Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[O:9][N:8]=[CH:7][CH:6]=1.O.[NH2:12][NH2:13]>C(O)CCC>[O:9]1[C:5]([CH2:4][C:3]([NH:12][NH2:13])=[O:2])=[CH:6][CH:7]=[N:8]1
Reactant: COC(=O)Cc1ccno1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)Cc1ccno1
Yield: 41 %

Procedure:
As described for example 112a, isoxazol-5-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. Evaporation of all volatiles and chromatography (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a white solid (yield: 41%). 1H-NMR (300 MHz, DMSO): δ=3.65 (s, 2H), 4.31 (s, 2H), 6.32 (s, 1H), 8.46 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1Oc1ccc(Cl)nn1
Temperature: 160 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 278.7 g (1.87 mol) of 3,6-dichloropyridazine, 202.3 g (1.87 mol) of 2-methylphenol and 259 g (1.87 mol) of potassium carbonate was stirred at 160° C. for 6 hours. The reaction mixture was cooled to 70° C. and 2 L of ethyl acetate was added. This mixture was washed successively with 1 mol/L sodium hydroxide aqueous solution (4×500 mL), water (4×500 mL) and brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was removed, and isopropyl ether was added to the residue to form crystal. The crystal was collected by filtration to obtain 234.2 g (1.06 mol, Yield: 56.7%) of 3-chloro-6-(2-methylphenoxy)pyridazine.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH:15]=O)[CH:10]=[CH:11][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]=[CH2:2])[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=CCCc1cccc(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of 1.34 gm (3.77 mmol) of methyltriphenylphosphonium bromide in THF at 0° C. was treated dropwise with 2.3 mL of 1.6 M n-BuLi in hexanes (3.77 mmol), stirred at 0° C. for 0.25 h, cooled to −78° C., treated dropwise with a solution of 3-(3-bromophenyl)propionaldehyde (0.7 gm, 3.28 mmol) in THF, stirred at −78° C. for 1 h, allowed to warm to room temperature, quenched with aqueous NH4Cl and concentrated under reduced pressure. The resultant residue was taken up in EtOAc, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of this concentrate on silica gel with a gradient of 0.5% EtOAc-hexanes to 2.0% EtOAc-hexanes gave 1-bromo-3-but-3-enylbenzene as an oil, 0.35 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.33 (m, 2H), 2.66 (t, 2H, J=7.4 Hz), 4.98 (m, 2H), 5.79 (m, 1H), 7.12 (m, 2H), 7.30 (m, 2H).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[N:16]=[CH:15][C:14]([O:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CS(C)=O.C(OCC)(=O)C.[Cu]>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16][CH:15]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: N#Cc1ccc(Oc2ccc(Br)nc2)cc1
Agent: [Cu]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(Oc2ccc(C#N)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A mixture of ethyl 2-bromo-2,2-difluoroacetate (22.13 mL, 109.05 mmol) and copper (13.85 g, 218.1 mmol) in dry dimethylsulfoxide (DMSO) (80 mL) was stirred at room temperature (rt) for 4 h. 4-((6-Bromopyridin-3-yl)oxy)benzonitrile (10 g, 36.35 mmol) was added and the mixture heated at 50° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with 200 mL of ethyl acetate (EtOAc) and stirred for 10 min. The mixture was filtered through a plug of Celite® and the filtrate was washed with saturated NH4Cl solution to remove any remaining copper. The solution was dried (Na2SO4) and solvent was removed under reduced pressure to give the title compound as brown oil (6.5 g, 56.5%): IR (thin film) 2229, 1767 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=2.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.73-7.64 (m, 2H), 7.49 (dd, J=8.6, 2.7 Hz, 1H), 7.16-7.07 (m, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); ESIMS m/z 319 ([M+H]+).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[CH:8]=1.[OH-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>>[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])[CH:8]=1
Reactant: Cc1ccccc1S
Reactant: CNCCCc1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCCCc1cccc(Sc2ccccc2C)c1

Procedure:
N-Methyl-3-chloro-benzenepropanamine hydrochloride (13.14 g, 0.06 mol), 25%, by weight, sodium hydroxide solution (9.6 g of solution; 0.06 mol of sodium hydroxide), sodium hydroxide pellets (2.0 g, 0.05 mol) and 2-methylbenzenethiol (6.2 g, 0.05 mol) were reacted to provide N-methyl-3-[(2-methylphenyl)thio]benzenepropanamine as an oil. The oil was purified by preparative HPLC and then converted to the hydrochloride salt as in Example 1. Recrystallization from methylene chlorideethyl acetate provided approximately 3.0 g of title compound. m.p. ≈90° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N+:19]#[C-:20]>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]=[CH:20][N:2]([CH3:1])[CH:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: [C-]#[N+]c1ccc(C)cc1C
Reactant: CNC=Nc1ccccn1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=CN(C)C=Nc2ccccn2)c(C)c1
Yield: 20.5 %

