Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[NH:4][C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@H:7]([CH2:19][CH3:20])[CH2:6]1.N1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:21])[CH2:6][C@H:7]1[CH2:19][CH3:20])=[O:30])[CH3:33]
Reactant: CC[C@@H]1C[C@H](NC(=O)OC)c2cc(C(F)(F)F)ccc2N1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@@H](NC(=O)OC)C[C@H]1CC
Temperature: -10 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
A clean, dry and nitrogen gas purged 100 L glass tank was charged with (2R, 4S)-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (5191 g, 17.17 mol), methylene chloride (21 L), and pyridine (4.16 L, 51.4 mol). The reaction vessel was cooled to −10° C. Ethyl chloroformate (4.10 L, 42.9 mol) was slowly added at such a rate that the internal temperature did not exceed −5° C. The reaction solution was brought to 0° C. and held for 20 hours. The reaction was quenched by adding to a mixture of diisopropyl ether (IPE) (36 L), methylene chloride (6.2 L) and 1.5M hydrochloric acid solution (52 L). The resulting phases were separated and the organic layer was extracted with 1 M sodium hydroxide solution (15 L). The resulting phases were separated and the organic layer was washed with saturated aqueous sodium chloride NaCl (15 L). The resulting phases were separated and the organic layer was concentrated by distillation to a volume of 40 L. Crystallization initiated at lower volume. The methylene chloride was displaced with IPE by distilling the mixture and periodically adding IPE to maintain a constant volume at 40L until a temperature of 68° C. was maintained (46 L total IPE used). The mixture was cooled and allowed to granulate with stirring at room temperature for 19 hours. The solids were filtered, rinsed with IPE (8 L), and dried under vacuum at 40° C. to afford 5668 g of the title compound (88%).
Reaction SMILES: C(O)(=O)C=C.C(Cl)(=O)C(Cl)=O.N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([NH2:23])(=[O:22])[CH:20]=[CH2:21]>[Pd]>[CH:16]1[CH:17]=[CH:18][C:13](/[CH:21]=[CH:20]/[C:19]([NH2:23])=[O:22])=[CH:14][CH:15]=1
Reactant: Nc1ccccc1
Reactant: C=CC(N)=O
Agent: [Pd]
Agent: C=CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: NC(=O)/C=C/c1ccccc1

Procedure:
Acrylic acid vii is converted to the acid chloride with oxalyl chloride, and the resulting acid chloride is reacted with an aniline in the presence of base. The resulting acrylamide viii is then reacted with an appropriately substituted aryl iodide ix in the presence of a palladium catalyst and a base to give the cinnamide vi.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]([O:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:28]([CH3:37])[CH2:27][CH2:26]4)[CH:20]=[N:19]2)[CH:15]1[CH3:46])(C1C=CC=CC=1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>C(OCC)(=O)C>[F:45][C:42]1[CH:41]=[CH:40][C:39]([O:38][C:24]2[C:23]([C:21]3[CH:20]=[N:19][N:18]([CH:16]4[CH2:17][NH:14][CH:15]4[CH3:46])[CH:22]=3)=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][C@H:28]([CH3:37])[N:29]3[C:33]([O:35][CH3:36])=[O:34])=[CH:44][CH:43]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CN(C(c5ccccc5)c5ccccc5)C4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CNC4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 50-mL round-bottom flask was charged with (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.020 g, 0.03 mmol), 1,2-dichloroethane (5 mL) and 1-chloroethyl chloroformate (1 mL), and the resulting solution stirred for 3 h at 80° C. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (20 mL). The organic phase was separated and washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting 25% ethyl acetate-petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV254&220. This afforded methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0021 g, 14%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.40 Hz, 3H), 0.85-0.97 (m, 1H), 1.10-1.18 (m, 3H), 1.29-1.39 (m, 3H), 1.52-1.65 (m, 1H), 1.99-2.25 (m, 2H), 2.41-2.75 (m, 2H), 3.82 (s, 3H), 4.05-4.17 (m, 2H), 4.26-4.35 (m, 1H), 4.62-4.73 (m, 1H), 5.16-5.23 (m, 1H), 6.73-6.81 (m, 2H), 6.93-6.99 (m, 2H), 7.51-7.62 (m, 2H), 7.85 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 451 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[CH2:15]=[O:16]>>[OH:16][CH2:15][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[C:3]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: C=O
Reactant: Cc1[nH]c(=O)ccc1-c1ccncc1
Product: Cc1[nH]c(=O)c(CO)cc1-c1ccncc1

