Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13]C(C)(C)C)=[O:12])=[O:7])=[C:4]([OH:30])[CH:3]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:10]=2[C:11]([OH:13])=[O:12])=[O:7])=[C:4]([OH:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
A solution mixture of the obtained tert-butyl 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoate (0.11 g) in trifluoroacetic acid (5 mL) and methylene chloride (2.5 mL) was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue. The solid substance was collected by filtration to obtain 0.077 g of 2-(4-chloro-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:17]([CH3:21])([CH3:20])[C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:22][CH:23](O)[CH3:24].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([CH:23]([CH3:24])[CH2:22][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([C:17]([CH3:21])([CH3:20])[CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:34]=[N-:35]
Reactant: COC1=C2C=c3c(cnn3CC(C)O)=C2C(C)(C)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 67.9 %

Procedure:
0.8 ml (10.2 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.4 g (5.1 mmol) of (RS)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.9 ml (20.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.66 g (10.2 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.03 g (68%) of (RS)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:14]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH2:12]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)(C)C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of o-(t-butyl)-phenol (11.3 g; 75 mmol) in acetone (150 ml) is added allyl bromide (10.9 g, 1.2 equiv.) and anhydrous K2CO3. After stirring 18 hr at reflux, the reaction is added to water (200 ml) and extracted with 3×150 ml portions of petroleum ether. The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel (sg) chromatography (hexane elution) to yield 1-prop-2-enyloxy-2-t-butylbenzene (11.6 g; 81% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2.C([Li])CCC.[C:24]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29])#[N:25]>O1CCCC1>[OH:29][CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2)[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:24]#[N:25]
Reactant: C[Si](C)(C)CCOCn1ccc2cc(Br)ccc21
Reactant: N#Cc1ccccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of 5-bromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indole (0.96 g, 2.9 mmol) in tetrahydrofuran (30 mL) cooled to −78° C. was added n-butyllithium (1.6 M in hexanes, 2.2 mL, 3.5 mmol). After stirring for 15 min at −78° C., 2-cyanobenzaldehyde (0.58 g, 4.4 mmol in 2 mL tetrahydrofuran) was quickly added. After stirring for 30 min at −78° C. and allowing to warm to room temperature, the reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 1:1 hexanes/ethyl acetate) gave 0.68 g (61%) of 2-{hydroxy[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]methyl} benzonitrile. 1H NMR (400 MHz, CDCl3): 7.99 (d, 1H), 7.60 (d, 1H), 7.57 (m, 2H), 7.53 (d, 1H), 7.27 (m, 2H), 7.10 (dd, 1H), 6.56 (m, 2H), 5.52 (s, 2H), 3.50 (m, 2H), 0.51 (m, 2H), 0.00 (s, 9H); MS (EI) for C22H26N2O2Si: 379 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[CH2:18]([OH:21])[C:19]#[CH:20]>C(NCC)C>[OH:21][CH2:18][C:19]#[C:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Reactant: C#CCO
Solvent: CCNCC
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 0.37 g (0.5 mmole) of dichlorobis (triphenylphosphine) palladium II, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml of diethylamine was stirred at room temperature for 4 days. The mixture was concentrated at reduced pressure and the residue was partitioned between ether and water. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give the product as an amber oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]([NH2:16])=[NH:15].[Cl:17][C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23]>>[NH2:25][CH2:24][C:21]1[C:22]([NH2:23])=[N:15][C:14]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=2)=[N:16][C:20]=1[C:19]1[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:18]=1[Cl:17]
Reactant: N=C(N)c1ccc2oc3ccccc3c2c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc3oc4ccccc4c3c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=434.9 (M+), was prepared from dibenzofuran-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH2:42])([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:39][CH2:40][CH2:41][NH:42][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)([CH2:37][CH3:38])[CH2:33][CH2:32]1)=[O:30])([CH3:25])([CH3:27])[CH3:26]
Reactant: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (180 mg, 0.494 mmol), 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.741 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) in 1,4-dioxane (3 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 197 mg of 4-{3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-4-ethylpiperidine-1-carboxylic acid tert-butyl ester. The intermediate is then subject to deprotection by dissolving the material (197 mg, 0.329 mmol) in MeOH (25 mL) and dichloromethane (12 mL) and bubbling anhydrous hydrogen chloride gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (184 mg, 98% yield). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C[O-].[Na+]>CO>[C:1]([N:4]1[C:8]2=[CH:9][C:10]3[C:11]([C:20]4[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=4)=[CH:12][NH:13][C:14]=3[CH:15]=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CC(=O)N1CCc2cc3[nH]ccc3cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCc2cc3[nH]cc(C4=CCN(C)CC4)c3cc21
Yield: 50.8 %

