Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].[C:10]([O-])([O-])=O.[K+].[K+].IC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1ncc(Cl)c(Cl)c1=O
Temperature: 115 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
25 g (151 mmoles) of 4,5-dichloropyridazinone are placed in a stainless steel reactor in the presence of 25.13 g (181 mmoles) K2CO3, 1 g (3.03 mmoles) of tetrabutylammonium bromide and 14.2 mL (227 mmoles) of iodomethane in 150 mL acetonitrile. The reaction medium is agitated for 4 h at 115° C. then filtered. The filtrate is concentrated to dryness then solubilized in AcOEt and washed in acid water (pH 1), then with NaCl-saturated water. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2). 19.1 g of intermediate 3a are thus obtained in the form of a yellow solid (yield 70%). TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70:30, Rf=0.48.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:27]=[CH:26][C:15]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]3)[O:18][C:14]=2[CH:13]=1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[CH:14]([OH:18])=[O:42].[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([NH:25][CH:22]1[CH2:23][CH2:24][N:20]([CH2:19][C:17]2[O:18][C:14]3[CH:13]=[C:12]([O:11][C:3]4[S:2][C:10]5[C:5]([N:4]=4)=[N:6][CH:7]=[CH:8][CH:9]=5)[CH:27]=[CH:26][C:15]=3[CH:16]=2)[CH2:21]1)=[O:42]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC1CCN(Cc2cc3ccc(Oc4nc5ncccc5s4)cc3o2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 1-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-ylmethyl]-pyrrolidin-3-ylamine hydrochloride (65 mg, 0.161 mmol) in DCM (2 mL) was added DIEA (64 μL, 0.484 mmol) followed by pivaloyl chloride (20 μL, 0.484 mmol) and the resulting solution was stirred (rt, 1 h). The reaction mixture was partitioned with DCM (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography using MeOH:DCM (0-10%) followed by reverse phase HPLC to provide the title compound as a yellow solid (32 mg, 40%). MS (ESI): mass calcd. for C24H26N4O3S, 450.2; m/z found, 451.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.48 (dd, J=4.8, 1.3, 1H), 8.30 (dd, J=8.0, 1.6, 2H), 7.72-7.68 (m, 2H), 7.38-7.29 (m, 2H), 6.92 (s, 1H), 4.47-4.37 (m, 1H), 4.13-4.02 (m, 2H), 3.19-3.04 (m, 2H), 2.89-2.75 (m, 2H), 2.38-2.30 (m, 1H), 1.84-1.77 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:35][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C:9]1=[O:53])(C)(C)C.COC(=O)N[CH:59](C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(CN5CCCC(N)C5=O)=NC=4)=CC=3)=CC=2)=CN=1)=O)[CH:60](C)C>>[CH3:1][O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]2[N:10]([CH:14]([C:15]3[NH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:33][C:34]([CH:37]7[CH2:41][CH2:40][CH2:39][N:38]7[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:45])[CH3:46])=[N:35][CH:36]=6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)=[CH:18][N:19]=3)[CH2:59][CH2:60]2)[C:9]1=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC1CCC2CCC(c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O

Procedure:
{3-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {1-[2-(5-{4′-[2-(6-Amino-5-oxo-octahydro-indolizin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for {1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester in method 805. C39H46N8O6 calculated 722.4 observed [M+1]+ 723.4; rt=1.62 min. 1H (DMSO-d6): δ=8.10 (m, 1H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 2H), 3.74 (m, 1H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd, J=8.8 Hz, J=17.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C:13]2[S:14][C:15]([C:24](O)=[O:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:62]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]>CN(C=O)C>[C:65]([O:64][C:62]([N:69]1[CH2:74][CH2:73][N:72]([C:24]([C:15]2[S:14][C:13]([NH:12][C:10](=[O:11])[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)([CH3:27])[CH3:28])=[N:17][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:25])[CH2:71][CH2:70]1)=[O:63])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carboxylic acid (46 mg, 0.11 mmol), HBTU (50 mg, 0.13 mmol), triethylamine (22 uL, 0.16 mmol) and N-Boc piperazine (27 mg, 0.15 mmol) in DMF (2 mL) was stirred at RT for 18 h and partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 596.2 (MH+).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([C:30]2[CH:31]=[C:32]([CH:38]=[CH:39][C:40]([O:42]CC)=[O:41])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])=[CH:18][C:19]2[C:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([C:30]2[CH:31]=[C:32]([CH:38]=[CH:39][C:40]([OH:42])=[O:41])[CH:33]=[CH:34][C:35]=2[O:36][CH3:37])=[CH:18][C:19]2[C:20]([CH3:28])([CH3:29])[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[C:24]=2[CH:25]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2OCCCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC3(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCCC(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
