Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:3]=12.[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].C1(C2C=CC=CC=2C2C(C(C)C)=C(C3CCCCC3)C(C(C)C)=C(P)C=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:29][C:30](=[O:40])[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:10][C:3]=23)=[C:34]([F:39])[CH:33]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccccc2)cc2c(Cl)ccnc21
Agent: [Pd]
Agent: CC(C)c1c(P)c(C(C)C)c(C2CCCCC2)c(C(C)C)c1-c1ccccc1C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3c2cc(-c2ccccc2)n3COCC[Si](C)(C)C)c(F)c1
Temperature: 110 °C
Yield: 83.9 %

Procedure:
4-Chloro-2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (312 mg, 0.87 mmol) and (3-fluoro-4-hydroxy-phenyl)-carbamic acid t-butyl ester (336 mg, 1.48 mmol) were dissolved in anhydrous toluene (5 mL) under nitrogen atmosphere. After adding dicyclohexyl-phosphino-2,4,6-triisopropylbiphenyl (41 mg, 0.087 mmol), Pd2 dba3 (40 mg, 0.044 mmol) and potassium carbonate, the mixture was heated at 110° C. The resulting reaction mixture was cooled to room temperature and filtered by passing through a celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate=9:1) to give the target compound as a white solid (404 mg, 0.73 mmol, 84% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][P:5]([CH2:10][CH2:11][NH2:12])(=[O:9])[O:6][CH2:7][CH3:8])[CH3:3].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:7]([O:6][P:5]([CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:9])[O:4][CH2:2][CH3:3])[CH3:8]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCNC(=O)OCc1ccccc1)OCC
Temperature: 25 °C

Procedure:
The HCl salt of (2-amino-ethyl)-phosphonic acid diethyl ester (4.5 g, 20.7 mmol) was dissolved in CH2Cl2 (100 mL). To this solution was added CBzCl (3.2 mL, 22.7 mmol), followed by iPr2NEt (14.4 mL, 82.8 mmol). The reaction was stirred at room temperature until complete, as determined by TLC (eluent: 100% EtOAc). The reaction was quenched by the addition of saturated NaHCO3. The mixture was then partitioned between CH2Cl2 and H2O. The layers were separated and the organic layer was washed with brine and then dried over Na2SO4. The drying agent was removed by vacuum filtration and (2-benzyloxycarbonylamino-ethyl)-phosphonic acid diethyl ester was isolated from the concentrated filtrate by silica gel column chromatography (EtOAc/hexanes) (5.98 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cccc(OC3CCOCC3)c2n1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1ncc2cccc(OC3CCOCC3)c2n1
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a mixture of 2,4-dichloro-8-(tetrahydro-2H-pyran-4-yloxy)quinazoline (4 g, 13.4 mmol), DIPEA (2.07 g, 16.8 mmol) and Pd/C (0.4 g, 10%) in ethyl acetate (10 mL) was stirred under 1 atm of H2 for 4 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered through a Celite pad, and the filtrate was concentrate in vacuo. The residue was purified by chromatography (petroleum ether:ethyl acetate=20:1, 10:1) to give the title compound (2 g, 57%) as a light yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.789 (d, 1H), 7.551 (t, 1H), 7.317 (d, 1H), 4.723 (m, 1H), 4.038 (m, 2H), 3.556 (m, 2H), 2.068 (m, 2H), 1.950 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:27]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=6[Cl:26])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:27]=2)=[CH:31][CH:30]=1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2ccc3c(c2)-c2nc(-c4ncnn4-c4ccccc4Cl)cn2CCO3)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
A mixture of 10-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 562 (79.7 mg, 16.8%). 1H NMR (CDCl3, 400 MHz): δ 8.12 (s, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.66-7.52 (dd, J=16 Hz, 2H), 7.46-7.04 (m, 7H), 7.04-7.02 (d, J=8 Hz, 1H), 7.11-7.09 (d, J=8 Hz, 1H), 4.46-4.44 (d, J=8 Hz, 4H). MS (ESI) m/z 474.08 [M+H+]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1I)[CH3:2].[CH3:14][C:15]([CH3:26])=[CH:16]B1OC(C)(C)C(C)(C)O1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH:14]=[C:15]([CH3:26])[CH3:16])[CH3:2]
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cccc(C)c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(C)c1C=C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of the 2-iodo-3-methylbenzoic acid ethyl ester (289) (2.9 g-0.01 mol) and 2-methyl-1-propenylboronic acid pinacol ester (3.64 g-0.02 mol-2 eq) in dry DMF (50 mL) and saturated NaHCO3 (10 mL) is degassed for 10 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (400 mg). The mixture is stirred at 110° C. overnight. The reaction is cooled and the DMF removed in vacuo and the residue diluted with water (120 mL). The aqueous is filtered through hyflo and extracted with EtOAc (3×75 mL). The organic extracts are washed with water (2×50 mL) and brine (2×50 mL), and dried over MgSO4. The organic extracts are concentrated in vacuo and purified by flash chromatography (400 g silica gel, 5% EtOAc in heptane) to give the product as pale yellow oil (1.85 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[O:24][C:23]([CH:25]=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)([OH:37])N.Cl([O-])=O.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([CH2:17][C:18]([C:20]3[O:24][C:23]([C:25]([OH:37])=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)o1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(C(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)o1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 139 (29 mg, 0.057 mmol) in dichloromethane (2 mL) and water (1 mL) cooled to 0° C. was added sulfamic acid followed by sodium chlorite. The reaction was left to stir, warming to room temperature over 2.5 hours. The layers were separated and the aqueous layer extracted further with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to a cream foam, which was purified by column chromatography on silica (50% ethyl acetate/49% dichloromethane/1% acetic acid) to obtain a white solid (10 mg).
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.OS(C(F)(F)F)(=O)=O.[C:25](=[NH:48])([O:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=2)=[CH:32][CH:31]=1)[NH2:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:27][C:25]3[NH:48][CH:2]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=4)[C:4](=[O:6])[N:26]=3)=[CH:31][CH:32]=2)=[CH:38][C:39]=1[C:44]([F:45])([F:46])[F:47]
Reactant: COC(=O)/C(=C/O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 160 °C
Yield: 21.4 %

