Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][NH2:29])=[N:26][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([NH:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=2)[N:3]=1
Reactant: Cc1ccc(CN)nc1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 95).
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[O:9]>C(O)C>[NH2:20][C:16]1[CH:15]=[C:14](/[CH:13]=[CH:12]/[CH2:11][NH:10][C:8](=[O:9])[C:7]([F:6])([F:23])[F:24])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NC/C=C/c1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1

Procedure:
Tin(II) chloride dihydrate (3.28 g, 14.5 mmol) was added to a solution of (E)-2,2,2-trifluoro-N-(3-(3-nitrophenyl)allyl)acetamide (1.0 g, 3.64 mmol) in ethanol. The reaction mixture was stirred under reflux overnight. The mixture was concentrated under reduced pressure to give dark brown viscous liquid. The reaction mixture was partitioned between sat NaHCO3 and EtOAc and then filtered through Celite which was thoroughly washed with ethyl acetate. Organic layer was separated and concentrated under reduced pressure to give (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide as a brown liquid. Yield (0.8 g, 89%); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (bs, 1H), 6.96 (t, J=7.8 Hz, 1H), 6.51-6.60 (m, 2H), 6.45-6.48 (m, 1H), 6.39 (d, J=16.0 Hz, 1H), 6.05-6.10 (m, 1H), 5.07 (bs, 2H), 3.95 (t, J=5.6 Hz, 2H); ESI MS m/z 243.09 [M−H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[CH3:20])[CH:3]=1.[N:34]1([CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][CH2:40][N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:43][CH:44]=3)[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Nc2ccc(CCN3CCOCC3)cc2)ncn1

Procedure:
A Smith vial (2-5 mL) is charged with N-{3-[1-(6-chloro-pyrimidin-4-yl)-1H imidazol-2-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (16.8 mg, 0.035 mmol), 4-(2-morpholin-4-yl-ethyl)-phenylamine (22 mg, 0.11 mmol), p-toluenesulfonic acid monohydrate (4.4 mg, 0.023 mmol) and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 1.5 hours in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound. 1H NMR 600 MHz (DMSO-d6) δ 11.00 (s, 1H), 10.54 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.97 (d, J=6.6 Hz, 1H), 7.79 (t, J=8.4 Hz 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28 (m, 3H), 7.06 (s, 1H), 6.95 (s, 1H), 4.03 (d, J=12.6 Hz, 2H), 4.03 (d, J=12.6 Hz, 2H), 3.69 (t, J=12.6 Hz, 2H), 3.52 (d, J=12.0 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H), 3.13 (br, 2H), 2.98 (t, J=7.8 Hz, 2H), 2.33 (s, 3H); MS m/z 643.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9](F)[C:8]([C:12]#[N:13])=[CH:7][C:6]=1[Cl:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[C:9]([O:17][CH3:16])[C:8]([C:12]#[N:13])=[CH:7][C:6]=1[Cl:14]
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Temperature: 130 °C

Procedure:
A solution of methyl(2-chloro-4-cyano-5-fluorophenyl)acetate (1.40 g, 6.15 mmol) in methanol (30 mL) was divided into two 20 mL microwave vials. Potassium carbonate (2×850 mg) was added to each vial. Each was heated in a microwave at 130° C. for 60 minutes at which time HPLC/MS indicated no starting material was left and the product was all hydrolyzed to the acid. Most of the methanol was removed in vacuo and the residue was diluted with water, acidified with 2M HCl and the mixture was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify the acid. The excess diazomethane was quenched with acetic acid and the mixture was concentrated. Flash chromatography (40% DCM/hexanes to 100% DCM) gave the methyl(2-chloro-4-cyano-5-methoxyphenyl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H), 3.83 (s, 2H), 4.07 (s, 3H), 7.139 (d, J=8.1 Hz, 1H), 7.468 (d, J=8.0, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:18])[CH:16]=[CH2:17].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)(=[O:18])[CH:16]=[CH2:17]
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc2cc3ccccc3cc2c1
Yield: 27.5 %

Procedure:
Anthracene (0.156 g), acryloyl chloride (0.11 g), and aluminium chloride (0.15 g) were treated in the same manner as described in Example 1 to obtain the title compound (56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([O:25]C)=[O:24])=[CH:13][C:12]=2[N:11]=1.[OH-].[Na+].C(O)(=O)C>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 62.1 %