Procedure:
To a stirred suspension of 1-acetyl-1,2,3,5-tetrahydropyrrolo[2,3-f]indole (J. Med. Chem. 1995, 38, 2524) (1.60 g, 8 mmole) and 1-methylpiperidin-4-one (1.81 g, 16 mmole) in dry methanol (70 ml) was added sodium methoxide (2.59 g, 48 mmole). The mixture was heated at reflux under argon for 24 hours, then cooled and concentrated by evaporation to approx. 25% volume; then treated with water (5 ml), stirred and the solid precipatate collected by filtration. The solid was suspended in ethanol (20 ml), heated to boiling, cooled and filtered to leave the title compound as a pale cream powder (1.20 g).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OCC4C=CC=CC=4)=O)[CH2:25]3)[C:8]2=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.Br.O>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[C:8]2=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c(=O)n(C2CCCCC2)c1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCNC2)c(=O)n(C2CCCCC2)c1=O
Temperature: 60 °C
Yield: 18.9 %

Procedure:
N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinl]carbonyl}glycine hydrobromide. Phenylmethyl 3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate (1.2 g, 2.15 mmoles) was stirred in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (5.0 mL) for 40 hours—reaction incomplete. The mixture was then heated at 60° C. for 2 hours, diluted with water and extracted with ethyl acetate (×5). The combined extracts were dried and evaporated, and recrystallized from diethyl ether-hexane to give the title compound (160 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (br. s., 1 H), 10.11 (s, 1H), 8.86 (s, 1 H), 5.12 (s, 1 H), 4.63 (t, J=12.00 Hz, 1 H), 4.09 (s, 2 H), 3.66 (t, J=11.37 Hz, 1 H), 3.28 (d, J=10.61 Hz, 2 H), 2.77 (t, J=11.12 Hz, 1 H), 2.36 (dd, J=12.38, 3.54 Hz, 1 H), 2.22-2.32 (m, 2 H), 1.89 (d, J=12.63 Hz, 1 H), 1.69-1.81 (m, 4 H), 1.55-1.67 (m, 4 H), 1.27 (q, J=12.88 Hz, 2 H), 1.11 (q, J=12.97 Hz, 1 H)
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light brown solid (49 mg, 63%), MS (ISP) m/z=313.4 [(M+H)+], mp 363° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20])=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[N:12][CH:11]=3.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41][CH:42]([CH3:44])[CH3:43])(=O)=O>CN(C=O)C.O>[C:49]([O:48][C:46](=[O:47])[NH:45][C@@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:39][O:20][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=3)[CH2:9][O:8][C:7]=2[C:2]=1[F:1])([CH3:50])([CH3:52])[CH3:51]
Reactant: CC(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc2c(cn1)COc1c-2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1F
Temperature: 90 °C
Yield: 37 %

Procedure:
To a stirred solution of N-(7-fluoro-8-hydroxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide, TFA (70 mg, 0.170 mmol) and potassium carbonate (97 mg, 0.704 mmol) in DMF (4 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (52.0 mg, 0.176 mmol) at room temperature and the reaction mixture was heated to 90° C. for 1 h. After completion of reaction, the volatiles were removed under reduced pressure to afford a brown residue. To this residue water (15 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (30 mL), brine (20 mL), dried over sodium sulphate and concentrated under reduced pressure to afford (S)-tert-butyl(1-((2-acetamido-7-fluoro-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (90 mg, 0.066 mmol, 37% yield) as a brown oil. The product was carried forward without further purification. LCMS (ESI) m/e 472.2 [(M−H)−, calcd for C25H31FN3O5 472.2]; LC/MS retention time (Method E): tR=1.99 min.
Reaction SMILES: C1(=O)[O:6][C:4](=[O:5])C=C1.N[C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:19]/[C:20]([NH2:22])=[O:21])/[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[C:4]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:19]/[C:20]([NH2:22])=[O:21])/[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([OH:6])=[O:5]
Reactant: NC(=O)/C=C(\C(=O)O)c1ccc(N)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: ClC(Cl)Cl
Product: NC(=O)/C=C(\C(=O)O)c1ccc(C(=O)O)cc1
Yield: 99 %

