Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:14]=2)[CH:5]=1)([O-])=O.[H][H]>[Pd]>[CH:5]1[C:6]2[C:15](=[N:14][C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=2)[CH:16]=[CH:17][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2nc3c(nc2c1)CCCC3
Agent: [Pd]
Product: Nc1ccc2nc3c(nc2c1)CCCC3
Yield: 94 %

Procedure:
A 18.0 g (0.078 mole) portion of 6,7,8,9-tetrahydro-2-nitrophenazine and 5 g of 5% Pd/C (50% H2O) were placed in a 1.7 liter stainless steel pressure bottle and subjected to hydrogenation at 40 psig. The hydrogen uptake was 18 lb (theory 17 lb). The reaction mixture was then filtered and concentrated. The filtrate was then concentrated to 1/3 volume, refrigerated, filtered, air dried, and dried to a constant weight at 60° to give 15 g (94%) of a yellow solid, m.p. 150°-152°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[N:6][CH:7]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.C(OCC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:18]([O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[N:17][C:9]=1[O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccnc1Oc1cncc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A 15 ml flask was charged with 2-(5-chloro-pyridin-3-yloxy)-nicotinic acid (0.056 grams, 0.22 mmole), benzyl alcohol (0.052 grams, 0.44 mmole), 4-DMAP (˜3 mg), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.048 grams, 0.25 mmole), diethyl ether (4 ml) and pyridine (1 ml) and stirred at room temperature. After 1 hour the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 9/1 ethyl acetate/hexane to give 0.060 g of the title compound as a colorless oil. Anal. calcd. for C18H13ClN2O3: M.S. m/z [M+] 341; 1H NMR (CD3OD) d 4.58 (s, 2H), 7.45(m, 7H), 7.71 (s, 1H), 8.28 (m, 2H), 8.38 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([CH2:34][NH2:35])[OH:33]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:35][CH2:34][CH2:32][OH:33])=[O:25])[C:6]1=[O:29]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those those described in Example 9 and was purified by recrystallization from DMSO and MeOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.53 (1H, br), 8.14 (1H, s), 7.26 (3H, m), 7.10 (2H, t, J=9 Hz), 4.92 (2H, s), 4.74 (1H, br t), 3.99 (2H, s), 3.45 (2H, m), 3.27 (2H, m), 3.08 (3H,), 2.78 (3H, s); HRMS calcd for C22H23FN4O5+H+: 443.1731. Found: 443.1738.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:24][C:17]1[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Reactant: O=C1NCCO1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)cc1C
Yield: 79 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4,5-trimethylphenyl)piperazin-1-yl]methanone (430 mg) described in Preparation Example 143 and oxazolidin-2-one (128 mg), the title compound (345 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][CH2:14][CH:15](N)[CH3:16].[C:18]([C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[N+:27]([O-:29])=[O:28])#[N:19]>ClC1C=CC=CC=1Cl>[CH3:25][N:24]1[C:20]([C:18]2[NH:13][CH2:14][CH:15]([CH3:16])[N:19]=2)=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([CH3:26])=[N:23]1
Reactant: CC(N)CN
Reactant: Cc1nn(C)c(C#N)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: Cc1nn(C)c(C2=NC(C)CN2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (15.2 g, 0.08 mol) is added in portions with stirring to 6 g (0.08 mol) of 1,2-diaminopropane under nitrogen. To the resulting melt (ca 100° C.) is added in portions 12.6 g (0.076 mol) of 5-cyano-1,3-dimethyl-4-nitropyrazole (mp 93° C.); the mixture is stirred and heated to 120° C. and 25 ml of o-dichlorobenzene is added; stirring is continued at 120°-130° for 0.5 hours then at 160° C. for three hours. The cooled mixture is extracted with 75 ml of 3N HCl. The aqueous extract is made strongly basic with a large excess of concentrated NH4OH and the mixture is extracted thoroughly with methylene dichloride. Evaporation of the extract gives 14.3 g (84%) of 2-(1,3-dimethyl-4-nitropyrazol-5-yl)-4-methylimidazoline, mp 98°-101°.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])[C:37]=1[CH2:49][OH:50].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:50][CH2:49][C:37]4[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])=[CH:39][C:40]([F:42])=[CH:41][C:36]=4[F:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4c(F)cc(F)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.2 g, 0.342 mmol) and (S)-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)methanol (0.094 g, 0.411 mmol) in DMF (1 mL) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 4 h, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated and purified by Prep HPLC: to afford (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (0.030 g, 0.046 mmol, 13.35% yield) as a colorless oil. LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>C(O)(C)C.C(O)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CC(C)O
Solvent: CCO
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 9 h

