Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1.CN(C=O)C.N1CCCC1.[CH:32](=[O:36])[CH2:33][CH2:34][CH3:35]>CCOC(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.[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc3cc(Br)ccc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CCCC(=O)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 115 °C
Yield: 73 %

Procedure:
To a vial was added tert-butyl 8-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.4 g, 4.0 mmol), Pd(dba)2 (75 mg, 2 mol %), BINAP (75 mg, 3 mol %), and crushed 4 Å MS (2.0 g). The vial was evacuated and backfilled under argon. To the vial was then added DMF (15 mL), pyrrolidine (660 μL, 8.0 mmol), and butyraldehyde (1.0 mL, 12 mmol). The vial was then sealed under argon and heated to 115° C. for 6 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (50 mL), and filtered through celite. The filtrate was washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified on silica gel (1:1 hexanes/EtOAc) to afford the title compound as a white solid (1.0 g, 73%).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:38])/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([O:34]COC)=[CH:30][CH:29]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:38])/[C:14](/[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccc(OCOC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 4a (45 mg, 0.0842 mmol) in MeOH (1 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 (126 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt and a little MeOH. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual solid was crystallized with Et2O to give 5 (68%). 5: colorless powder; 1H-NMR (CD3OD) δ 0.98 (3H, t, J=7.4 Hz), 2.45 (6H, s), 2.61 (2H, q, J=7.4 Hz), 2.90 (2H, t, J=5.3 Hz), 4.14 (2H, t, J=5.3 Hz), 6.54 (2H, d, J=8.8 Hz), 6.63 (2H, d, J=8.6 Hz), 6.92-6.97 (6H, m), 7.52 (2H, d, J=9.0 Hz). HRMS calcd for C27H31N2O4 [M+H]+: 447.2284. Found: 447.2298.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(OCF)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethoxy)picolinic acid [CAS 1174321-03-9; J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=445.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCn2ccc(-c3nc(C)c(C(=O)NCc4ccc(F)cc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and 1-(2-bromo-ethyl)-4-methoxy-benzene as describe in Example 83 and isolated as a white solid (0.045 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 7.30-7.35 (m, 2H), 7.14 (d, J=2 Hz, 1H), 7.04 (t, J=8 Hz, 2H), 6.97 (d, J=8 Hz, 2H), 6.80 (d, J=8 Hz, 2H), 6.71 (d, J=2 Hz, 1H), 6.03-6.09 (m, 1H), 4.57 (d, J=4 Hz, 2H), 4.32 (t, J=7 Hz, 2H), 3.77 (s, 3H); 3.12 (t, J=7 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=451.2; Rt=1.49 min; HRMS (M+H)+=451.16.
Reaction SMILES: C[NH:2][C:3]1C=CC=CC=1.C([Li])CCC.C1C=CC([N:20]=C(Cl)Cl)=CC=1.[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[C:3]([NH2:2])(=[NH:20])[C:26]1[CH:25]=[CH:24][CH:29]=[CH:28][CH:27]=1
Reactant: CNc1ccccc1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N=C(N)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2.14 g (0.02 mol) of N-methylaniline in 20 ml of anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere was added 8 ml of 2.5 M n-butyl lithium in hexane. The solution was stirred for one hour at 0° C. To the lithium N-methylanilide solution at -23° C. was added 3.48 g (0.02 mol) of phenyl isocyanide dichloride in 5 ml of tetrahydrofuran dropwise. The mixture was stirred for 15 minutes at -23° C. and one hour at 0° C. to afford a clear yellow solution to which 4.8 g (0.04 mol) of benzamidine in 15 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 21 hours at ambient temperature, concentrated and chromatographed on 150 g of silica gel using 1:6 methanol-dichloromethane. The chromatographed product was precipitated by adding a methanolic solution of the product to a large volume of ether and finally recrystallized twice from methanol-ether to afford 1.72 g (24%) of (N-methyl-N,N'-diphenylguanyl)benzimidamide hydrochloride, mp 243°-244° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
