Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH2:9][CH2:10][CH2:11][C@@H:12]([C:13]4[N:17]5[CH:18]=[CH:19][N:20]=[C:21]([NH:22]CC6C=CC(OC)=CC=6OC)[C:16]5=[C:15]([C:34]5[CH:52]=[CH:51][C:37]([C:38]([NH:40][C:41]6[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][N:42]=6)=[O:39])=[CH:36][CH:35]=5)[N:14]=4)[C:7]3=[N:6][N:5]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[NH2:22][C:21]1[C:16]2[N:17]([C:13]([C@@H:12]3[CH2:11][CH2:10][CH2:9][N:8]4[C:4]([CH:1]5[CH2:3][CH2:2]5)=[N:5][N:6]=[C:7]34)=[N:14][C:15]=2[C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][N:42]=3)=[O:39])=[CH:51][CH:52]=2)[CH:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2nccn3c([C@@H]4CCCn5c(C6CC6)nnc54)nc(-c4ccc(C(=O)Nc5cc(C(F)(F)F)ccn5)cc4)c23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccn2c([C@@H]3CCCn4c(C5CC5)nnc43)nc(-c3ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12

Procedure:
A solution of (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (30 mg, 0.04 mmol) in TFA (1.5 mL) was stirred at 110° C. for 2 hrs. The reaction mixture was purified by Pre-HPLC to give the title product.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[NH:16][CH3:17])=[CH:11][N:10]=1)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:17][NH:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:19])=[O:5])=[N:10][CH:11]=1)=[O:18]
Reactant: CNC(=O)c1ccc(CCC(=O)OC(C)(C)C)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(CCC(=O)O)nc1
Reaction time: 8 h

Procedure:
tert-Butyl-3(5-methylcarbamoyl-pyridin-2-yl)propionate (0.29 g, 1.10 mmol) was dissolved in 10 mL of a 4 N hydrogen chloride solution in dioxane and stirred overnight. Evaporation of the solvent gave 0.27 mg of 3(5-methylcarbamoyl-pyridin-2-yl)propionic acid hydrochloride. LCMS 209 (M+1)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CC(OC([N:52]1[C:60]2[C:55](=[CH:56][CH:57]=[C:58]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:59]=2)[CH:54]=[C:53]1[C:66](O)=[O:67])=O)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:66]([C:53]2[NH:52][C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[C:58]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])[CH:59]=3)=[O:67])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2ccc(NS(C)(=O)=O)cc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
HATU (0.083 g, 0.218 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.045 g, 0.146 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.037 g, 0.146 mmol) and diisopropylethylamine (0.038 mL, 0.218 mmol) in DMF (1 mL). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer wa sdired over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.036 g, 45%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 9.53 (br. s., 1H), 8.94 (t, 1H), 7.78 (s, 1H), 7.52 (d, 1H), 7.48 (br. s., 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 6.91 (dd, 1H), 4.52 (d, 2 H), 2.87 (s, 3H). ES MS: m/z 547 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c(N)cc23)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (310 mg, 1 mmol) and SnCl2.2H2O (171 mg, 4.5 mmol) in ethyl acetate (35 mL) was refluxed for 2 h. After cooled to room temperature, the mixture was treated with 5% aqueous NaHCO3 to adjust its pH to 9-10, and then subjected to extraction with EtOAc. The organic layers were washed with saturated brine and H2O and dried. The solvent was removed under reduced pressure to give 225 mg (81%) N4-(3-ethynylphenyl)-7-fluoroquinazoline-4,6-diamine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:17][CH:18]4[CH:22]5[O:23][CH2:24][CH:25]([OH:26])[CH:21]5[O:20][CH2:19]4)[NH:16][C:11]3=[CH:10][C:9]=2[Cl:27])=[CH:4][CH:3]=1.[C:28]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[Cl:27][C:9]1[CH:10]=[C:11]2[NH:16][C:15]([O:17][C@H:18]3[C@H:22]4[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]4[O:20][CH2:19]3)=[N:14][C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:29]#[C:28][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:3][CH:4]=1
Reactant: C#CC1CCNCC1
Reactant: OC1COC2C(Oc3nc4nc(-c5ccc(Br)cc5)c(Cl)cc4[nH]3)COC12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C#CC4CCNCC4)cc3)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3R,3aR,6R,6aR)-6-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (25 mg, 0.055 mmol), 4-ethynylpiperidine (10.5 mg, 0.072 mmol), copper (I) iodide (2.1 mg, 0.011 mmol), chloro(tri-tert-butyl)-2-[-(2′amino-1,1′-biphenyl)]palladium (II) (5.7 mg, 0.011 mmol, prepared by a procedure analogous to procedures described in J. AM. CHEM. SOC. 2010, 132, 14073-14075), and cesium carbonate (54.0 mg, 0.166 mmol) were placed under nitrogen in dry, degassed toluene (138 μl) and dimethylacetamide (138 μl). The mixture was stirred at 50° C. for 2 hours. The resulting residue was diluted with dimethylformamide (0.7 mL), then filtered through a filter disc (0.45 micron). The material was purified by reverse phase HPLC purification using 0-100% acetonitrile in water over 10 minutes. The desired product fraction was concentrated under reduced pressure to afford the title compound as an off-white solid. LC-MS: calculated for C25H25ClN4O4 480.16 observed m/e: 481.14 (M+H)+ (Rt 1.43/4 min). 1H NMR δ (ppm) (CD3OD): 7.80 (1H, s), 7.62 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 5.53 (1H, m), 4.95 (1H, t, J=5.5 Hz), 4.46 (1H, t, J=5.0 Hz), 4.27 (1H, m), 4.15 (1H, dd, J=9.5, 6.0 Hz), 4.09 (1H, dd, J=10.0, 4.9 Hz), 3.88 (1H, dd, J=8.0, 7.0 Hz), 3.58 (1H, t, J=8.5 Hz), 3.42 (2H, m), 3.18 (2H, m), 3.09 (1H, m), 2.17 (2H, m), 1.96 (2H, m)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([NH:19][CH3:20])[N:3]=1.[NH3:21]>>[NH2:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([NH:19][CH3:20])[N:3]=1
Reactant: N
Reactant: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1F
Product: CNc1nc(N)nc2c1ncn2Cc1ccccc1F