A solution of 3.75 g (6.18 mmol) of ethyl 3-{3-[3-(7-tert-butoxycarbonylheptyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained in Example 22(b) dissolved in 60 ml of dichloromethane was placed in a round-bottomed flask, 4.76 ml (61.8 mmol) of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 4 hours. The reaction medium was poured into water and extracted with ethyl ether, and the organic phase was decanted, dried over magnesium sulfate, filtered and evaporated. 3.4 g (100%) of the expected compound were obtained in the form of a white foam.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C>[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][CH2:25][N:26]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
The 4-pyridin-4-yl-benzoic acid hydrochloride salt (100 mg, 0.502 mmol), [2-(4-chlorobenzylamino)-ethyl]-carbamic acid tert-butyl ester (143 mg, 0.502 mmol), HOBt (77 mg, 0.502 mmol), and EDCI (56 mg, 0.552 mmol) were dissolved in 1.7 mL DMF, then treated with triethyl amine (77 μL, 0.552 mmol) to room temperature. The reaction was allowed to stir overnight to completion and partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with hexanes/ethyl acetate gradients plus 2% triethylamine) to afford the {2-[(4-chlorobenzyl)-(4-pyridin-4-yl-benzoyl)-amino]-ethyl}-carbamic acid tert-butyl ester as a colorless oil (184 mg, 93%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (d, J=4.8 Hz, 2H), 7.65 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.48 (d, J=4.4 Hz, 2H), 7.34 (m, 2H), 7.13 (m, 2H), 4.91 (m, 1H), 4.59 (brs, 2H), 3.62 (m, 2H), 3.44 (m, 2H), 1.46 (s, 9H). LCMS (APCI+) m/z 466 [M+H]+; Rt=3.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([F:30])[CH:3]=1.IC.[C:33](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9][C:10]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:33])[CH:12]=2)=[O:18])=[C:4]([F:30])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccc(Cl)cc2F)c1
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 161, step 1, ethyl 3-(1-(4-chloro-2-fluorophenyl)-3-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)propyl)benzoate was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=442.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:14]1[CH2:15][CH2:16][C@:10]2([N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)[CH:7]=[CH:6][N:5]=3)[CH2:12][CH2:11]2)[C:13]1=[O:18]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1CC[C@@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CC[C@@]2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)=N2)C1=O
Temperature: 120 °C
Yield: 89.6 %

Procedure:
To a solution of (5S)-2-(4-bromo-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (640 mg, 2.0768 mmol) in MeCN (8 mL) and water (1 mL) in a Smith microwave vessel was added [4-(trifluoromethyl)-phenyl]boronic acid (394.44 mg, 2.0768 mmol), bis(triphenylphosphine)palladium (II) dichloride (60 mg, 0.0855 mmol) and sodium carbonate (484.26 mg, 4.5689 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 120° C. for 25 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge, and evaporated. The crude residue was purified by silica gel chromatography (50 g, SiO2) eluting with ethyl acetate in iso-hexane (10-100%). Evaporation of desired fractions gave (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (D118) (695 mg, 1.8614 mmol, 89.6% yield);
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[N:50](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CO.N.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:23][CH2:24][C:25]([NH2:50])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
The resulting 3-(bis(2-((Z)-octadec-9-enyloxy)ethyl)amino)propanoic acid (85 mg, 0.125 mmol) was dissolved in chloroform (3 mL), and stirred overnight at room temperature after adding 0(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 95 mg, 0.251 mmol), a 7 mol/L ammonia methanol solution (0.090 mL, 0.627 mmol), and diisopropylethylamine (0.109 mL, 0.627 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 88/12) to give compound 84 (72.3 mg, 85.0%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:11]=1[C:12]([OH:14])=[O:13]>CO>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:11]=1[C:12]([O-:14])=[O:13].[CH2:1]([NH3+:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(O)cccc1O