Procedure:
A mixture of N-methyl-N'-(2-pyridyl)-formamidine (2.5 g, 0.0185 m), 2,4-dimethylphenylisocyanide (2.4 g, 0.0185 m), cuprous oxide (trace amount) and dry toluene (60 ml) was heated on a steam bath with occasional agitation for 4 hours. The reaction mixture was then cooled, filtered through "Hyflo" (diatomaceous earth) and alumina, and the toluene filtrate evaporated to dryness in vacuo to yield a viscous oil. The oil was triturated with 60°-80° petroleum ether to yield a white solid. Crystallisation of this solid from ether/60° -- 80° petroleum ether yielded the product, 5-(2,4-dimethylphenyl)-3-methyl-1-(2-pyridyl)-1,3,5-triazapenta-1,4-diene, (1.0 g) m.p. 100°.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.42 mL, 2.1 mmol) and benzyl bromide (162 μL, 1.4 mmol), and the mixture was stirred at 40° C. for 3 hr. Then, water (2 mL) was added to make the system homogeneous, which system was analyzed by HPLC. As a result, the objective N-Boc-(O-benzyl)tyrosine (353 mg, conversion yield 95%) was confirmed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.Cl.[I-:47].[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=2[CH3:63])=[CH:52][CH:51]=1>ClCCCl>[I-:47].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=4[CH3:63])=[CH:52][CH:51]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C[n+]1ccccc1Nc1ccc(CN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [I-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(Nc4cccc[n+]4C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AD using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.13 mmol), CDI (33 mg, 0.2 mmol), DIPEA (0.14 mL, 0.81 mmol) and 2-{[4-(aminomethyl)phenyl]amino}-1-methylpyridinium iodide hydrochloride (53 mg, 0.14 mmol) in DCE (1.0 mL).
Reaction SMILES: C(C(C(=[P:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)CC1CS[C@@H]2[C@H](NC(=O)CC3SC=CC=3)C(=O)N2C=1C(OC(C)(C)C)=O)=O)C.O>O1CCCC1>[C:45]1([P:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCC(=O)C(CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of t-butyl 3-(2-ethylcarbonyl-2-triphenylphosphoranylideneethyl)-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (500 mg.) in tetrahydrofuran (10 ml.) was treated with aluminum amalgam (500 mg., prepared as described in L.G. Fiester and M. Fieser, Reagents for Organic Synthesis, P. 20) and water (0.2 ml.), and the mixture stirred at 23°After 2 and 3 hours further amounts (0.2 ml., and 0.1 ml. respectively) of water were added. After a total of 4 hours the mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in benzene and filtered through a short column of Merck Kieselgel (0.05 - 0.2mm, 10 g.) to give, on evaporation, triphenylphosphine (130 mg., 73%). Further elution with benzene ethyl acetate (1:1) gave the title compound (230 mg., 72%) as a foam, λmax. (EtOH) 270 nm (ε, 5,020), νmax. (CHBr3) 3450 and 3360 (NH), 1786 (β-lactam), 1730 (CO2R) and 1686 and 1518 cm-1 (CONH), τ(CDCl3) 3.51 (NH, doublet, J 9 Hz), 4.26 (C(7) -H, double doublet, J 9 and 4.5 Hz), 5.09 (C(6) -H, doublet, J 4.5 Hz), 5.88 and 8.74 (OCH2CH3, quartet and triplet), 6.17 (CH2CONH), 6.50 and 6.8 (C(2) -CH2, AB-quartet, J 18 Hz), 7.3-7.7 (--CH2CH2 --0--, 4 proton multiplet) and 8.47 (C[CH3]3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH2:44][C:45]2([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]2)/[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:20])[CH3:19].CO>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:27]2([CH:35]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[O:43][CH2:44][C:45]3([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:17])[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC2(C#N)CCCC2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C#N)CCCC2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Temperature: 70 °C
Yield: 6.2 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30 mmol) in toluene (30 mL) was added E/Z-6-Chloro-3-[5-chloro-2-(1-cyano-cyclopentylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6 g, 11.7 mmol). Then the reaction mixture were heated at 70° C. overnight. After the solution was cooled to room temperature, methanol was added. The solution was concentrated and the residue was purified by flash column to give the title compound as a white solid (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:18][CH:17]=[CH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the phenol from step 2 (16.5 g, 75 mmol), allyl bromide (10.8 g, 90 mmol) and cesium carbonate (48.7 g, 150 mmol) in DMF(300 mL) was stirred at 25° C. for 6 h. The mixture was poured into water (1.0 L) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (3×100 mL), dried over magnesium sulfate and concentrated. The crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([O:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:24]2=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C=CC(=O)N1C1CCCCC1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1C1CCCCC1
Yield: 61.1 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 4.48 g (25 mmole) of N-cyclohexylmaleimide. The residue was crystallized from ethanol to give 6.0 g (61%) of a white solid, mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:26])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: NCC(F)(F)F
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCC(F)(F)F)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with 2,2,2-trifluoro-ethylamine using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=495.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: [H][H]
Reactant: C=Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 23.5 %