Procedure:
The reaction of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is carried out by heating the reactants at about 75° to 125° C. It is preferably run using an acidic pH of about 2 to 5, a large molar excess of formaldehyde and a reaction temperature of about 90° to 110° C. The quantity of formaldehyde can vary widely provided it is in excess of said 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone. In practice, a large excess, e.g., from about 10-fold to 100-fold or greater can be used; however, as little as a 2-fold excess or less of formaldehyde can be used although the reaction time is longer. Because of its ready availability and low cost, 37% aqueous formaldehyde solution is preferred.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.ClC1C=CC(S[CH2:14][N:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]2=[O:22])=CC=1.C1CCCCC=1>ClCCl>[Cl:4][CH2:14][N:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[N:17][C:16]1=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=c1ncc(Cl)cn1CCl
Reaction time: 0.25 h

Procedure:
Sulphuryl chloride (3.0 mmol) in dry dichloromethane (10.0 ml) was added to 1-(4-chlorophenylsulphenyl) methyl-5-chloropyrimidin-2-one (see Example 2) (3.0 mmol) in dry dichlormethane 30.0 ml) at -30° C. for 3 mins. The mixture was stirred at -25° C. for 50 mins before cyclohexene (3.5 mmol) in dry dichloromethane (10 ml) was added. After stirring for 15 mins the mixture was filtered, evaporated and the residue washed three times with Pet. ether. Insoluble 1-chloromethyl-5-chloropyrimidin-2-one (0.45 g), 84% was used in Example 31 without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Ethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.062 g, 0.147 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1.0 mL) at room temperature. The resulting reaction mixture is stirred at room temperature for 5 hours. Solvent is evaporated in vacuo to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.035 g) after drying in lypholizer. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (t, J=7.2 Hz, 3H), 2.83-2.88 (q, 2H), 4.14 (s, 2H), 4.30-4.33 (m, 1.5H), 4.41-4.45 (m, 0.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.08 Hz, 1H), 5.93 (d, J=4.55 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.12-8.15 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.85 (d, J=8.8 Hz, 1H), 8.90 (d, J=2.12 Hz, 1H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH2:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)[CH3:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[NH:24][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:13][CH:14]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
411 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester were dissolved in 10 ml of anhydrous DMF and cooled to 0° C. 191 mg of 4-toluenesulfonyl chloride and 0.34 ml of diisopropylethylamine were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the solvents removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/1). Yield 295 mg. MS (ES+): m/e=506.2 (M+H)+; 450.2.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31](Cl)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:1][C:2](=[O:11])[CH2:3]2)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1OC
Reactant: O=C1CNc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)N2CC(=O)Nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a stirred solution of 3,4-dihydroquinoxalin-2(1H)-one (142 mg, 0.96 mmol) and triethylamine (0.16 mL, 1.14 mmol) in anhydrous THF (15 mL) at 0° C. was added a solution of (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride in THF (2 mL) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of 1N hydrochloric acid, and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product which was purified by flash chromatography (hexane-EtOAc, 25:10) to give (E)-4-(3-(3,4-dimethoxyphenyl)acryloyl)-3,4-dihydroquinoxalin-2(1H)-one (160 mg, 47%). 1H-NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 3.90 (s, 3H), 4.63 (br s, 2H), 6.71 (d, J=15.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 7.02 (dd, J=7.6, 1.2 Hz, 1H), 7.07-7.13 (m, 2H), 7.22 (dd, J=7.6, 1.2 Hz, 1H), 7.28 (br d, J=8.0 Hz, 1H), 7.76 (d, J=15.6 Hz, 1H), 8.89 (s, 1H); LC-MS (ES-API); rt 8.14 min; m/z calculated for C19H18N2O4[M+H]+ 339.1, found 339.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CC[O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:14](=[O:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][NH:5]2)=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1F
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2cc(F)c(OC)cc2c1=O
Temperature: 110 °C
Yield: 46.5 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (3.00 g, 21.26 mmol) and diethyl ethoxymethylene malonate (4.59 g, 21.26 mmol) is heated at 110° C. for 1 hour then cooled to room temperature. Hexane is added and the solids collected by filtration. This material is suspended in 45 mL of a 3:1 mixture of diphenyl ether:biphenyl and the mixture is heated at reflux for 2 hours to provide a brown solution. The reaction mixture is cooled to room temperature and hexane is added. The resultant solid is collected by filtration washing with hexane to provide 2.62 g of ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate as a white solid, mp>300° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.O1CCCC1.[CH2:18]([NH2:21])[C:19]#[CH:20]>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:18][C:19]#[CH:20])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: C#CCN
Solvent: C1CCOC1
Product: C#CCNC(=O)c1ccccc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
Isatoic Anhydride (4.00 g, 24.5 mmol) was dissolved in tetrahydrofuran (100 mL, 1.230 mol) at 0° C. Prop-2-ynylamine (2.52 mL, 36.8 mmol) was added and the reaction was stirred for 2 hours and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-amino-N-prop-2-ynyl-benzamide as a white solid (4.27 g, 100%). m.p.=75° C.; LCMS (m/e) 120 (M—NHCH2CCH); 1H-NMR (CDCl3, 400 MHz) δ 7.35 (d, 1H, J=7.9 Hz), 7.24 (dd, 1H, J=7.3 and 8.2 Hz), 6.73-6.64 (m, 2H), 6.19 (bs, 1H), 5.56 (bs, 2H), 4.26-4.20 (m, 2H), 2.29 (t, 1H, J=1.5 Hz).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClCl.[I:12]Cl.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([I:12])=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: ClI
Agent: ClCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc(I)ccc1O
Reaction time: 14 h