Procedure:
0.650 g 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (5.7 mmoles) is dissolved in 5 ml isopropanol. 1 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (6.32 mmoles) is added. The mixture is boiled for 9 h. A further 1 g of epoxyester is added and boiling is continued for a further 9 h. After cooling, the solvent is decanted and the dark mass obtained is taken up in ethanol. The solid obtained is filtered, to give oxiracetam, m.p. 167°-70° C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[Br:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Nc1nnc(-c2cccc(Br)c2)c(-c2ccccc2)n1
Yield: 41.9 %

Procedure:
6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine (218 mg, 52%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and 3-bromophenylboronic acid (0.32 g, 1.59 mmol) according to the general procedure of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2ccccc2)c(-c2ccc(Cl)s2)n1
Temperature: 140 °C

Procedure:
A biphasic mixture of 30 mg (0.068 mmol) of 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione, 10 mg (0.081 mmol) of phenylboronic acid, 4.0 mg (0.0034 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2 mL of 1,4-dioxane and 0.5 mL of 2 M aqueous Na2CO3 was heated in a microwave at 140° C. for 20 min. The reaction mixture was cooled to rt, diluted with 5 mL of water and extracted twice with CH2Cl2 and twice with a 3:1 mixture of CHCl3 and iPrOH. The combined organic extracts were concentrated and the crude products separated by C-18 prep HPLC to give 1-{2-[4-(5-chlorothiophen-2-yl)-5-phenylpyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 442; and 5,5-dimethyl-1-{2-[5-phenyl-4-(5-phenylthiophen-2-yl)pyrimidin-2-ylamino]ethyl}imidazolidine-2,4-dione: MS (M+H)+ 484.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CCOCC.[I:22]N1C(=O)CCC1=O>C(#N)C>[I:22][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)c1ccc(O)c(I)c1
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a stirring solution of 4-hydroxy-benzoic acid (6.91 g, 50.03 mmol) in dry acetonitrile (250 mL) at −20° C. under an atmosphere of N2 was added HBF4.Et2O (10.50 g, 9.50 mL, 55.00 mmol) dropwise via syringe. The solution was stirred at 0° for 0.5 hours at which time solid N-iodosuccinimide (13.5 g, 60 mmol) was added at one time. The solution was left to stir for 16 hours and then filtered to remove precipitated succinimide. The solution was diluted with water (500 mL) and extracted with ethyl acetate (2×250 mL). The organic portions were combined and washed with 10% sodium bisulfite (250 mL), water (2×250 mL) and saturated aqueous NaCl (250 mL). The solvent was removed in vacuo to yield 8.76 g of crude solid. The crude solid was purified by column chromatography (6:4:0.1 hexane:ethyl acetate:formic acid) to yield 7.54 g (57%) of the desired product as white crystals. 1H NMR (DMSO-d6) δ 12.74 (br s, 1H), 11.18 (s, 1H), 8.20 (s, 8.20, 1H), 7.79 (d, 1H), 6.94 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N[C@@H:14](CCC)C(O)=O>>[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:14])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH2:14])=[CH:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:6]2
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)C=C(CN)CO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC1=Cc2cc(OC)ccc2OC1
Reaction time: 0.5 h

Procedure:
A solution of 0.49 g (2.57 mmol) of the amine obtained in Step B of Example 40 in 10 ml of dichloromethane is cooled to 0° C.; 1 ml (7.7 mmol) of triethylamine and also 0.41 g (3.85 mmol) of butyryl chloride are then added in succession to the medium. After 30 minutes of stirring under an inert atmosphere, the reaction mixture is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant: PE/AcOEt: 40/60) yields the title amide in the form of a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C1COCC1>[CH3:8][C:9]([CH3:14])=[CH:10][C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: CC(C)=CC(=O)Cl
Reactant: Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Oc1ccccc1
Reaction time: 5 h

