Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:44]=[C:39]1[NH:38][CH2:43][CH2:42][N:41]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:40]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 47 mg (0.47 mmol) of piperazin-2-one and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 39 mg (52% of theory)
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([CH3:47])[CH2:12][C@H:13]([N:17]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14](O)=[O:15].[NH2:48][C@H:49]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:10][CH:11]([CH3:47])[CH2:12][C@H:13]([N:17]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([NH:48][C@@H:49]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Referring to FIG. 45, DIPEA (270 μL, 1.6 mmol, 2.5 eq) was added to a mixture of acid (S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenyl-N-((pivaloyloxy)methyl)butanamido)pentanoic acid (345 mg, 0.64 mmol), H-Phe-OBn (283 mg, 0.97 mmol, 1.5 eq) and HATU (370 mg, 0.97 mmol, 1.5 eq) in CH2Cl2 (10 mL) and the mixture was stirred for four hours at RT. The mixture was poured into water and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-80% EtOAc in heptanes) and product (330 mg, 67%) was isolated as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=O)=[CH:15][CH:14]=3)[CH2:9]2)[CH:2]=1.FC(F)(F)C(O)=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.[N:47]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]=N1>C(Cl)Cl.CN(C=O)C>[NH2:47][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:49][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:11][CH2:12][C@H:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:9]2)=[CH:25][CH:24]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Nc3cccnc3)C2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](Nc3cccnc3)C2)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a suspension of compound 365 (19 mg, 0.56 mmol) in DCM 500 μL was added trifluoroacetic acid (200 μL). The solution was refluxed at 50° C. for 3 h and concentrated in vacuo to produce a white solid. This material was dissolved in DMF (500 μL) and was treated with Et3N (16 μL, 0.118 mmol) and BOP (30 mg, 0.067 mmol). The reaction mixture was stirred for 10 min. and 1,2-henylenediamine (7 mg, 0.061 mmol) and another portion of Et3N (23 μL, 0.168 mmol) were added. The mixture was stirred for 2 h at room temperature and DMF was removed in vacuo at 80° C. The residue was partitioned between EtOAc and H2O. The organic layer was collected and extracted with 1N HCl and neutralized with sat. NaHCO3. A precipitate formed which was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using MeOH/CHCl3 (7:93) as the eluent to afford the title compound (11 mg, 52% yield). 1H NMR: (CD3OD) δ(ppm): 7.97 (d, J=2.7 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.78 (dd, J=4.7, 1.0 Hz, 1H), 7.18-7.10 (m, 3H), 7.05 (td, J=7.4, 0.6 Hz, 1H), 6.89 (dd, J=7.8, 1.2 Hz, 1H), 6.76 (td, J=7.4, 1.4 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 4.25 (quint, J=4.9 Hz, 1H), 3.77 (dd, J=10.2, 6.1 Hz, 1H), 3.57 (dd, J=17.0, 7.0 Hz, 1H), 3.49 (td, J=8.0, 5.3 Hz, 1H), 3.29 (q, J=6.7 Hz, 1H), 2.41 (sext, J=7.2 Hz, 1H), 2.10 (sext, J=4.9 Hz, 1H). m/z: 372.4 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][C@H:23]([NH2:26])[CH2:24][CH3:25]>CS(C)=O>[C@H:23]([NH:26][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:24][CH3:25])[CH3:22]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC[C@H](C)N
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.439 mmol, 1.00 equiv), (S)-butan-2-amine (2 mL), DMSO (1 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with H2O. The resulting solids were collected by filtration. The residue was applied onto a silica gel column with PE/EA (50:1). This resulted in 114 mg of (R)-methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][CH:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)CO)n(C)n1
Yield: 66 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.6 mmol) was converted, using DL-2-amino-1-propanol instead of 2-amino-2-methyl-1-propanol, to the title compound (155 mg, 66%) which was obtained as a white solid. MS: m/e=389.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[Cl:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:11]([F:21])([F:22])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]1[CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:13]
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)Cl
Reaction time: 1 h

