Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: C1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Solvent: CN1CCCC1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCCCC2)s1
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-N-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)-thiazole-5-carboxamide (intermediate F) (30 mg, 0.063 mmol) and piperidine (10.8 mg, 0.126 mmol) in NMP was heated to 120° C. in a sealed microwave tube. After heating for 2 hr., the mixture was allowed to cool to room temperature. The crude product was purified using preparative reverse-phase HPLC, providing 2-piperidin-1-yl-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide. MS calcd. for C25H23ClN4O2S [(M+H)+] 479.1, obsd. 478.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[C:14]=1[OH:25])=[O:12].CC(C)=CCC1C(O)=CC(O)=CC=1C1OC2C=C(O)C=CC=2C=1.OC1C=C(O)C=C2C=1C(=O)C[C@@H](C1C=CC(O)=CC=1O)O2>CO>[CH3:24][C:22]([CH3:23])=[CH:21][CH2:20][C:15]1[C:16]([OH:19])=[CH:17][CH:18]=[C:13]2[C:11](=[O:12])[CH2:10][C@@H:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[O:25][C:14]=12
Reactant: CC(C)=CCc1c(O)ccc(C(=O)C=Cc2ccc(O)cc2O)c1O
Agent: CC(C)=CCc1c(O)cc(O)cc1-c1cc2ccc(O)cc2o1
Agent: O=C1C[C@@H](c2ccc(O)cc2O)Oc2cc(O)cc(O)c21
Solvent: CO
Product: CC(C)=CCc1c(O)ccc2c1O[C@H](c1ccc(O)cc1O)CC2=O

Procedure:
Bright yellow powder; UV (MeOH) λmax (log ε) 286 (3.99), 207 (4.41) nm; 1H NMR (CD3COCD3, 500 MHz) δ 1.61 (3H, s, H-4″), 1.65 (3H, s, H-5″), 2.72 (1H, dd, J=3.0 and 16.7 Hz, H-3), 2.95 (1H, dd, J=13.3 and 17.0 Hz, H-3), 3.34 (1H, brd, H-1″), 5.26 (1H, m, H-2″), 5.69 (1H, brd, J=10.3 Hz, H-2), 6.43 (1H, brd, J=8.4 Hz, H-5′), 6.48 (1H, brd, H-3′), 6.62 (1H, d, J=8.6 Hz, H-6), 7.36 (1H, d, J=8.5 Hz, H-6′), 7.59 (1H, d, J=8.6 Hz, H-5); EIMS m/z 324 (M+, 9), 322 (24) 279 (47), 191 (19), 205 (10), 176 (14), 161 (26), 149 (43), 45 (100).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].I[CH3:39]>C(#N)C.[Ag]=O>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][CH3:39])[CH:20]=[C:19]1[C:33](=[O:37])[N:34]([CH3:35])[CH3:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=[Ag]
Solvent: CC#N
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](COC)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 120 h
Yield: 97.8 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(dimethylcarbamoyl)-2-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 139, 1.64 g, 3.03 mmol) and silver oxide (2.81 g, 12.13 mmol) were dissolved in acetonitrile (40 mL). To this solution was added iodomethane (1.897 mL, 30.34 mmol) under N2 and stirred over for 5 days protected from the light. The reaction mixture was then filtered through Celite, rinsed with EtOAc, and the crude product was loaded onto silica gel. The product was purified by flash chromatography (0-20% MeOH/DCM) to yield the desired product (1.643 g, 98%) as an off-white solid.
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])=[N:14][N:11]=[N:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1C=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
20.3 g (147 mmol) of triethylamine hydrochloride and 21.0 g (322 mmol) of sodium azide are added to a solution of 14.0 g (107 mmol) of 2-cyano-benzaldehyde in 350 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 3 hours (argon atmosphere). The black reaction solution is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 2-(tetrazol-5-yl)-benzaldehyde; m.p. 130° C.; TLC: Rf=0.10 (CHCl3/methano/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: S(=O)(=O)(O)O.[P:6]([CH2:10][N:11](CC(O)=O)[CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]>>[P:6]([CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])([OH:9])([OH:8])=[O:7]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=S(=O)(O)O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 110 °C
Yield: 95.3 %