Procedure:
In a manner analogous to that described in Example 2 it is also possible, by reacting 2-chloro-9-(2-fluorobenzyl)-6-(N-methylamino)-9H-purine (Example 6) with ammonia, to obtain the 2-amino-9-(2-fluorobenzyl)-6-(N-methylamino)-9H-purine, which has a melting range of from 207° to 208°.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+].[CH3:6][C:7]#N>>[CH2:2]1[CH2:1][O:4][CH2:7][CH2:6]1.[O:3]1[CH2:7][CH2:6][CH2:2][CH2:1]1
Reactant: CC(=O)[O-]
Reactant: CC#N
Agent: [NH4+]
Product: C1CCOC1
Reaction time: 0.04 h

Procedure:
Analytical HPLC/MS Analytical HPLC/MS was performed on a system consisting of a Waters Acquity UPLC, Waters Micromass LCT Premier XE mass spectrometer, Waters Acquity PDA. Column: Acquity UPLC HSS T3 1.8 μm; 2.1×50 mm; solventsystem: A=10 mM Ammonium acetate+0.1% HCOOH and B═CH3CN+0.1% HCOOH; flow rate=0.7 mL/min; method (4.8 min): Linear gradient method going from 1% B to 95% B in 2.6 minutes and staying at 95% B for 1.2 minute. General Procedure of Preparation:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[N:14]=1)([O-])=O.CCO.[Cl-].[NH4+]>[Fe].O>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]2)[N:14]=1
Reactant: O=[N+]([O-])c1cccc2c1ccn2-c1ccnc(N[C@H]2CC[C@H](O)CC2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1ccn2-c1ccnc(N[C@H]2CC[C@H](O)CC2)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of trans-4-[4-(4-nitroindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (2.44 g), EtOH (35 mL) and water (11 mL) was heated to 80° C. To the hot suspension was added ammonium chloride (1.46 g) followed by iron(0) (Fisher, 1.55 g) and the resulting mixture heated to 80° C. for 2 h, then to 50° C. for an additional 24 h. The reaction mixture was filtered through a CELITE™ pad, the filter cake washed with EtOAc/MeOH (3:2), and the filtrate evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/DCM, gradient from 2.5:97.5 to 10:90) to give trans-4-[4-(4-aminoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol as a light yellow solid. MS=324 [M+H]+; MP=218.9-220.1° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1)=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Cl:12][C:11]1[C:6]2[N:7]([C:2]([CH3:1])=[CH:4][N:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: CC(=O)CNc1nccnc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cnc2c(Cl)nccn12