In pyridine (20 ml) was dissolved 2.00 g (8.12 m-mol) of 2'-deoxy-5-fluorouridine, and the solution was cooled to -10° C. To this solution was added a solution of 2.05 g (8.16 m-mol) of N-benzyloxycarbonylvaline and 2.45 g (8.11 m-mol) of TPS in pyridine (20 ml), and the mixture was allowed to stand for 2 days under cooling (about 5° C.). The solvent was distilled off under reduced pressure from the reaction mixture and the residue was subjected twice to silica gel column chromatography [column size: 3.0×10 cm; developing solvent: CHCl3 -CH3OH (98:2)] under the same operation conditions whereby 1.70 g (yield: 43.7%) of 5'-O-(N-benzyloxycarbonylvalyl)-2'-deoxy-5-fluorouridine was obtained as amorphous powders.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH2:16][C:17]([NH2:19])=[O:18].O>CN(C=O)C>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)ccc1N
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(N)=O)ccc1N
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of NaH (299 mg, 7.48 mmol) in DMF (20 ml) at 0° under argon atmosphere was added methyl 2-amino-5-hydroxybenzoate (1.25 g, 7.48 mmol) and 2-iodoacetamide (1.38 g, 7.48 mmol). The mixture was stirred at 0° for 1 hr and at r.t overnight. At 0° water was given to the reaction mixture. The product was extracted with EtOAc. The organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a methylenchloride gradient to obtain the title compound (1.03 g, 64%) as off-white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:17]Br>ClCCl>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[C:4]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: BrBr
Solvent: ClCCl
Product: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine (230 mg, 1 mmol, Oakwood Products) in dichloromethane (5 mL) was added a solution of bromine in dichloromethane (1.5 mL, 1 M, 1.5 mmol). The reaction mixture was stirred at 25° C. for 2 h. The precipitated yellow solid was filtered, washed with small amount of methanol and dried in vacuo to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 311 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[CH2:27](N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N(OCC(C)C)=O>C(#N)C.CC(N(C)C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: NCc1ccccc1
Agent: CC(C)CON=O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-thienylacetamido) ceph-3-em-4-carboxylic acid (3.96 g., 10 m. moles) in acetonitrile (70 ml) and dimethylacetamide (5 ml) was added benzylamine (1.28 g., 12 m. moles) and isobutyl nitrite (2.47 g., 24 m. moles) and the mixture heated to 45° over 2 hours. Initially a solid formed in the mixture but with vigorous stirring it had all dissolved after 1-1.25 hours as the reaction proceeded. After removal of the solvent in vacuo, the gum was taken up in ethyl acetate (50 ml) washed with dilute H2SO4 (25 ml.), 5% NaHCO3 solution (50 ml.) and water (50 ml.), and the organic residue after evaporation of the organic solvent crystallised from hot isopropanol to yield the title ester (2.40 g., 42% based on the input acid) m.pt. 135° - 139°. T.l.c. indicated the presence of some trace impurities.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH2:38][OH:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C.N1C=CC=CC=1>CS(C)=O>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH:38]=[O:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N[C@H](CO)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N[C@H](C=O)CC1CCCCC1