Reactant: NCc1ccccc1
Solvent: CO
Product: O=C([O-])c1c(O)cccc1O
Product: [NH3+]Cc1ccccc1
Reaction time: 8 h

Procedure:
Benzylamine (1.07 g; 10 mmol) was added dropwise to a solution of 2,6-dihydroxybenzoic acid (1.54 g; 10 mmol) in methanol (10 cm3). The mixture was left to stand at 20° C. overnight which resulted in the formation of pale pink crystals. The product was collected by filtration and recrystallized from water to produce white crystals. Found: C, 63.8%; H, 5.9%; N, 5.1%. Calculated for C14H15NO4 : C, 64.30%; H, 5.74%; N, 5.36%. M.pt. 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O:19]CC2C=CC([N+]([O-])=O)=CC=2)=[O:18])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:36]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O-:19])=[O:18])=[CH:30][CH:31]=1.[Na+:36]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Oc3ccc(Cl)cc3)SC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)[O-])=C(Oc3ccc(Cl)cc3)SC12
Yield: 53.7 %

Procedure:
A mixture of a solution of 205 mg of 4-nitrobenzyl 3-(4-chlorophenoxy)-6-ethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 37.5 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. Then, the mixture was filtered through Celite, and then lyophilized to yield 83 mg of the title compound as a pale yellow crystalline solid (53%).
Reaction SMILES: ClC1C=C(C=CC=1)NC1C(CN)=CC=CN=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:18].ClC1C=C(N2C3N=CC=CC=3CNC2=O)C=CC=1.[O:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:48]([O:47][CH2:51][CH3:50])(=[O:18])[CH3:49].[CH2:48]([O:47][CH2:51][CH3:50])[CH3:49]
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NCc1cccnc1Nc1cccc(Cl)c1
Agent: O=C1NCc2cccnc2N1c1cccc(Cl)c1
Product: CCOC(C)=O
Product: CCOCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
Sodium hydride (previously washed in hexanes) was added to a solution of 2-(3-chloroanilino)-3-aminomethylpyridine (10.3 g, 44.1 mmole) in tetrahydrofuran (200 ml). The solution was stirred at room temperature for 5 minutes. 1,1'-Carbonyldiimidazole (10.7 g, 66.1 mmole) was added gradually to the solution with stirring; after the addition the solution was refluxed for 22 hours. The solvents were removed and H2O was added to the residue. The solid material was extracted in ethyl acetate, washed with H2O and dried over MgSO4. The MgSO4 was removed by filtration and the solvents by evaporation. The product was recrystallized out of ethyl acetate/ethyl ether yielding 5.7 g (21.9 mmole, 50% yield) of 1-(3-chlorophenyl)pyrido[2,3-d]pyrimidine-2(1H,3H)-one (mp 188°-187° C.), as a tan solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 219.4 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(4-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (74%) which was obtained as a light yellow solid. To a solution of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (832 mg, 98%) which was obtained as an off white solid. MS: m/e=343.1 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=2)[C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 84 (179 mg, 0.438 mmol) dissolved in CH2Cl2 (2 mL) at 0 (C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was recrystallized (EtOAc:hexanes) to afford 120 mg (78%) of 85 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (br s, 6H), 2.13 (m, 4H), 6.45 (d, J=16.0 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 6.76 (dd, J=12.3 Hz, 1.7 Hz, 1H), 6.85 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.1 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H) 9.76 (s, 1H), 12.31 (br s, 1H). LRMS (ESI): m/z 353 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Fc1ccc(Br)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To 5-bromo-2-fluorobenzaldehyde (2.50 g, 12 mmol) and morpholine (1.61 mL, 1.61 g, 18 mmol) in 1,2-dichloroethane (100 mL) was added sodium triacetoxyborohydride (5.21 g, 2.5 mmol) portionwise with stirring at room temperature over 5 min. The mixture was stirred under nitrogen for 1 h, then 2 N sodium hydroxide solution (100 mL) was added, and the mixture was stirred for a further 5 min. The biphasic mixture was separated, and the aqueous layer was washed with dichloromethane (2×75 mL). The combined organic layers were washed with saturated sodium chloride solution (1×50 mL) and were concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 75% diethyl ether in isohexane (+1% triethylamine), to yield 4-(5-bromo-2-fluorobenzyl)morpholine (3.18 g, 94%).