Procedure:
To a solution of methyl 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (0.100 g, 0.256 mmol) in MeOH (15 mL), sodium hydroxide (0.052 g, 1.3 mmol) was added. The reaction mass was refluxed for 3 h. Methanol was removed under vacuum. Water was added and reaction mixture was acidified with dilute acetic acid. The reaction mixture was filtered and obtained solid was dried to afford 0.060 g of the desired product. 1HNMR (DMSO-d6): δ 2.62 (s, 3H), 7.37 (m, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.65 (s, 1H), 9.80 (s, 1H), 11.53 (s, 1H), 13.00 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:19])[CH3:18]>>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Product: CC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969) and acetyl chloride
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=2[CH2:33][CH2:32]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:42][C:39]2[CH:40]=[CH:41][C:34]3[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:37][CH2:36][C:35]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)cc2CC1
Yield: 75 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (84 mg, 0.00021 mol), 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (47 mg, 0.00021 mol), and 10-Camphorsulfonic acid (58 mg, 0.00025 mol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.5 mL satd. sodium bicarbonate, then extracted 2×10 mL DCM, dried over sodium sulfate and conc. onto 1 g Celite. Chromatography (ISCO, Amine-capped SiO2, 14 g, 25-100% EtOAc:Hex) afforded 3-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-morpholin-4-yl-phenoxy)-propionitrile as a light pink solid (91 mg, 74%). MP: 91-96° C., LCMS 578 (M+H); 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H, J=7.9 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.56 (d, 1H, J=8.8 Hz), 6.50 (s, 1H), 4.28 (t, 2H, J=6.3 Hz), 3.88 (m, 4H), 3.53 (t, 2H, J=6.3 Hz), 3.38 (s, 3H), 3.14 (m, 4H), 2.90 (m, 6H), 2.72 (m, 6H).
Reaction SMILES: [CH2:1]1[CH2:11]CN2C(=NCCC2)C[CH2:2]1.[OH:12][CH:13]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][CH2:27][C@@H:26]2[CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([OH:41])=[O:40])=[CH:36][CH:35]=2)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].IC(C)C>CC(C)=O>[CH:1]([O:40][C:39]([C:37]1[S:38][C:34]([CH2:33][CH2:32][CH2:31][C@H:26]2[CH2:27][CH2:28][C:29](=[O:30])[N:25]2[C:22]2[CH:21]=[CH:20][C:19]([CH:13]([OH:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=2)=[CH:35][CH:36]=1)=[O:41])([CH3:11])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Solvent: CC(C)=O
Solvent: CC(C)I
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OC(C)C)s2)cc1
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
DBU (5.2 μL, 0.035 mmol) was added to a solution of acid 43 (7.5 mg, 0.017 mmol) in acetone (0.1 mL) at rt under nitrogen. After 10 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 21 h at rt, the reaction was quenched with 0.01 N HCl (3 mL) and extracted with EtOAc (3×4 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica (CH2Cl2→1% MeOH/CH2Cl2) afforded 4.6 mg (53%) of the title compound (44).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:14])=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH2:40])=[CH:37][CH:36]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:7]1[CH:6]=[C:5]2[C:10]([C:2](/[CH:40]=[CH:39]/[C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[N:3][N:4]2[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: C=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Br)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(/C=C/c3ccc(F)cc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 46.8 %

Procedure:
To a solution of 600 mg of 3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole in 6 mL of N,N-dimethylformamide were successively added 292 mg of 4-fluorostyrene, 71 mg of 2-(di-tert-butylphosphino)biphenyl, 27 mg of palladium acetate (II) and 0.85 mL of triethylamine, and stirred at 80° C. for 6.5 hours. The solvent was evaporated, and the resulting residue was dissolved in 25 mL of ethyl acetate. The organic layer was successively washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained crude crystal was recrystallized from ethyl acetate-diisopropylether, to afford 304 mg of the title compound as bright yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[C:6]([F:50])[C:5]=1[OH:51])([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[C:6]([F:50])[C:5]=1[OH:51]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4c(F)c(O)c([N+](=O)[O-])c(F)c4F)c(F)c3F)c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1c(O)c(F)c(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)c(F)c1F
Reaction time: 72 h
Yield: 93 %

Procedure:
50 g of 4-(4-nitro-3-hydroxy-2,5,6-trifluoro-phenoxy)-4'-(4-benzyloxycarbonylphenoxy)octafluoro-biphenyl prepared as described in Example 5 (0.069 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[CH2:16]([O:15][C:13]([N:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-methylglycine (7.0 g) was added to water (50 ml) and the pH of the solution adjusted to 9 with solid sodium bicarbonate. The solution was cooled to 0° C. and stirred vigorously, while benzyl chloroformate (19 ml) was added dropwise over 20 minutes. The mixture was stirred for a further 2 hours at 0° C. and an additional 2 hours at room temperature, then extracted with diethyl ether (2×130 ml). The aqueous solution was then acidified to pH 3 with 5N HCl and the product isolated by extraction with ethyl acetate (2×130 ml). The combined organic extracts were dried over anhydrous sodium sulphate and the solution concentrated in vacuo to give N-(benzyloxycarbonyl)-N-methylglycine as a pale yellow oil (16.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Yield: 62.5 %