Procedure:
To an ice bath cooled solution of 1.29 g (54 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3×10 ml hexane wash) in 20 ml of dry THF was added slowly under oxygen a solution of 5 g (53 mmol) of phenol in 50 ml of dry THF. The mixture was then treated with a solution of 7 g (59 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture was stirred for a further 2 5 h. The reaction mixture was then poured into 150 ml of water containing 1 ml of glacial acetic acid. The mixture was extracted with 150 ml ether and the ether extract washed with saturated NaCl solution and then dried (MgSO4) The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ether in hexanes) to give the title compound as a yellow oil. PMR (CDCl3)): & 1.99 (3H, s), 2.24 (3H, s), 5.93 (1H, broad s), 7.10 (2H, d, J~7.8 Hz) 7.22 (1H, t, J~7.8 Hz), 7.38 (2H, t, J~7.8 Hz).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:33])([O-:28])=[O:27]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)c1cccc([N+](=O)[O-])c1)c1ccc(OC)c(OC)c1
Yield: 95.3 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenvl)propionate hydrochloride (1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 10 milliliters of tetrahydrofuran was added 3-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. A thick slurry resulted. The cooling bath was removed after 15 minutes, the mixture diluted with 10 milliliters of tetrahydrofuran and the mixture stirred for an additional hour. The reaction mixture was diluted with 50 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid washed with copious amounts of water, air-dried, and dried in vacuo (60° C., <1 mm) to afford 1.85 grams (95%) of the product as an off white powder: 1H NMR (CDCl3, 250 MHz) δ 8.63 (t, J=1.9 Hz, 1 H), 8.35 (m, 1 H, Ar), 8.20 (m, 1 H, Ar), 7.77 (d, J=8 Hz, 1 H, NH), 7.63 (t, J=8.0 Hz, 1 H), 6.95-6.75 (m, 3 H, Ar), 5.86 (m, 1 H, CHCO), 3.85 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.68, (s, 3 H, CO2CH3), 3.01 (m, 2 H, CH2); 13C NMR (CDCl3) δ 172.0, 164.1, 149.1, 148.6, 148.2, 135.8, 133.1, 132.7, 129.8, 126.1, 122.0, 118.2, 111.2, 109.9, 55.9, 55.8, 52.0, 50.2, 39.5.
Reaction SMILES: F[C:2]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](O)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1)[CH3:21].C(N1C2C=CC=C(N)C=2C=N1)C1C=CC=CC=1>>[CH2:4]([N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:32]([C:29]3[N:26]4[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[CH:24][C:25]4=[N:31][CH:30]=3)=[O:33])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=1
Reactant: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Reactant: CCOc1ccn2c(C(=O)O)cnc2c1
Agent: Nc1cccc2c1cnn2Cc1ccccc1
Product: CCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1

Procedure:
Prepared according to the method of Example 109, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with 7-ethoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=412 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH2:9](OB(C=C)OCCCC)[CH2:10]CC.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH2:10]
Reactant: O=Cc1cc(Br)co1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: C=Cc1coc(C=O)c1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carbaldehyde (1.1 g, 6.29 mmol) and vinylboronic acid dibutyl ester (1.67 mL, 7.54 mmol) using the same conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). Purification by flash chromatography (0-30% EtOAc in heptane) provided 4-vinylfuran-2-carbaldehyde as an orange oil; Yield 282 mg (37%). 1H NMR (400 MHz, CDCl3) δ ppm 5.31 (dd, J=10.88, 0.93 Hz, 1H), 5.61 (dd, J=17.57, 0.54 Hz, 1H), 6.56 (dd, J=17.55, 10.91 Hz, 1H), 7.37 (s, 1H), 7.67 (s, 1H), 9.66 (d, J=0.59 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([OH:8])=[C:3]1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:22](I)[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([O:8][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)(C)CI
Reactant: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)COC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reaction time: 18 h

Procedure:
To a mixture of 5,5-dimethyl-3-hydroxy-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one (500 mg, 1.77 mmol, Example 109, Step 1) in DMF (6 mL) were added NaH (65 mg, 1.2 eq.), and neopentyl iodide (585 μL). After a period of 18 h at 70° C., the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and the organic phase separated, dried over MgSO4 and evaporated under reduced pressure. The resulting oil was purified by flash chromatography to provide the title compound (124 mg) as a white solid after precipitation with Et2O.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=O>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][CH2:20][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=Cc1nccs1
Product: c1csc(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)n1
Yield: 38.8 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (188 mg, 0.73 mmol) and 2-formylthiazole (90 mg, 0.80 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow foam (101 mg, 39%), MS (ISP) m/e=357.3 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:1]([N:8]([CH2:9][P:10]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:17])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(Cc1ccccc1)CP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of diethyl (benzylamino)methylphosphonate (intermediate 5.2) (12 g, 46.69 mmol, 1.00 equiv) in acetonitrile (150 mL), DIEA (12 g, 2.00 equiv). This was followed by the addition of ethyl 2-bromoacetate (8.4 g, 50.30 mmol, 1.10 equiv) dropwise with stirring. The mixture was stirred for 30 min at room temperature. The resulting solution was heated to reflux for 6 hr. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20 to 1:5). This resulted in 8.0 g (50%) of ethyl 2-(benzyl((diethoxyphosphoryl)methyl)amino)acetate as yellow oil.