Procedure:
To a mixture of maleic anhydride (5.0 g. 50.9 mmol) in chloroform (100 ml) was added p-aminophenyl maleamic acid (6.99 g, 50.9 mmol). The resulting mixture was heated to reflux for 3 h. The solution was then cooled and a precipitate formed. The precipitate was filtered, washed with ethyl acetate and dried, to give 2N-(4-carboxyphenyl)maleamic acid (99%) as a solid.14 mp: 218-220° C. 1H NMR (DMSO-d6): δ 6.30 (d, J=12.0 Hz, 1H), 6.47 (d, J=1.20 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 10.59 (s, 1H), 12.83 (brs, 1H); HRMS (m/z): [M−H]− calcd for C11H8NO5, 234.0408; found, 234.0406.
Reaction SMILES: C(C=C=O)CCC.[CH2:8]([C@H:12]1[C:13](=[O:21])[O:14]/[C:15]/1=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH3:11]>ClCCl>[CH2:8]([C@@H:12]1[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:13]1=[O:21])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC/C=C1\OC(=O)[C@@H]1CCCC
Agent: CCCCC=C=O
Solvent: ClCCl
Product: CCCCC[C@@H]1OC(=O)[C@@H]1CCCC
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
The purified n-butyl ketene dimer 2a, (5.1 mmol, 1.0 g) was dissolved in 40 mL dichloromethane (0.1 M) and transferred to a Parr bomb apparatus under a N.sub.2 atmosphere using an additional 10 mL dichloromethane as wash solvent. Pd/C (107 mg, 1 mol %, 5 wt %) was then added at one time under N.sub.2 atmosphere. The Parr bomb was then subjected to three consecutive evacuation-saturation cycles of hydrogen gas and then pressurized to 30 psi hydrogen gas pressure. Hydrogenation with shaking (Parr shaker) was continued for 30 min at this pressure and then the heterogeneous slurry was vacuum filtered through a plug of Celite, and concentrated yielding a colorless oil. Flash chromatography with gradient elution (5→15% diethyl ether/hexanes; 2.5×35.0×5 cm pad) gave 3-butyl-4-pentyl-oxetan-2-one (3a, 897 mg, 90%) as a colorless oil (>96% ee, chiral GC): Rf 0.47 (15% Et2O:hexanes); IR (thin film) 1824 cm−1; 1H NMR (300 MHz, CDCl.sub.3) δ 4.54 (ddd, J=2.1, 3.6, 5.7 Hz, 1H), 3.59 (ddd, J=4.5, 5.4, 8.4 Hz, 1H), 1.46-1.84 (m, 6H), 1.31-1.44 (m, 8H), 0.88-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) δ 173.1, 76.5, 53.3, 32.2, 30.9, 30.5, 26.0, 24.4, 23.2, 23.2, 14.7, 14.5; ESI LRMS Calcd. for C12H22O2 [M+Li]: 205. Found: 205.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16]N(C=O)C.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:13][C:12]([C:10]1[O:11][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=2[CH:9]=1)=[O:14]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2Cl2 (250 mL) at 0° C. was added DMF (0.100 mL) followed by (COCl)2 (2M in CH2Cl2, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0° C. for 1 h and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2Cl2 (250 mL). The solution was cooled to 0° C., were added pyridine (4.8 mL, 48.03 mmol) followed by McOH (10 mL, excess) and stirred overnight. The extractive work-up with CH2Cl2 gave the expected 2-methoxycarbonyl-5-nitrobenzofuran (R926609). 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: ret. time: 26.94 min.
Reaction SMILES: N1[C:5]2([CH2:9][O:8][C:7]([SH:10])=[N:6]2)[CH2:4][O:3]C=1S.Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:3][CH2:4][C:5]1[N:6]=[C:7]([S:10][CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17])[O:8][CH:9]=1
Reactant: FC(F)=C(F)CCBr
Reactant: SC1=NC2(CO1)COC(S)=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
7.5 g of 3,8-dioxa-1,6-diazaspiro[4,4]nona-1,6-diene-2,7-dithiol, 7.5 g of 4-bromo-1,1,2-trifluoro-1-butene and 7.0 g of potassium carbonate were added to 200 ml of acetonitrile and refluxed for 5 hours. The reaction mixture was cooled to room temperature and filtered by sucction and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate:dichloromethane=1:4) to obtain 7.0 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 74.2%). n20D=1.4910.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[F:21][C:22]([F:28])([F:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[F:21][C:22]([F:28])([F:27])[CH2:23][C:24]([NH:7][C:6]1[S:5][C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:3][C:2]=1[CH3:1])=[O:25]
Reactant: Cc1nc(-c2cccnc2)sc1N
Reactant: O=C(Cl)CC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccnc2)sc1NC(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
286 mg (1.49 mmol) of 4-methyl-2-(pyridin-3-yl)-1,3-thiazole-5-amine were dissolved in THF, 0.52 ml of triethylamine was added, and 263 mg of trifluoropropionyl chloride were added while cooling with an ice bath. The mixture was stirred at room temperature overnight and then concentrated. Ethyl acetate, saturated sodium chloride solution and aqueous phosphate buffer pH=7 were added to the residue, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography (silica gel, cyclohexane, acetone).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1([CH3:26])[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:16](=[O:25])[NH:15]1.[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH2:31]>O1CCCC1>[CH3:27][O:28][CH:29]([O:32][CH3:33])[CH2:30][NH:31][C:22](=[O:24])[CH2:21][CH2:20][N:17]1[C:18](=[O:19])[C:14]([CH3:13])([CH3:26])[NH:15][C:16]1=[O:25]
Reactant: CC1(C)NC(=O)N(CCC(=O)O)C1=O
Reactant: COC(CN)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CNC(=O)CCN1C(=O)NC(C)(C)C1=O)OC
Yield: 53.7 %