Procedure:
Fuming sulfuric acid (5%, 150 grams) was added to a glass reaction vessel fitted with a stirrer and thermometer. The fuming sulfuric acid was heated to 110° C. and N-phosphonomethyl-imino-diacetic acid (70 grams) was added over a 1 hour period while maintaining the temperature at 110° C. The reaction mixture was heated to 110° C. for an additional hour at which time nuclear magnetic resonance spectra analysis showed that none of the starting N-phosphonomethyl-imino-diacetic acid remained. Assay of the reaction mixture (214.0 grams, 22.35% assay) showed that a 95.3% yield of N-phosphonomethyl glycine had been obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[C:42](O)=[O:43]>>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:42]([C:34]1[NH:33][C:41]2[C:36]([CH:35]=1)=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:43])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc2ccccc2[nH]1
Yield: 42.1 %

Procedure:
In a manner analogous to that described in Example 27, from 27 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 11.3 mg of 2-indolecarboxylic acid there were obtained 15 mg of N-[3(S)-[[N-(2-indolylcarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester: MS: m/e 592 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[O:12])[CH:7]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Cn2cc(Cl)cnc2=O)c1
Yield: 20.5 %

Procedure:
A solution of 5-chloropyrimidin-2-one (504 mg) and 2-bromo-3'-methoxyacetophenone (880 mg) in triethylamine (1 ml) and ethanol (50 ml) was stirred at ambient temperature for 20 hours. After evaporation of solvents, the residue was triturated with water (50 ml). The resulting solid was crystallised from ethyl acetate to give the title pyrimidinone (220 mg,); m.p. 134°-137°; λmaxEtOH 249.5 nm (ε 12660), 317 nm (ε 4070), λinf 334.5 nm (ε2950), 344.5 nm (ε 1990).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:2].[OH:16]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[CH3:15][O:14][C:12]([C:10]1[CH:9]=[CH:8][C:6]2[CH:7]=[C:3]([C:1]([OH:16])=[O:2])[O:4][C:5]=2[CH:11]=1)=[O:13]
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1ccc2cc(C=O)oc2c1
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2cc(C(=O)O)oc2c1
Temperature: 25 °C
Yield: 289.3 %

Procedure:
Methyl 2-formyl-1-benzofuran-6-carboxylate (1.23 g, 6.0 mmol) is dissolved in DMSO (12 ml). KH2PO4 (229 mg, 1.68 mmol) in H2O (2 ml) and NaClO2 (80%, 949 mg, 8.4 mmol) in H2O (12 ml) are added drop-wise to the solution, and the reaction is stirred over the weekend at RT. The pH is adjusted to 10 with 2N NaOH and the mixture is extracted with Et2O (3×50 ml). The pH is adjusted again to 3 with concentrated HCl and the slurry is filtered. The cake is dried overnight, yielding 1.07 g (81%) of 6-(methoxycarbonyl)-1-benzofuran-2-carboxylic acid as an ivory solid. HRMS (FAB) calcd for C11H8O5+H: 221.0450, found 221.0436 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[NH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15]C1(Br)C(=O)NC(=O)NC1=O>O1CCCC1>[Br:15][CH2:2][C:1]([C:4]1[C:5](=[O:14])[NH:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(C)(C)C)[nH]c1=O
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)CBr)c(=O)[nH]1
Yield: 71.7 %

