:81][CH:82]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:80])[CH2:74][O:75][C:76](Cl)=[O:77])([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67].[N:96]1C=CC=CC=1>O1CCCC1>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@H:38]([C:52]4[CH:57]=[CH:56][C:55]([N:58]([NH2:96])[C:76]([O:75][CH2:74][C@@H:73]([C:66]([O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:67])[C:79]([O:81][CH:82]([C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)=[O:80])=[O:77])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:27])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)[C@@](N)(COC(=O)Cl)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N(N)C(=O)OC[C@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)C)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 12, 3.63 g of 3-acetoxymethyl-7β-[(2S)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate are reacted with 3.03 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride and 0.76 ml of pyridine in 100 ml of tetrahydrofuran and worked up. The crude product is chromatographed over 400 g of silica gel (500 ml fractions), fractions 1-12 being eluted with toluene/ethyl acetate (1:1), fractions 13-19 with toluene/ethyl acetate (2:3) and the later fractions with ethyl acetate. By reprecipitating fractions 14-25 from CH2Cl2 /ether/hexane, 3-acetoxymethyl-7β-{(2S)-2-[4-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. [α]D20 =19°±1° (0.96% in CHCl3), IR: 3570, 3400, 1795, 1750-1700 (wide), 1620, 1608, 1510 cm-1 (CH2Cl2).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:24][CH2:23][CH2:22][O:21]2)[C:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][C:17]2([O:21][CH2:22][CH2:23][O:24]2)[C:16]1([CH3:31])[CH2:25][CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)CCCC1(C)C(OCc2ccccc2)CCCC12OCCO2
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of pyridine (70.3 g, 0.89 mol) and chromium trioxide (44.5 g, 0.445 mol) in methylene chloride (1.8 l) in a nitrogen atmosphere is stirred for 45 minutes. Celite (180 g) is added followed by (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-hydroxypentyl)-cyclohexane (25.8 g, 0.074 mol) in methylene chloride (100 ml). The mixture is stirred for 90 minutes at 23° C. The mixture is then filtered and the celite cake is washed with methylene chloride (10×200 ml). The filtrate and washings are combined and the solvents are removed under reduced pressure to give a dark oil, which is diluted with ether (750 ml) and filtered. The ether phase is dried (MgSO4) and the solvents are removed at reduced pressure. The crude product (21 g) is chromatographed on SilicAR CC-7 (300 g, Mallinckrodt) in hexane. Elution with 6% ethyl acetate/hexane gives (2S*, 3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-oxopentyl)-cyclohexane as a clear colorless oil (15.7 g, 61%): ir (neat) 1712 cm-1 (CO); nmr (CDCl3)δ 1.06 (s, 3H, --CH3), 2.04 (s, 3H, ##STR50## 2.30 (m, 2H, --CH2 --CO), 3.50 (m, 1H, ##STR51## 3.98 (s, 4H, ketal), 4.55 (d of d, J=10 Hz, 2H, --O--CH2Ph), 7.20 (s, 5H, aromatic).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]2[C:31](=[O:32])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C/C=C/c1ccc(Br)cc1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc(Br)cc1
Yield: 64 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-bromophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 11 as a white solid (95 mg, 64%). Analytical data for 11: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=8.0 Hz, 1H), 7.89 (ddd, J=9.1, 6.1, 3.2 Hz, 1H), 7.47-7.41 (m, 2H), 7.39-7.30 (m, 3H), 7.09-7.02 (m, 1H), 7.02-6.92 (m, 5H), 4.08 (d, J=6.9 Hz, 1H), 3.56 (ddd, J=9.8, 6.8, 5.0 Hz, 1H), 3.27 (dd, J=14.9, 4.9 Hz, 1H), 2.41 (dd, J=14.9, 9.9 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.6, 159.1 (d, JCF=243.6 Hz), 155.4 (d, JCF=240.8 Hz), 148.9, 136.9, 136.8, 136.5, 131.7, 130.8, 129.3, 128.4, 127.9, 120.6, 118.3 (dd, JCF=12.4, 9.4 Hz), 117.1 (dd, JCF=25.7, 8.3 Hz), 116.6 (dd, JCF=24.5, 9.6 Hz), 114.5 (dd, JCF=26.9, 3.8 Hz), 110.7 (d, JCF=3.7 Hz), 47.1, 38.5, 32.3; IR (film) cm−1 1773, 1618, 1529, 1481, 1463, 1240, 1171, 1119, 1099, 1071, 1011, 765, 740, 699; LRMS (ESI): Mass calcd for [M+H]+ C25H18BrF2N2O2: 495.0. found 495.0; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 10% IPA/hexanes; 1.0 mL/min, 280 nm), Rt1 (major)=33.1, Rt2 (minor)=52.8 min; er=96:4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[N:59]=[CH:58][C:57]([C:60](Cl)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[CH:58]=[N:59][O:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1cnon1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2cnon2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 33 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,2,5-oxadiazole-3-carbonyl chloride as starting materials in 33% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.41 (s, 2H), 9.02 (s, 1H), 8.30 (m, 2H), 8.20 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.47 (s, 1H), 4.38 (m, 1H), 4.02 (m, 1H), 3.19 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C27H27ClN9O3 (M+H)+: m/z=560.2.