Procedure:
To the solution of methyl (2E)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (177 mg, 0.789 mmol) and 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-phenyl)ethyl imidocarbamate triflate (267 mg, 0.526 mmol) in NMP (10 mL) was added K2CO3 (218 mg, 1.577 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (60 mg, 21.41% yield). LCMS: rt=3.58 min, [M+H+]=532.9
Reaction SMILES: [CH2:1]1[S:24][C:4]2([CH2:21][CH2:20][C@H:19]3[C:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[C:17](=[CH2:22])[CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH:11]=[CH:12][C:13]3=[O:23])=[CH:5]2)[S:3][CH2:2]1.[K].O.[Na+].[Cl-].O1CC[CH2:31][CH2:30]1>C#C>[CH2:2]1[S:3][C:4]2([CH2:21][CH2:20][C@H:19]3[C:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[C:17](=[CH2:22])[CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH:11]=[CH:12][C@:13]3([C:30]#[CH:31])[OH:23])=[CH:5]2)[S:24][CH2:1]1
Reactant: C=C1C[C@]2(C)C(=O)C=C[C@H]2[C@@H]2CCC3=CC4(CC[C@@H]3[C@@H]12)SCCS4
Reactant: C1CCOC1
Agent: C#C
Agent: [Cl-]
Agent: [K]
Solvent: O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC5(CC[C@@H]4[C@H]3C(=C)C[C@@]21C)SCCS5