Procedure:
To a tetrahydrofuran (5.0 mL) solution of 3-(acetyl)-6-tert-butylpyridin-2(1H)-one (0.50 g), 5,5-dibromobarbituric acid (0.41 g) was added, and the resultant was heated to reflux for 2 hours. A deposit formed during the course of concentration of the reaction solution under reduced pressure was filtered to obtain the title compound (0.28 g) as a light brown solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1ccc(-c2cnco2)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
(183) A solution of 2-(oxazol-5-yl)pyridine (95 mg, 0.65 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.72 mmol, 0.29 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.30 mmol, 2.6 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.65 mmol, 124 mg) was added, and the solution was stirred for 10 min at 0° C. Palmitoyl chloride (2 equiv, 1.3 mmol, 357 mg, 0.39 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)hexadecan-1-one (183) (103 mg, 0.27 mmol, 42% yield) as an off-white powder: mp 78-80° C.; 1H NMR (CDCl3, 250 MHz) d 8.66 (br d, J=5.1 Hz, 1H), 7.88-7.76 (m, 3H), 7.34-7.27 (m, 1H), 3.10 (t, J =7.3 Hz, 2H), 1.83-1.70 (m, 2H), 1.24 (br s, 24H), 0.87 (br t, J=6.9 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 157.4, 153.2, 150.1, 146.3, 137.0, 126.8, 124.1, 120.4, 39.2, 31.9, 29.6 (2C), 29.6 (2C), 29.4 (2C), 29.3 (3C), 29.2 24.0, 22.7, 14.1; IR (KBr) umax 2935, 2847, 1699, 1605, 1425, 1381 cm−1; MALDI-FTMS (DHB) m/z 385.2841 (C24H36N2O2+H+ requires 385.2849).
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>O1CCCC1.CO>[CH2:10]([O:9][C:8]1[C:4]([N:31]2[CH2:32][CH2:33][N:28]([C:16]3[N:15]=[C:14]([NH2:13])[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=3)[CH2:29][CH2:30]2)=[N:5][S:6](=[O:12])[N:7]=1)[CH3:11]
Reactant: CCOC1=NS(=O)N=C1OCC
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1=NS(=O)N=C1N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.9 g (10 mMoles) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide are added to 2.9 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline dissolved in 50 ml of tetrahydrofuran and 10 ml of methanol, followed by stirring for 5 hours at room temperature. The solid accumulating is separated off and recrystallized from 15 ml of dimethyl formamide and 10 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cncc(Cl)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cncc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-3-yl)oxy]benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.41 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=2.5 Hz), 8.13 (1H, d, J=2.8 Hz), 7.96 (2H, d, J=8.4 Hz), 7.45 (1H, dd, J=8.7, 2.8 Hz), 7.37–7.28 (1H, m), 7.31 (2H, d, J=8.4 Hz), 7.20 (1H, dd, J=2.5, 2.0 Hz), 6.90 (1H, d, J=8.7 Hz), 5.37–5.22 (1H, m), 3.91 (3H, s), 1.51 (3H, d, J=6.9 Hz).
Reaction SMILES: CO[C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].[H-].[CH2:16]([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[CH:4]([CH3:16])[CH:3]=[O:14]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)Cc1cc(OC)ccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(C(C)C=O)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid methyl ester (850 mg) was dissolved in toluene (40 mL) and cooled to −78° C. Diisobutylaluminium hydride (20% in toluene, 3.69 mL) was added over a period of 15 minutes. Stirring was continued for 45 minutes at −78° C. Methanol (2 mL) was added followed by 1M potassium sodium tartrate solution (10 mL). The cooling bath was removed and the mixture was allowed to warm to r.t. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The title compound was obtained as a light yellow oil (710mg, 96%) and was used without further purification. 1H-NMR (δ, CDCl3): 9.72 (s, 1H), 7.34 (d, 1H), 6.79 (dd, 1H), 6.66 (d, 1H), 4.10 (q, 1H), 3.79 (s, 3H), 1.43 (d, 3H).
Reaction SMILES: O.CO[CH:4]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6].C(OCC)(=O)C>C(O)(=O)C.II>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(C(=O)O)c1cccs1
Agent: II
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Red phosphorous (180 mg) and iodine (60 mg) were added to acetic acid (2.85 ml), and the mixture was stirred for 30 min. A solution of water (60 mg) and α-methoxy-2-thiopheneacetic acid (860 mg, 5 mmol) in acetic acid (1.5 ml) was added to this mixture and the resulting mixture was heated under reflux for 2 hr. with vigorous stirring. After cooling to room temperature, water and ethyl acetate were added thereto. After filtering off the precipitate by the use of celite, the organic layer was separated. It was washed with saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After filtration, the solution was concentrated under a reduced pressure, and the crystals which remained were recrystallized from ethyl acetate:n-hexane to give 2-thiopheneacetic acid (610 mg) melting at 62° C. (Literature value: 62°-65° C.).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH2:12][CH3:13])[CH2:10]1>C(O)C>[CH2:1]([NH:8][CH2:10][CH:11]([OH:9])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1CO1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCC(O)CNCc1ccccc1
Temperature: 150 °C