Procedure:
A solution of 50 mF (0.16 mmol) 2-amino-4-furan-2-yl-6-(4-vinyl-benzylamino)-pyrimidine-5-carbonitrile in 10 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether/hexane afforded 12 mg (24%) 2-amino-4-(4-ethyl-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′-Chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=490.9.
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:18]1[C:13]([NH:1][CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCCC1CC(=O)N(CN)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(CNc2ncccc2[N+](=O)[O-])C1
Yield: 52.6 %

Procedure:
A mixture of 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 (1 eq, 17.09 mmol, 2.67 g), 2-chloro-3-nitropyridine (1 eq, 17.09 mmol, 2.709 g) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) is refluxed 48 h. After cooling, the crude mixture is filtrated and the dioxane is distilled under vacuum. The residue is purified by preparative chromatography to afford 2.5 g of 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:31][CH2:30][C:21]2([CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:31][CH2:30][C:21]2([CH2:22][CH:23]([O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:24]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Oc1ccccc1F)C2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
After dissolving 148 mg of 2-fluorophenol in 10 mg of dimethylformamide, 53 mg of sodium hydride (70% suspension in oil) was added, the mixture was stirred at 80° C. for 30 minutes, a solution of 148 mg of 7-(tert-butoxycarbonyl)-2-methanesulfonyloxy-7-azaspiro[3.5]nonane in N,N-dimethylformamide (7 ml) was added and the mixture was stirred at 80° C. for two nights. After cooling it to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was washed with a 1N sodium hydroxide solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (163 mg, 100% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][CH:38]([O:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:39][CH2:40]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(Nc1ccc(O)c([N+](=O)[O-])c1)C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-hydroxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine (10.0 g), triphenylphosphine (22.1 g) and 4-hydroxy-N-(t-butoxycarbonyl)piperidine (17.0 g) in THF (30 mL) was added DEAD (13.5 mL) drop-wise. The reaction was stirred at ambient temperature for 1 hour, concentrated and purified on silica gel column (ethyl acetate/hexane, gradient) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[C:20]3[CH:19]([N:27]([CH:29]4[CH2:31][CH2:30]4)[CH3:28])[CH2:18][CH2:17][C:16]([CH3:33])([CH3:32])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:29]1([N:27]([CH3:28])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:33])([CH3:32])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([O:23][CH:24]([CH3:25])[CH3:26])[C:20]2=3)[CH2:30][CH2:31]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 129, 0.045 g, 0.098 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent to afford the title product as a white solid (0.027 g, 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14]CC)=O)=[C:7](O)[CH2:6][CH2:5]2.[NH2:18][C:19]([NH2:21])=[NH:20]>>[NH2:20][C:19]1[NH:21][C:12](=[O:14])[C:8]2[C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[CH2:5][CH2:6][C:7]=2[N:18]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1=C(O)CCc2cc(Br)ccc21
Product: Nc1nc2c(c(=O)[nH]1)-c1ccc(Br)cc1CC2

Procedure:
Ethyl 6-bromo-3,4-dihydro-2-hydroxy-1-naphthoate (6.0 g, 20.2 mmoles) was reacted with guanidine (6.9 g of hydrochloride salt, 72.2 mmoles) in the same manner as in example 1. The product was precipitated from aqueous sodium hydroxide with acetic acid, filtered, washed with water and dried to give 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)- one as an off-white solid. (2.75 g, 46%) 1H NMR(DMSO-d61 300MHz) δ: 2.55(t, J=7.5 Hz, 2H, CH2); 2.79(t, J=7.4 Hz, 2H, CH2); 6.75(br s, 2H, NH2); 7.32(dd, J=8.4, 2.3 Hz, 1H, Ar); 7.34(s, 1H, Ar); 8.40(d, J=8.4 Hz, 1H, Ar); 11.00(br s, 1H, NH).