Reaction SMILES: OCC1COC(=O)O1.CN(C)C1CCCCC1.[N-:18]=[C:19]=[O:20].[N-:21]=[C:22]=[O:23].[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:30][C:24]1[C:25](=[CH:26][C:27](=[CH:28][CH:29]=1)[N:21]=[C:22]=[O:23])[N:18]=[C:19]=[O:20]
Reactant: Cc1ccccc1
Reactant: [N-]=C=O
Agent: O=C1OCC(CO)O1
Solvent: C1CCOC1
Solvent: CN(C)C1CCCCC1
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 25 °C

Procedure:
To a one-liter, round bottom 3-necked flask, fitted with a mechanical stirrer, thermometer and dropping funnel, was added 118 g of glycerin carbonate (I) (1.0 moles) and 200 ml. of dry tetrahydofuran (THF). After addition of 1.0 g dimethylcyclohexylamine (DMCHA), the resulting solution was stirred under nitrogen at ambient temperature. Then, 87 g (1.0 equiv.) of Rubinate® 80/20 (Huntsman Corp.) toluenediisocyanate (TDI) (II) was then added dropwise while controlling the exothermic reaction so that the temperature did not exceed 60° C. After the addition of compound II was complete the reaction product was maintained at 50° C. for one hour. The resulting product was primarily a solution of III in THF, a light yellow mobile liquid. The reaction is shown diagrammatically below.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].Cl.[OH-].[K+].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]1[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC(CO)c1ccccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccccn2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
To a solution of 2-amino-2-(pyridin-2-yl)ethanol (3.8 g, 28 mmol) (as the bis HCl salt) in water (50 mL) cooled to 0° C. was added potassium hydroxide (11 g, 19 mmol) followed by THF (50 mL) and the reaction stirred for 20 minutes at 0° C., followed by addition of bis(trichloromethyl) carbonate (8.2 g, 28 mmol) as the solid and stirring at 0° C. for 2 hours. The reaction was next poured into water and extracted with EtOAc and the combined organic layers were washed with 1N NaOH, brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using EtOAc as eluent to yield 4-(pyridin-2-yl)oxazolidin-2-one (1.4 g, 8.5 mmol, 31% yield).
Reaction SMILES: [C:1]([OH:4])#[C:2][CH3:3].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.Cl>>[C:1]([O:4][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)#[C:2][CH3:3]
Reactant: CC#CO
Reactant: C1=COCCC1
Agent: Cl
Product: CC#COC1CCCCO1

Procedure:
Prop-1-ynol was added to dihydropyran in the presence of hydrochloric acid to give prop-1-ynyltetrahydropyranyl ether. The ether was alkylated with 5-methylhexyl bromide. The resultant product was hydrolyzed with sulfuric acid to the desired alcohol, 8-methylnon-2yn-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21](C=O)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[C:31](=[O:34])([O-:33])[O-].[Na+].[Na+].[Mn]([O-])(=O)(=O)=[O:38].[K+]>C(O)(C)(C)C.O>[CH2:29]([O:28][C:26]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][C:8](=[O:38])[N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:31]([OH:33])=[O:34])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: O=C([O-])[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(C(=O)O)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.70 g, 1.64 mmol), sodium carbonate (0.26 g, 1.64 mmol) and 16.4 mL of 1:1 tert-butyl alcohol-water was treated with potassium permanganate (0.26 g, 1.64 mmol). After stirring for 2 hours at room temperature, the mixture was quenched with sodium sulfite, acidified with 1M hydrochloric acid and extracted 3× with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo, affording 1-[6-(4-Carboxy-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup (0.5 g). 1H NMR (CDCl3, 500 MHz): 8.14 (d, 2H, J=8.5 Hz), 8.10 (d, 1H, J=3.0 Hz), 7.80 (dd, 1H, J=2.5, 8.5 Hz), 7.24 (d, 2H, J=8.0 Hz), 7.02 (d, 1H, J=9.0 Hz), 4.21 (q, 4H, J=7.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.21 (t, 6H, J=7.5 Hz) ppm. MS (APCl, m/z): 443 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([NH:39][C:40]1[C:41]([CH3:47])=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:48]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57]O)=[CH:52][CH:51]=1)#[N:49]>C1COCC1.O>[C:32]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:57][CH2:56][C:53]2[CH:54]=[CH:55][C:50]([C:48]#[N:49])=[CH:51][CH:52]=2)[C:41]=1[CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1c(O)cccc1NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OC(C)(C)C)cccc1OCCc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
Triphenylphosphine (1.31 g, 13.5 mmol) and diethylazodicarboxylate (1.7 mL) were dissolved in THF (20 mL) under nitrogen. After 15 minutes 3-t-butoxycarbonylamino-2-methylphenol (2.48 g; 11.1 mmol; from step (i) above) dissolved in THF (20 mL) and 2-(4-cyanophenyl)ethanol (1.9 g, 13 mmol) were added. After 5 days at room temperature water was added and the stirring continued for 30 minutes. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography afforded 2.98 g (77%) of the sub-title compound.