Procedure:
A solution of 3.5 g of 11-methylene-oestr-4,15-diene-3,17-dione-3-ethylenedithioacetal in 52.5 ml of dry tetrahydrofuran was added, at -15° C. to -20° C., with stirring, to a tetrahydrofuran solution of potassium acetalide, prepared from 8.4 g of potassium tert.-butylate in acetylene. The reaction mixture was stirred for a further hour at this temperature, with continuous passage of acetylene. Thereafter, a mixture of 10 ml of water and 10 ml of tetrahydrofuran was added dropwise to the reaction mixture at -15° C. to -20° C. The reaction mixture was then poured out into a mixture of 1 liter of saturated NaCl solution and 0.5 liter of water. The precipitate was filtered off, washed neutral with water and dried in vacuo. After purification by chromatography over silica gel and crystallisation from diethyl ether/hexane, 2.6 g of 11-methylene-17α-ethinyl-17β-hydroxy-oestra-4,15-diene-3-one-3-ethylenedithioacetal were obtained, melting point 170.5° C.; [α] D20 =-21 (chloroform, c=1%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=O)[NH:8][C:7]=2[CH:12]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23]C(F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:9]=1[NH:8][C:7]1[CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:10]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2o1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Nc2cc(C(F)(F)F)ccc2O)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 60 step (ii) using 5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one and the product from example 7 step (ii).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[CH:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
Rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-phenyl)-amide (475 mg) was resolved on Berger SFC system under 30° C., 100 Bar, 35% MeOH on a O.D. Column to give two peaks. Peak 1, desired, 38 mg white solid; Peak 2, undesired, 38 mg white solid;
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.CN1CCOCC1.[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2>CO>[CH3:20][C:21]1([CH3:34])[C@H:25]2[CH2:26][CH2:27][C@:22]1([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:23](=[O:28])[CH2:24]2.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH2:12])[CH2:6]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: Br
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: CN1CCOCC1
Product: N[C@H]1Cc2ccc(Br)cc2C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-bromo-2,3-dihydro-1H-inden-2-amine hydrobromide (107 mmol, 31.27 g) and N-methylmorpholine (112 mmol, 12.32 mL, 11.33 g) in methanol (66.6 mL) was heated to 58-62° C. and a solution of ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (107 mmol, 24.79 g) in methanol (53.4 mL) was added over 3 min maintaining internal temp at 60-65° C. The addition funnel was rinsed with MeOH (13.3 mL) and rinsings added to reaction. The mixture was stirred at 60-65° C. for 10 min until a clear solution was obtained. The reaction was then allowed to cool to room temperature and stirred for a total of 4 h. The solids were collected by filtration and washed with a pre-cooled mixture of isopropyl acetate/methanol 2:1 (2×15 mL) followed by water (2×15 mL). The crude product was dried in a vacuum oven at 50° C. overnight to yield (18.03 g) of a fluffy white solid. This was suspended in methanol (130 mL) and heated to reflux for 4 h then allowed to cool to room temperature with stirring over 2 h and stirring continued at room temperature for a further 1 h. Solids were then isolated by filtration and washed with a pre-cooled solution of isopropylacetate/methanol (2:1, 2×18 mL). The colourless solid (13.82 g) was dried in the vacuum oven for 60 h. Refluxing in methanol followed by washing the solid with isopropyl acetate/methanol was repeated until the desired enantiomeric ratio was obtained. (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate was obtained as a colourless solid (12.28 g, e.e. 100:0, 25.9%).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:14]([O:21][C:22](=[O:37])[C@H:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:14]([O:21][C:22](=[O:37])[C@H:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[NH:24][C:1](=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material compound 3 was prepared as follows. To a solution of hippuric acid (0.90 g, 5×10−3 moles) and L-glutamic acid dibenzyl ester (2.50 g, 5×10−3 moles) in DMF (35 ml) was added 1-hydroxybenzotriazole (0.73 g, 5.5×10−3 moles), triethylamine (1.4 ml, 9.7×10−3 moles) and 1(3-dimethyl-aminopropyl)-3-ethylcarbodiimide, HCl salt (1.05 g, 5.5×10−3 moles). The mixture was stirred overnight at room temperature, poured into water (400 ml) and extracted twice with ethyl acetate (100 ml). The combined extracts were washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to obtain the desired starting material as a yellow oil. 2.06 g (84%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1cccc(Cl)c1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1[N+](=O)[O-]