Procedure:
To a mixture of the dipeptide alcohol [18a] (2.0 g, 3.65 mmol), triethylamine (1.30 g, 12.85 mmol, 3.5 eq) and DMSO (6 ml) is added at room temperature SO3.pyridine (2.03 g, 12.75 mmol, 3.5 eq) in DMSO (6 ml) and the mixture is stirred for 35 minutes. The reaction mixture is poured on ice, and the resultant aqueous mixture is extracted with ethyl acetate (20 ml×3). The organic layer is subsequently washed with 10% aqueous citric acid, saturated aqueous sodium chloride (×2), 7% aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over MgSO4, and concentrated to dryness in vacuo. The resultant residue is purified with silica gel chromatography (SiO2 :100 g, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-3-cyclohexylalaninal [14a] (1.67 g, 84%) in amorphous powder.
Reaction SMILES: [C:1](Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.ClCCl.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[Cl:28].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:28][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:18]=1[NH:17][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)=[O:12])[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Temperature: 25 °C

Procedure:
A 3.5 g portion of 4-nitrophenyl chlorocarbonate was added at 0° C. to a 30 ml dichloromethane suspension of 3 g of methyl 4-amino-3-chlorobenzoate and 4 ml of pyridine and stirred at room temperature for 2Hours. The reaction solution was diluted with chloroform and washed with 1 M hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, water and saturated brine in that order, and the organic layer was dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was recrystallized from hexane-ethyl acetate to obtain 4.23 g of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate as a pale brown powder.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].C(Cl)(Cl)(Cl)Cl.[Br-:12].[CH2:13](O)[CH3:14]>>[CH2:5]([O:4][CH:1]([O:3][CH2:13][CH3:14])[CH2:2][Br:12])[CH3:6]
Reactant: C=COC(C)=O
Reactant: [Br-]
Reactant: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(CBr)OCC
Reaction time: 48 h

Procedure:
To a mixture of 10 g of vinyl acetate and 20 ml of carbon tetrachloride under cooling (temperature 10° C.) 10 ml of carbon tetrachloride and 18.5 g of bromide solution are added. 60 ml of ethanol are added to the mixture and it remains standing for 2 days. The organic phase is washed twice with 50 ml of water, then it is distilled in vacuo.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:15])[O:7][C:8]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=O)[CH2:2][CH3:3].C(CC(OCC)=O)#[N:17].[O-][CH2:25][CH3:26].[Na+].[Na]>C(O)C>[C:3]([C:2]1[C:10]2[C:9]([CH:8]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:6]([OH:7])=[O:15])[C:1]=1[CH2:25][CH3:26])#[N:17]
Reactant: CCOC(=O)CC#N
Reactant: CC[O-]
Reactant: CCC(=O)c1c2cccccc-2oc1=O
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCc1c(C#N)c2cccccc-2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
3.62 g (17.9 mmol) of 3-propionylcycloheptafuran-2-one and 3.8 ml (35.8 mmol) of ethyl cyanoacetate were dissolved in 50 ml of ethanol. The solution was mixed with a solution of sodium ethoxide prepared from 80 ml of ethanol and 1.65 g (71.7 mmol) of sodium, at 0° C. After the mixed solution was stirred overnight at room temperature, the obtained reaction solution was concentrated up to two times an initial concentration thereof. The concentrated solution was diluted with 200 ml of water and extracted with dichloromethane. Thereafter, an aqueous phase of the extract was mixed with dilute hydrochloric acid to acidify the aqueous phase, thereby obtaining a crystallized product. After filtration, the crystallized product was dried under a reduced pressure to obtain 3.73 g of 1-cyano-2-ethylazulene-3-carboxylic acid (yield: 93%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 2-phenoxyethanol (10.0 mL, 80.0 mmol) and triethylamine (13.5 mL, 96.9 mmol) in anhydrous CH2Cl2 (250 mL) at 0° C. is added methanesulfonyl chloride (6.80 mL, 87.9 mmol). The resulting cloudy mixture is stirred at 0° C. for 2 h. The mixture is diluted with water (75 mL) and extracted. The organic layer is washed with 1N HCl (75 mL) then saturated NaHCO3/brine (1:1; 75 mL) dried (Na2SO4), filtered, and concentrated. The residue is dried to constant weight under reduced pressure to provide the title compound as a pale yellow oil (17.1 g, 99%). This material is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:14]([OH:20])(=[O:19])[CH2:15]C(O)=O.C([O-])(=O)C.[NH4+:25]>C(O)C>[NH2:25][CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=1)[CH2:15][C:14]([OH:20])=[O:19]
Reactant: [NH4+]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.5 g of 4-(trifluoromethoxy)benzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are boiled under reflux for 8 hours and stirred at room temperature overnight. The cooled reaction mixture is then filtered with suction, washed with ethanol and ether and dried in air. 3-amino-3-(4-trifluoromethoxyphenyl)propionic acid is obtained, melting point 258-260°.
Reaction SMILES: [NH:1]=[C:2]=N.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[C:17]=1[O:29][Si](C(C)(C)C)(C)C)=S.CS(Cl)(=O)=O.C([N:44](CC)CC)C>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]([C:2]#[N:1])[C:13]([NH:12][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=2[F:4])=[NH:44])=[C:17]([OH:29])[C:18]=1[S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24]
Reactant: N=C=N
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(F)c2F)c1O[Si](C)(C)C(C)(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2cccc(F)c2F)c1O