Procedure:
To a solution of benzylamine (29.65 g, 277.0 mmol) in ethanol (40 mL) was added 1,2-epoxybutane (4 g, 55.47 mmol) and the mixture was heated to 150° C. for 2 h in a autoclave. It was concentrated and distilled at 140-150° C./2 mm Hg to give product as color less liquid, which slowly crystallizes at room temperature after 2 days. Yield: 8.5 g (85%)
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:32](=[O:33])[N:18]3[CH:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]([CH:23]=O)[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[C:6]1([CH2:12][C:13]([NH:15][CH:16]2[C:32](=[O:33])[N:18]3[CH:19]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:20](=[CH:23][O:3][C:1](=[O:4])[CH3:2])[CH2:21][S:22][C@H:17]23)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)C1C(C=O)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Yield: 72.5 %

Procedure:
Anhydrous sodium acetate (1.0 g.) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-formylcepham-4-carboxylate (2.0 g.) in acetic anhydride (5 ml.) and stirred at 65° to 70° C. for an hour. To the resultant solution were added water (200 ml.) and ethyl acetate (200 ml.), and adjusted to pH 8.0. The organic layer was separated, washed with aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo to give t-butyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (1.6 g.), mp. 178° to 183° C.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1([F:10])[CH2:6][C:7](=[O:9])[O:8][C:3]1=[O:4]
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1CC(F)(F)C(=O)O1

Procedure:
2,2-Difluorosuccinic acid (120 g, 0.78 moles) and trifluoroacetic anhydride (540 mL) are refluxed (bath temperature 80° C.) for 2 hours. Most of the rifluoroacetic acid is distilled utilizing a short Vigreux column, the final traces are removed under vacuum (12 mm Hg, 50° C.) and finally by stripping twice with carbontetrachloride. The oily residue solidifies on scratching with petroleum ether. Filtration and washing with petroleum ether yields 2,2-difluorosuccinic anhydride as slightly violet crystals: 98 g (92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[N:21]5)=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:71][N:72](C)CCN(C)C>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[F:28][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[N:21]5)=[CH:15][N:16]=3)[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:71]#[N:72]
Reactant: Fc1cc(-c2cnc3ncc(Cc4ccc5nccnc5c4)n3n2)ccc1Br
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cnc3ncc(Cc4ccc5nccnc5c4)n3n2)cc1F
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A mixture of 6-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylquinoxaline (120 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (8.8 mg, 0.0096 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11 mg, 0.019 mmol), zinc cyanide (20.1 mg, 0.171 mmol), and N,N,N′,N′-tetramethylethylenediamine (49.9 μL, 0.331 mmol) in N,N-dimethylformamide (0.2 mL) was irradiated under microwave at 160° C. for 10 min. After cooling to RT, the mixture was concentrated and the residue was purified by chromatography on silica gel with MeOH in methylene chloride (0-5%) to afford the desired product (65 mg, 62%). LCMS: (M+H)=382.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]#[N:17]>C(O)C>[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](=[CH:6]/[C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)/[C:16]#[N:17]
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccccc1CC#N
Solvent: CCO
Product: Cc1ccccc1/C(C#N)=C/c1ccc[nH]1
Temperature: 90 °C
Yield: 30.5 %

Procedure:
A thick walled tube was charged with 1H-pyrrole-2-carbaldehyde (2.0 g, 21.0 mmol), 2-methylphenylacetonitrile (2.5 g, 18.9 mmol, 0.9 equivalents), ethanol (75 ml), and 40% aqueous Triton B (4.0 ml, 3.3 mmol). The tube was sealed and heated to 90° C. for 4 days. Removal of the solvent, followed by chromatography on silica gel using dichloromethane/petroleum spirits (20:80) as eluant afforded a yellow solid (1.2 g). This is Compound 16 in Table 8.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[CH:5]=2)=[O:15])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc2c(O)cc(C(=O)O)cc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 550 mg of 4-Hydroxy-7-methyl-naphthalene-2-carboxylic acid and 1.0 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 8.3 ml of DMF, 458 mg of HOBT and 573 mg of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.