Procedure:
A solution of 4-amino-3-nitrobenzoic acid (0.5 g), 3-chloroaniline (0.29 mL), BOP (1.46 g) and DIEA (0.72 mL) in DMF (5 mL) was stirred at room temperature for 20 h. Then saturated NaHCO3 aqueous solution was added. The aqueous layer was extracted with CH2Cl2, and the organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=12:88 to 100:0) to give 4-amino-N-(3-chloro-phenyl)-3-nitrobenzamide as a yellow solid: MS (m/z) 292 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 10.32 (s, 1H), 8.73 (s, 1H), 7.97 (d, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.69 (d, 1H), 7.37 (t, 1H), 7.16 (d, 1H), 7.10 (d, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:11])=[C:5]([OH:10])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl.Cl.[N:14]1([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[NH4+].OO>O.C(O)C>[NH2:2][C:3]1[C:8](=[N:23][C:22]2[CH:21]=[CH:20][C:19]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH3:9])[C:5](=[O:10])[C:4]=1[Cl:11]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: Nc1ccc(N2CCCC2)cc1
Agent: Cl
Agent: OO
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1=CC(=Nc2ccc(N3CCCC3)cc2)C(N)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.9 %

Procedure:
1.94 g of 3-amino-2-chloro-6-methylphenol hydrochloride are added to 2.35 g of 4-(pyrrolidin-1-yl)aniline dihydrochloride in solution in 15 ml of water and 15 ml of ethanol. The pH is adjusted to 9.5 with 20% ammonium hydroxide and then 18 ml of 9% aqueous hydrogen peroxide solution are added. The mixture is left stirring at ambient temperature for 4 hours and then the precipitate formed is filtered off. 1.7 g of 3-amino-2-chloro-6-methyl-4-[(4-pyrrolidin-1-ylphenyl)imino]cyclohexa-2,5-dien-1-one (1m) are thus obtained.
Reaction SMILES: I[CH2:2][C:3]1([CH3:22])[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[N:23]([CH2:2][C:3]1([CH3:22])[O:20][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:21])[NH:11][C:10](=[O:16])[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8]3)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CI)C2C
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN=[N+]=[N-])C2C
Temperature: 150 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
2-Iodomethyl-8-isopropyl-2,3,5-trimethyl-6,7-dihydrofuro[2,3-f]quinoline-7-one (2.10 g, 5.11 mmol) was dissolved in dimethylformamide (75 ml). To the solution, sodium azide (4.50 g, 69.2 mmol) was added, and the mixture was stirred at 150° C. for 4 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted from chloroform-water. The organic phase was washed with saturated aqueous sodium chloride solution, dried, and condensed under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform) to obtain pale yellow crude crystals. The obtained crude was recrystallized from chloroform-ether-hexane to obtain 1.25 g of the title compound (syn:anti=1) as a colorless powder (75.0%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br[CH:20]([CH2:26][CH2:27][CH2:28][Br:29])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:24][N:23]([CH3:25])[C:21](=[O:22])[CH:20]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:26][CH2:27][CH2:28][Br:29]
Reactant: CN(C)C(=O)C(Br)CCCBr
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Product: CN(C)C(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 73 %

Procedure:
In analogy to the procedure described in example 15B, 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 15 A) and (rac)-2,5-dibromo-N,N-dimethyl-pentanamide (intermediate 9) gave the title compound in 73% yield as light yellow oil. MS: 466.2 (1Br, MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH:11]=[CH:12]O[C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:17]=[C:16]3[C:10]([CH:11]=[CH:12][N:20]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:14]3=[O:15])=[CH:9][CH:8]=2)=[CH:18][CH:19]=1
Reactant: O=c1occc2ccc(Oc3ccc(Cl)cc3)cc12
Reactant: NCc1cccnc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2ccn1Cc1cccnc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture of 100 mg of 7-(4-chlorophenoxy)isocoumarin and 377 mg of 3-aminomethylpyridine was heated at 180° C. without solvent under stirring for 5 hours. After finishing the reaction, the mixture was chromatographed on a column of silica gel, eluting with ethyl acetate to give 97 mg of the titled compound.