Procedure:
An amount of 53 mg (0.33 mmol) of 2-chloro-5-chloromethylpyridine dissolved in 6 mL of anhydrous acetonitrile was added to 68 mg (0.33 mmol) of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by the above method, following which 50 mg (0.36 mmol) of potassium carbonate was added and refluxing under heating was carried out for 1 hour. Following reaction completion, the reaction mixture was returned to room temperature then concentrated under reduced pressure. Diethyl ether was added to the concentrate, whereupon a solid separated out. The solid was collected by filtration and dried, affording the target compound in an amount of 49 mg (yield, 45%).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C([Li])CCC.CO[C:13]([C:15]1[S:23][C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH:16]=1)=[O:14].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:2][O:3][N:4]([CH3:5])[C:13]([C:15]1[S:23][C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH:16]=1)=[O:14]
Reactant: CNOC
Reactant: COC(=O)c1cc2cnccc2s1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc2cnccc2s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A suspension of O,N-dimethylhydroxylamine hydrochloride (2.32 g, 23.8 mmol) in THF (20 mL) was purged with N2 and cooled to −78° C. before adding n-butyllithium (1.6 M in hexanes, 30.0 mL, 48.1 mmol). Removed bath and stirred 15 minutes before replacing the bath and adding a solution of thieno[3,2-c]pyridine-2-carboxylic acid methyl ester (0.92 g, 4.76 mmol) in THF (10 mL). After 45 minutes, saturated NH4Cl was added. The mixture was diluted with EtOAc; washed with water, 1 M HCl, water, 5% NaHCO3, water, and brine; dried over Na2SO4, and evaporated to give 0.54 g (51%) of an oil which solidified upon standing. The product thus obtained was used in the next step without further purification. MS m/z 223 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21](O)=[O:22])=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.[CH2:48]([O:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1)[CH3:49]>C(Cl)Cl>[CH2:48]([O:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:21]([C:7]2[CH:8]=[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])[C:4]3[N:5]([C:24]([CH3:25])=[C:2]([CH3:1])[N:3]=3)[CH:6]=2)=[O:22])=[CH:53][CH:52]=1)[CH3:49]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Reactant: CCOc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)c2cc(NCc3c(C)cccc3CC)c3nc(C)c(C)n3c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). 4-ethoxyanilin(0.19 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was added to a column with silica gel and was purified by chromatography using methylene chloride:methanol (95:5) as eluent. The residue was treated with a hot mixture of hexane:ethyl acetate (2:1) and the product was filtered off and dried to obtain 0.14 g (74%) of the desired compound as white crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:16][CH:15]=2)[N:6]=1.[CH3:30]I>CN(C=O)C>[CH3:30][N:20]([C:17]1[CH:16]=[CH:15][C:14]([N:7]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:5]([C:4]([F:3])([F:28])[F:29])=[N:6]2)=[CH:19][CH:18]=1)[C:21]([N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22]
Reactant: O=C(Nc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCCC1)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Under an inert atmosphere (Ar), NaH (60% in mineral oil, 3.8 mg; 95 μmol) was added in one portion to a stirring solution of N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide (17.7 mg; 44 μmol) in anhydrous DMF (1.5 mL). After stirring at room temperature for 1 hour, MeI (20 μL; 0.32 mmol) was added in one portion, and the reaction stirred at this temperature for 2 hours 10 minutes. The reaction was quenched with methanolic ammonia (1M, 1 mL), concentrated in vacuo and purified by column chromatography, giving the desired material as a yellow oil (15.4 mg; 84%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1.[CH3:16][C:17]([CH3:19])=O.C>>[CH:17]([N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:2]1)([CH3:19])[CH3:16]
Reactant: O=C1Nc2ccccc2C12CCCNC2
Reactant: CC(C)=O
Agent: C
Product: CC(C)N1CCCC2(C1)C(=O)Nc1ccccc12
Yield: 75 %

Procedure:
The compound was prepared according to PROCEDURE 1, Method A by reaction with spiro[indoline-3,3′-piperidin]-2-one and acetone (5 equivalents). Yield: 75%. 13C NMR (CDCl3): δ 17.6, 17.7, 21.7, 32.1, 48.6, 48.8, 54.0, 54.8, 109.6, 121.6, 126.2, 127.2, 134.8, 140.1, 182.4; MS (CI, CH4): m/z (rel. int.) 245 (M+1, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:25]I>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:25])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COC(=O)CCCC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Product: COC(=O)CCCC(=O)N(C)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
(prepared from 4-cyano-4'-(4-methoxycarbonylbutyrylamino]biphenyl by methylation with methyliodide)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[C:23]([Cl:30])[N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[OH:31][CH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1C(OC(C)(C)C)=O.[H-].[Na+].Cl>CN1CCCC1=O>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([O:31][CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)=[C:23]([Cl:30])[N:22]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1nc(OC[C@H]2CCCN2)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Yield: 145.9 %