Procedure:
Analogously to Example 1, 165.43 g (1.02 mol) of 1,1'-carbonyldiimidazole and 700 ml of tetrahydrofuran are introduced into an apparatus, allowed to react with 202.86 g (1.0 mol) of 3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propionic acid and subsequently reacted with 107.21 g (1.02 mol) of 2-aminoacetaldehyde dimethyl acetal. The reaction mixture is evaporated to dryness at 80° C./0.1 mbar in a rotary evaporator, and the resultant residue is purified analogously to Example 1, giving 154.2 g (54.2% of theory) of N-(2,2-dimethoxyethyl)-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propionamide, which melts at 123° C.
Reaction SMILES: C([O:8][C:9]1[CH:45]=[CH:44][C:12]([O:13][C:14]2[CH:29]=[CH:28][C:17]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[O:19])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:28]=[CH:29][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:45][CH:44]=2)=[C:15]([NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:42])[CH3:43])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:16]=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4F)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4F)ccc3Oc3ccc(O)cc3)ncnc2n1

Procedure:
A solution of the product of Example 43E and pentamethylbenzene (72 mg, 0.5 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation under vacuum and co-evaporated with methylene chloride/hexanes (2×) to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (11 mg, 22%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.28 (m, 1 H) 6.77 (m, 2 H) 6.93 (m, 3 H) 7.26 (m, 3 H) 7.58 (m, 1 H) 7.88 (d, J=8.82 z, 1 H) 8.00 (dd, J=8.64, 2.02 Hz, 1 H) 8.14 (d, J=2.21 Hz, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.09 Hz, 1 H) 9.47 (s, 1 H) 10.13 (s, 1 H) 11.48 (s, 1 H); MS (ESI+) m/z 510 (M+H)+.