Procedure:
4-Bromobenzylbromide (3 g) was stirred with 4-hydroxypiperidine (1.21 g) and potassium carbonate (1.99 g) in dimethylacetamide (15 ml) at 50° C. for 3 h The reaction mixture was then allowed to cool, poured into water (80 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with a gradient of 0-3% methanol in dichloromethane, to afford the product as a viscous, colourless oil (2.02 g).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:16])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH:16][C:3]([CH3:2])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-1-(naphthalen-2-yl)propan-2-amine hydrochloride (5.9 g, 25.0 mmol), 3-chloro-4-fluoro-1-nitrobenzene (5.27 g, 30.0 mmol) and K2CO3 (6.9 g, 50.0 mmol) in DMSO (50 mL) was stirred at 140° C. overnight. The mixture was cooled to rt and poured into 150 mL of water. The mixture was then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as yellow foam (3.78 g, 43%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(OCC)C.C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
4-bromobenzotrifluoride (4.8 g, 21.3 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 50 ml of anhydrous diethylether was added, and then 10 ml of n-butyllithium solution (25.6 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. In the meanwhile, the color of the mixture changed from transparent to cloudy green. The mixture was kept at −78° C. and continuously stirred for 60 minutes. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.2 ml, 25.6 mmol) was slowly added to the mixture at −78° C., and then the temperature was slowly raised to and kept at 20° C. for 12 hours for reaction. The color of the mixture in the reaction flask changed from cloudy green to cloudy white. Deionized water was slowly added to the mixture to terminate the reaction in the reaction flask. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride solution to collect an organic layer, followed by dehydration of the organic layer using sodium sulfate (Na2SO4) to thereby obtain a crude product. The crude product was recrystallized in a mixed solvent having dichloromethane and n-hexane (dichloromethane:n-hexane=1:1) at 20° C., thereby obtaining white crystals (4.27 g, 73% yield).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].O=[C:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH:11]1[C:20](OC)=[O:21]>CN(C)C=O>[NH2:7][C:6]1[N:8]=[C:20]([OH:21])[C:11]2[CH2:12][CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]3[C:10]=2[N:5]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCC2CCCCC2C1=O
Agent: O=C(O)O
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1CCCCC1CC2
Temperature: 160 °C
Reaction time: 0.17 h

Procedure:
In a 500 mL round bottomed flask, a suspension of guanidine carbonate (11.1 g, 61.4 mmol) in N,N-dimethylformamide (100 mL) was heated with stirring to 160° C. for 10 minutes, and a solution of the product from Example 12A (6.46 g, 30.7 mmol) in N,N-dimethylformamide (15 mL) was added dropwise over 2 minutes. The flask that contained the product from Example 12A was rinsed with an additional 10 mL of N,N-dimethylformamide and this was added to the reaction over 2 minutes. The reaction was heated to 165° C. for 20 minutes, cooled to room temperature and partitioned between 1 M sodium hydroxide (650 mL) and ether (200 mL). The layers were separated and the ether layer was extracted with 1 M sodium hydroxide (25 mL). The ether layer was disposed of. The combined aqueous sodium hydroxide layers were cooled in an ice bath and acidified to pH ˜7 with concentrated hydrochloric acid. After standing at ambient temperature for 15 minutes, the resulting solid was collected by filtration, washed with water and dried overnight in a drying oven with heating under vacuum to provide the title compound: 1H NMR (DMSO-d6) δ 0.78-0.96 (m, 1H), 1.00-1.35 (m, 5H), 1.61-1.74 (m, 3H), 1.75-192 (m, 2H), 2.01-2.18 (m, 1H), 2.28-2.58 (m, 2H), 6.13 (br s, 2H), 10.66 (s, 1H); MS (DCl/NH3) m/z 220 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5](=[O:12])[CH2:4][CH2:3][CH2:2]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
A 3.32 g portion of 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one and 4.31 ml of triethylamine were dissolved in 33 ml of dichloromethane and, with stirring on an ice bath, 4.59 g of p-nitrobenzoyl chloride was added to the resulting solution. The reaction solution was stirred at room temperature for additional 60 minutes. The reaction solution was then mixed with a saturated sodium bicarbonate aqueous solution and subjected to phase separation. The dichloromethane layer was separated and washed with a 1N hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution once for each. The thus washed layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 5.68 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: Br([O-])(=O)=[O:2].[Na+].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C.O>[C:6]([OH:2])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccccc1
Yield: 86.5 %

Procedure:
The separated catalyst was added to a fresh batch of sodium bromate (0.3 g) and benzyl alcohol (0.216 g, 2 mmol) in acetonitrile:water (5:7, 12 ml). The above procedure was repeated to give benzoic acid as a white solid (0.21 g, 87%).