Reaction SMILES: CC[CH2:3][O:4][CH2:5][CH2:6][N:7]([C:18]([CH2:20][Cl:21])=[O:19])[C:8]1[C:9]([CH2:16][CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14]C.[CH3:22]C1C(N(C(CCl)=O)CCOC)=C(C)C=CC=1.CCC1C=CC=C(CC)C=1N(C(CCl)=O)COC.CC(N(C(CCl)=O)C1C=CC=CC=1)C.CCC1C=CC=C(C)C=1N(C(CCl)=O)COCC>>[CH3:17][CH2:16][C:9]1[C:8]([N:7]([C:18]([CH2:20][Cl:21])=[O:19])[CH:6]([CH2:5][O:4][CH3:3])[CH3:22])=[C:13]([CH3:14])[CH:12]=[CH:11][CH:10]=1
Reactant: COCCN(C(=O)CCl)c1c(C)cccc1C
Reactant: CCCOCCN(C(=O)CCl)c1c(CC)cccc1CC
Agent: CC(C)N(C(=O)CCl)c1ccccc1
Agent: CCOCN(C(=O)CCl)c1c(C)cccc1CC
Agent: CCc1cccc(CC)c1N(COC)C(=O)CCl
Product: CCc1cccc(C)c1N(C(=O)CCl)C(C)COC

Procedure:
Pretilachlor, Dimethachlor, Alachlor, Propachlor, Trimexachlor, acetochlor.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[C:13](=[O:20])[NH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:12]1[CH:11]=[C:10]([I:9])[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[C:13]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(I)c2cnccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2ccncc2c(I)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Benzyl bromide (0.057 g, 0.34 mmol) was added to a mixture of 4-iodo-2,6-naphthyridin-1(2H)-one trifluororoacetate (0.100 g, 0.26 mmol) and Cs2CO3 (0.253 g, 0.78 mmol) in anhydrous DMF (10 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min, then allowed to warm to rt and stirred for 17 h. After that time the reaction was concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2×25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-benzyl-4-iodo-2,6-naphthyridin-1(2H)-one (0.070 g, 74%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.78 (d, J=5.3 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.31-7.40 (m, 5H), 5.20 (s, 2H); ESI MS m/z 363 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=[O:6].[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[Cl:18][C:2]([Cl:1])([Cl:17])[CH2:3][O:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:12][CH:13]=2)[CH2:8]1)=[O:6]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Crude 3,4-dihydro-1H-isoquinoline-2-carboxylic acid 2,2,2-trichloro-ethyl ester (D6) (46 g, 150 mmol) was added dropwise over 40 minutes to chlorosulphonic acid (70 ml) cooled with an ice bath to maintain the temperature between 5 and 15° C. The mixture was then allowed to warm to room temperature, stirred for 16 hours, then poured onto crushed ice (500 ml) and dichloromethane (500 ml) added. This mixture was washed with water (3×250 ml), and brine (50 ml) then dried (sodium sulphate), filtered and evaporated to an orange oil which slowly crystallised on standing. This was recrystallised from ether-hexane to give the title compound (D7) as a white crystalline solid (64.5 g 83%); δH (CDCl3) ppm 3.03 (2H, app.t), 3.81-3.86 (2H, m), 4.74-4.85 (4H, m), 7.42 (1H, d), 7.82-7.88 (2H, m).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:23])[C:5]([Cl:22])=[C:6]([CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])[CH:7]=1.[I:24]I.N(OC(C)(C)C)=O>CS(C)=O>[Cl:22][C:5]1[C:4]([Cl:23])=[CH:3][C:2]([I:24])=[CH:7][C:6]=1[CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(N)cc(Cl)c2Cl)c1=O
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(I)cc(Cl)c2Cl)c1=O
Yield: 110.3 %

Procedure:
By the method of Example 2, Step B, 2.67 grams (0.00725 mole) of 3-(5-amino-2,3-dichlorophenylmethyl)-1-methyl-6-trifluoromethyluracil, 1.84 grams (0.00725 mole) of iodine, and 1.12 grams (0.0109 mole) of tertiary-butyl nitrite were reacted in 10 mL of dimethyl sulfoxide, yielding 3.83 grams of 3-(2,3-dichloro-5-iodophenylmethyl)-1-methyl-6-trifluoromethyluracil as a light brown solid, m.p. 142°-144° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:36]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[S:26]([C:23]2[C:24]([Cl:36])=[N:25][CH:20]=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: ClCCl
Reactant: CC(C)CNc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (4-fluoro-phenyl)-isobutyl-amine (250 mg, 1.5 mmol) in DCM (5 mL) was added pyridine (242 μL, 3.0 mmol) followed by 6-chloropyridine-3-sulfonylchloride (379 mg, 1.8 mmol) and the reaction was stirred at room temperature for 2 hours. Water and saturated NaHCO3 were added and then extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-20% EtOAC in cyclohexane) to give chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (411 mg, 80%) LCMS (m/z, Method A) ES+ 343 [M+1]+.