Procedure:
A 2.67 g (0.01 mol) sample of 3-chloro-2-(2-oxo-1-propanamino)pyrazine is dissolved in 10 ml of trifluoroacetic anhydride under nitrogen and after the exothermic reaction subsides, the mixture is concentrated under vacuum. The residue is partitioned between chloroform and aqueous sodium bicarbonate, and the chloroform extract dried over sodium sulfate, filtered and concentrated under vacuum to give the solid 8-chloro-3-methylimidazo[1,2-a]pyrazine.
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:22]([OH:24])[CH3:23])[CH:16]([CH2:19][O:20][CH3:21])[CH2:17][OH:18])#[N:8]>[O-2].[O-2].[O-2].[Cr+6].ClCCl>[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:22]([CH3:23])=[O:24])[CH:16]([CH2:19][O:20][CH3:21])[CH:17]=[O:18])#[N:8]
Reactant: COCC(CO)C(CCCCCCC#N)C(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(C=O)C(CCCCCCC#N)C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a mixture of 1.874 g. of pyridine (dried over barium oxide) and 60 ml. of dichloromethane (dried over calcium chloride) was added in one portion 1.237 g. of chromium trioxide (dried over phosphorus pentoxide). The mixture was stirred at room temperature for 15 mins. then 0.255 g. of 3-(6-cyanohexyl)-2-methoxymethyl-1,4-pentanediol in 5 ml. of dry dichloromethane was added in one portion. The reaction mixture was stirred at room temperature for 0.5 hr., at the end of which the supernatant was decanted into a separatory funnel. The residue was washed several times with diethyl ether (total 150 ml.). The combined organic solutions were washed three times with 20 ml. portions of 5% aqueous potassium hydroxide solution, twice with 20 ml. portions of 5% hydrochloric acid, once with 20 ml. of sodium bicarbonate and finally with 15 ml. of brine. Drying over anhydrous magnesium sulphate and removal of the solvent in vacuo gave the desired 3-(6-cyanohexyl)-2-methoxymethyl levulinaldehyde (0.195 g., 78% yield). Infra-red and proton NMR spectroscopy were in agreement with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]3[C:19](=[O:25])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH3:26][C:16]1([CH3:27])[C:15]2[CH:14]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=3)[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]=2[C:19](=[O:25])[CH2:18][CH2:17]1
Reactant: C=Cc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(=O)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
A solution of [4-(8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 70, 0.082 g, 0.22 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithium hydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1.5 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.065 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Br.Br[CH2:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[NH:28][CH2:27][CH2:26][O:25][C:24]=2[CH:23]=1)=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:19][C:20]([C:22]3[CH:31]=[N:30][C:29]4[NH:28][CH2:27][CH2:26][O:25][C:24]=4[CH:23]=3)=[O:21])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1cnc2c(c1)OCCN2
Agent: Br
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc2c(c1)OCCN2

Procedure:
200 mg (0.79 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 319.86 mg (0.95 mmol) of 2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone hydrobromide were used in the reaction. After purification by chromatography on silica gel (eluent: 90/10 DCM/MeOH), 110 mg of (8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:1]12[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: BrCc1ccccc1
Product: O=C1NC2C=CC=CC2(Cc2ccccc2)C(=O)O1

Procedure:
Following the procedure set forth in Step (2) of Preparation A, isatoic anhydride was reacted with benzyl bromide to give 1-benzyl-isatoic anhydride.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][O:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:14])[O:6][C@H:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][O:3]1
Reactant: CCOC(=O)/C=C/[C@@H]1COC(C)(C)O1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC[C@@H]1COC(C)(C)O1
Reaction time: 8 h

Procedure:
To a methanol (200 mL) solution of ethyl (2E)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]acrylate (15.3 g, 76.7 mmol) was added 10% palladium on carbon (1.5 g). The reaction mixture was stirred under an atmosphere of hydrogen overnight. The catalyst was removed by filtration, and the solvent was removed in vacuo. Chromatography over silica afforded the title compound. 1H NMR (400 MHz, CDCl3): δ 4.05-4.15 (m, 2H), 4.02-4.04 (m, 2H), 3.52-3.55 (m, 1H), 2.30-2.47 (m, 2H), 1.83-1.90 (m, 2H), 1.33 (s, 3H), 1.26 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6](/[CH:7]=[CH:8]/[CH2:9][OH:10])=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6](/[CH:7]=[CH:8]/[CH:9]=[O:10])=[CH:5][CH:4]=1
Reactant: OC/C=C/c1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C/C=C/c1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.15 g of trans-4-(trifluoromethyl)cinnamyl alcohol, and 14 g of active manganese dioxide were added to the solution at 0° C., followed by stirring of the resulting mixture for 15 minutes and then stirring at room temperature for 2 hours. The solid was removed by filtration and the filtrate was concentrated to obtain a crystalline residue. The residue was recrystallized from a mixed solvent of benzene-hexane to obtain the title compound having a melting point of 60 to 61° C. in a yield of 90%.
Reaction SMILES: [CH:1]1([C:7]([CH:9]([OH:14])[CH2:10][CH2:11][CH:12]=[CH2:13])=[CH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCCCCC.O=[Mn]=O>[CH:1]1([C:7]([C:9](=[O:14])[CH2:10][CH2:11][CH:12]=[CH2:13])=[CH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCCC(O)C(=C)C1CCCCC1
Agent: O=[Mn]=O
Solvent: CCCCCC
Product: C=CCCC(=O)C(=C)C1CCCCC1
Reaction time: 96 h
Yield: 83.9 %