Procedure:
Procedure as for Example 115 using 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66a) (0.29 g), tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.15 g) and sodium hydride (0.04 g of a 60% dispersion in oil) in N-methylpyrrolidinone (20 mL). The adduct was deprotected with HCl (4M in dioxane) to afford the titled adduct (0.2 g) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[F:27][C:28]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:36]=[C:35]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[N:4][CH:3]=2)[CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31]
Reactant: CN1CCC(COc2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(COc2ccc(Nc3ncc(-c4ccc(C(N)=O)c(F)c4)n4ccnc34)cc2)CC1
Yield: 85.2 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-amine (20 mg, 0.048 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (25.5 mg, 0.10 mmol), Pd(PPh3)4 (13.9 mg, 0.001 mmol) and 1M Na2CO3 (0.8 mL) in dioxane (2 mL). Purification by silica gel column chromatography eluting with a mixture 95:5 followed by 90:10 DCM:MeOH affords a solid that was triturated with ethyl acetate to give the title compound (19.4 mg, 85%). LCMS: Rt 1.96min (94%), m/z (APCI) 475 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 1.48-1.61 (2H, m), 1.98-2.02 (3H, m), 2.51-2.58 (4H, m), 2.70 (3H, br s), 3.91 (2H, d), 6.98 (2H, d), 7.55 (1H, s), 7.65-7.87 (6H, m), 7.98 (2H, d), 8.06 (1H, s), 9.68 (1H, s).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[CH:8]=1.CN([CH:21]=[O:22])C>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([Cl:17])[C:8]=1[CH:21]=[O:22]
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
A 2M n-BuLi solution (5.8 mL, 11.6 mmol) was added to a −78° C. THF solution (60 mL) of 1,3-dichloro-5-(trifluoromethyl)benzene (2.5 g, 11.6 mmol). After 45 min neat DMF (0.39 mL, 5.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][CH3:14])[C:10](=[S:15])[NH:9][C:8]=2[CH:16]=1)([O-])=O.C(O)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][CH3:14])[C:10](=[S:15])[NH:9][C:8]=2[CH:16]=1
Reactant: CCC1Oc2ccc([N+](=O)[O-])cc2NC1=S
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCC1Oc2ccc(N)cc2NC1=S

Procedure:
1 g of 6-nitro-2-ethyl-1,4-benzoxazine-3-thione is dissolved with 7.6 ml of glacial acetic acid and 1 ml of water, and it is mixed with 950 mg of iron powder. After several hours at room temperature, it is poured onto water. The crystals are suctioned off and washed with water, dissolved again with ethyl acetate and washed neutral with brine, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After column chromatography with hexane/ethyl acetate, a yield of 811 mg results.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 2-chloro benzylamine (45 mg, 0.32 mmol). The title compound was obtained as a solid (29 mg, 22% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.36 (1H, m), 8.98 (2H, m), 8.53 (1H, s), 7.45 (1H, m), 7.33 (3H, m), 4.46 (2H, m). MS m/z: 471.97, 473.95 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>[Pt].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Yield: 99.3 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D21) (21.62 g, 0.0644 mol), triethylamine (40 mL) and 5% Pt/C catalyst (21 g, 56% w/w water) in MeOH (400 mL) was hydrogenated at room temperature and atmospheric pressure overnight. The catalyst was removed by filtration and washed with further MeOH. The filtrate was concentrated in vacuo, re-dissolved in DCM (200 mL) and washed with 2M NaOH solution. The aqueous wash was re-extracted with DCM (×2, 100 mL) and all organic phases were combined, washed with brine, dried and concentrated to give the title compound (19.53 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:9](=[O:24])[C:10]3[N:11]=[C:12]([CH2:22]Br)[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[CH3:38][S-:39].[Na+].Cl>CN(C=O)C>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:9](=[O:24])[C:10]3[N:11]=[C:12]([CH2:22][S:39][CH3:38])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: O=c1c2nc(CBr)n(-c3ccccc3)c2nc(-c2ccc(-c3ccccc3)cc2)n1-c1ccc(Cl)cc1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1
Reaction time: 0 h
Yield: 87.2 %

Procedure:
A solution of 2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (17 mg, 0.030 mmol) in anhydrous DMF (0.2 mL) was treated with sodium thiomethoxide (3 mg, 0.042 mmol). The reaction mixture was stirred for (0 min and acidified with 1N aqueous HCl. The resulting precipitate was collected by filtration to give 2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methylsulfanylmethyl-9-phenyl-1,9-dihydro-purin-6-one (14 mg, 86%) as a white solid. HPLC-MS calculated for C31H23ClN4OS (M+H+): 535.1. Found 535.1.
Reaction SMILES: [NH:1]([C:8]1[C:9]([C:18](O)=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:8]2[C:9]=1[CH:10]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=[CH:17]2
Reactant: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2ccccc2nc2cc3ccccc3cc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 3-anilino-2-naphthoic acid (10.0 g, 37.98 mmol) and phosphorous oxychloride (35.4 ml, 379.8 mmol) was refluxed at 150° C. under nitrogen with stirring for 2 hours. The resulting purple mixture was cooled and evaporated under reduced pressure to dryness. The content was added with stirring to a mixture of chloroform/ice/conc. ammonium hydroxide (200 ml/200 g/200 ml). The chloroform layer was separated and dried over calcium chloride. Removal of the solvent under reduced pressure gave -12-chlorobenz-[b]acridine (9.4 g, 95%). Rf 0.8 (silica gel, hexane/ethyl acetate 2:1). MS (EI): m/z 263 (M).