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2,3-difluorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (347 mg, 0.69 mmol), methanesulfonyl chloride (0.12 mL, 1.38 mmol) and triethylamine (0.2 mL, 1.04 mmol) were reacted to form the desired product (340 mg, crude). 1H NMR (CDCl3) δ 0.39 (s, 6H), 1.03 (s, 9H), 2.86 (s, 6H), 6.95 (t, 1H), 7.03 (m, 2H), 7.08 (d, 1H), 7.31 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19]Cl)[N:10]=1.[CH:32]1([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(#N)C.[Ag-]=O>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[N:11]([CH2:19][O:39][C:37]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:38])[N:10]=1
Reactant: O=C(O)C1CCCC1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CCl)c1=O
Agent: O=[Ag-]
Solvent: CC#N
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-chloromethyl-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 (0.64 mmol) in acetonitrile (18 mL) at 25° C. was treated with cyclopentanecarboxylic acid (73.4 μL, 0.67 mmol) followed by silver (I) oxide (155.4 mg, 0.67 mmol). The reaction mixture was stirred at 25° C. in the dark for 3 d. At this time, the reaction was filtered through a pad of celite® and was rinsed with a solution of 90/10 methylene chloride/methanol (1×100 mL). The filtrate was then concentrated in vacuo. Biotage flash chromatography (40S, 0.5-1.25% methanol/methylene chloride) followed by reverse phase chromatography (Pursuit C-18 column, acetonitrile gradient with trifluoroacetic acid) followed by lyophilization afforded cyclopentanecarboxylic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (75.7 mg, 21%) as an off-white solid. ES+-HRMS m/e calcd for C24H22N6O6Cl2 (M+Na+) 583.0870, found 583.0871.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]([O:30][C:31](=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)[CH2:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:12].[OH:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1.[C:52](=[O:55])([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:48]([C:47]1[CH:50]=[CH:51][C:44]([O:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]([O:30][C:31](=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH:52]=[O:55])=[CH:46][CH:45]=2)[CH2:16][O:17][C:18](=[O:29])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:43][C:44]2[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=2)=[O:12])=[CH:45][CH:46]=1)=[O:49]
Reactant: O=C(CCCCCCCCCBr)OCC(COC(=O)CCCCCCCCCBr)OC(=O)CCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCOc2ccc(C=O)cc2)OC(=O)CCCCCCCCCOc2ccc(C=O)cc2)cc1
Yield: 70.5 %

Procedure:
A mixture of 10.0 g 1,2,3-tris(10-bromodecanoyloxy)propane, 4.6 g 4-hydroxybenzaldehyde, 52.4 g anhydrous potassium carbonate and 250 ml ethyl-methyl ketone is heated under gentle reflux overnight. The reaction mixture is filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent and recrystallisation from acetonitrile to yield 8.1 g of 1,2,3-tris(10-[4formylphenoxy]decanoyloxy)propane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH2:8])[CH:7]=1.C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].[C:26](O)(=[O:28])[CH3:27]>>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([NH:8][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(NC(C)=O)cc([N+](=O)[O-])c1

Procedure:
A mixture of 2.5 g. (0.015 mol) of 3,5-diaminonitrobenzene, 100 ml. of toluene, 15 ml. of acetic acid and 3 ml. (3.24 g., 0.32 mol) of acetic anhydride was refluxed for five hours. The reaction mixture was cooled, filtered and the solid washed well with toluene, then boiled in 150 ml. of ethanol for 20 minutes to give 3,5-bis-acetamidonitrobenzene, m.p.>290° C.