Procedure:
To a solution of salicylaldehyde (10 g, 82 mmol) in 50 mL of CH2 Cl2 is added 22 mL of a 1M ICl solution in CH2Cl2. The solution is stirred for 14 h. After this time, a saturated solution of sodium sulfite is added until the color is discharged. The solution is diluted with CH2Cl2. The layers are separated. The organic layer is washed with water. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is recrystallized from cyclohexane to give the title compound (7.2 g, 32 mmol) as white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:28])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:28])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.42 G. 1-acetamido-2-nitro-4-benzylthiobenzene in 25 ml. chloroform is treated at -20° to -15° C with 1.6 g. 40% peracetic acid in 2 ml. methanol. The mixture is allowed to warm slowly to room temperature, held for 6 hours and washed with sodium bisulfite solution and sodium bicarbonate solution, dried and stripped. The residue is recrystallized from methanol giving 1-acetamido-2-nitro-4-benzylsulfinylbenzene.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH2:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].[C:28](O)(=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32].Cl.CN(C)CCCN=C=N.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][NH:24][C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Reactant: C=CCCC(=O)O
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 97.7 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg), 4-pentenoic acid (33 mg), N-ethyl-N,-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg), 1-hydroxybenzotriazole (64 mg) and N,N-dimethylformamide (1.5 ml) was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with methylene chloride three times. The organic layers were combined, washed with water four times and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:methanol =30:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(4-pentenoylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (172 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.0 g, 10.1 mmol; purity 90%) was initially charged in dry THF (135 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 3.85 g, 16.17 mmol; 1.6 eq.) was added and the mixture was then stirred at RT for 2 h. Ethyl acetate (300 ml) was then added to the reaction mixture. The organic phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from cyclohexane/ethyl acetate. The crystals obtained were dried under high vacuum. The title compound was obtained as a solid (2.8 g, 65% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C@@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]([CH3:21])[CH3:20].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:17][C@@H:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A mixture of N-[(benzyloxy)carbonyl]glycine (, 2.4 g, 11.5 mmol), tert-butyl D-valinate hydrochloride (2.4 g, 11.4 mmol) and N-methylmorpholine (2.53 ml, 22.9 mmol) in DCM (20 ml) was stirred at room temperature. TBTU (4.79 g, 14.9 mmol) was added and the mixture was stirred for three days. The solvent was removed under reduced pressure. Water was added and the mixture was extracted two times with toluen. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography using DCM:EtOAc:aceton 4:1:1 as eluent to give 3.92 g (94%) of the title compound. NMR (500 MHz, CD3COOD) 0.88-0.99 (m, 6H), 1.48 (s, 9H), 2.08-2.19 (m 1H), 3.85 (ABq, 2H), 4.24 (d, 1H), 5.12 (ABq, 2H), 7.28-7.41 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C(Cl)Cl>[CH3:29][N:30]([CH:32]=[C:10]1[CH2:11][CH2:12][N:6]([C:4](=[O:5])[C:3]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=2[Cl:1])[C:7]2[CH:16]=[CH:15][S:14][C:8]=2[C:9]1=[O:13])[CH3:31]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc21
Solvent: ClCCl
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc2C1=O

Procedure:
A mixture of 3.0 g of 4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one and 20 ml of tert-butoxy-bis(dimethylamino)methane is heated on a steam bath 2 hours followed by the addition of 10 ml of methylene chloride. The reaction mixture is refluxed for 1 hour. The reaction mixture is evaporated in vacuo to a residue which is diluted with 100 ml of methylene chloride and filtered through a pad of hydrous magnesium silicate. The filtrate is filtered through a short column of silica gel to give 2.45 g of the desired product as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH2:30]=[O:31]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:30][OH:31])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Reactant: C=O
Solvent: CO
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Temperature: 100 °C
Yield: 92.1 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (2.0 g, 4.60 mmol) in methanol (30 mL) was treated with a solution of 37% aqueous formaldehyde (7.5 mL, 100.72 mmol). The resulting mixture was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and was diluted with water. The resulting precipitate was collected by filtration, was washed with water and was dried in vacuo to afford 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (1.97 g, 92%) as a light yellow solid. ES+-HRMS m/e calcd for C18H14N6O5Cl2 (M+H+) 465.0476, found 465.0475.