Procedure:
2-Cyclohexyl-hepta-1,6-dien-3-ol (85 g, 0.44 mol) were oxidized with MnO2 (804 g, 9.2 mol) in 2 l of hexane at RT. After stirring for 96 hours, the reaction mixture was filtered over Celite and concentrated in vacuo yielding 71 g of a yellow oil. Distillation (0.04 Torr/70° C.) yielded 43.5 g (51%) of pure product.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>>[C:2]1([C:1]2[O:8][CH:11]=[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1coc(-c2ccccc2)n1
Temperature: 120 °C
Yield: 38 %

Procedure:
A mixture of benzamide (60.0 g) and ethyl 4-chloroacetoacetate (49.4 g) was heated at 120° C. for 2 hours. After cooling, aqueous sodium bicarbonate solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with ethyl ether-hexane (1:9) to yield ethyl 2-phenyl-4-oxazoleacetate as an oil (26.4 g, 28.0%). NMR (CDCl3)δ: 1.27 (3H, t, J=7 Hz), 3.68 (3H, s), 4.15 (2H, q, J=7 Hz), 7.4 (3H, m), 7.67 (1H, s), 8.0 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([NH:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[C:11]([N+:39]([O-:41])=[O:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH:17]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=1)[C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[N+:39]([O-:41])=[O:40]
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile (2.7 g, 5 mmoles) was dissolved in ethanol (100 ml) and hydrazine hydrate (0.65 ml, 20 mmoles) added. The reaction was heated to 60° C. for 3 hours then at room temperature for 48 hours. The solids that precipitated were filtered off and the residue submitted to flash chromatography to yield 4-[2-Amino-1-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitrile (1.5 g). 1HNMR(CDCl3): 7.75 (s,1H), 7.3-7.5 (m, 7H), 7.05 (s,1H), 6.45 (d, 2H), 5.80 (bs, 1H), 5.32 (m, 1H), 5.19 (s, 2H), 3.81 (s, 3H), 3.25 (dd, 1H), 3.0 (dd, 1H), 1.65 (bs, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:22][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[N:13]=1)=O)C.[NH3:23]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@@H:10]3[CH2:22][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([NH2:23])=[O:3])=[N:13]1
Reactant: N
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Product: NC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 100 °C
Yield: 67.5 %

Procedure:
(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (200 mg, 0.657 mmol) was partially dissolved in a 7 M methanolic solution of ammonia (2 mL, 14.00 mmol). The mixture was heated under microwave irradiation in a sealed, thick-walled glass tube for 1 h at 100° C., then 2 h at 120° C. and 12 h at 125° C. The methanol was removed under reduced pressure. The remaining residue was triturated with ether and the precipitate was collected by filtration to give the title compound (122 mg) as a tan solid. LCMS m/z=276.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40 (td, J=4.4, 3.4 Hz, 1H), 1.15 (td, J=7.8, 4.7 Hz, 1H), 2.15-2.20 (m, 1H), 2.23-2.30 (m, 1H), 2.77 (d, J=16.7 Hz, 1H), 2.89 (dd, J=16.4, 6.4 Hz, 1H), 7.22 (bs, 1H), 7.28-7.33 (m, 1H), 7.35 (bs, 1H), 7.56-7.62 (m, 1H), 7.77 (td, J=8.9, 6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]/[C:12]2[N:13]([CH2:26][CH:25]=[C:24]([CH3:28])[CH3:23])[CH:14]=[CH:15][CH:16]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CC(C)=CCBr
Reactant: N#C/C(=C\c1ccc[nH]1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of (Z)-2-(4-Chloro-phenyl)-3-(1H-pyrrol-2-yl)acrylonitrile being Compound 2 in Table 8 (200 mg, 0.875 mmol) in dry acetone (35 ml) was treated with K2CO3 (121 mg) followed by dimethylallyl bromide (111 μl, 0.962 mmol, 1.1 equivalents). The mixture was heated to a gentle reflux for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was chromatographed on silica gel using ethylacetate/petroleum spirits (1:1) as eluant to afford the title compound as a yellow oil (85 mg). This is Compound 80 in Table 8.