Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:20][C:21]([F:22])([F:23])[F:24])=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 3-chloro-4-(trifluoromethoxy)aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.72 min, UPLC-MS (Condition 3) tR=1.34 min, m/z=429.0 [M−H]−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[N:39]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[CH:27]=[CH:26][S:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 37.2 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide (0.076 mmol) in DMF (4 mL) was reacted with K2CO3 (22 mg, 0.16 mmol), sodium iodide (2 mg) and pyrrolidine (26.98 mL, 0.4 mmol) to afford the title compound (14.2 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:10]1[C:11]([Br:12])=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Br)c(Br)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
The procedure of Cheeseman, G. W. H., J. Chem. Soc. 1170 (1962) was adapted. To a stirred suspension of 6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (576 mg, 1.8 mMol) in concentrated H2SO4 (6 mL) at 0° C. for 30 min. was added KNO3 (220 mg, 2.18 mMol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The color of mixture was changed from red to yellow brown. Then it was poured into ice (60 g) resulting in the separation of a bright yellow precipitate, which was collected by filtration and washed with distilled water (2×2 mL) followed by ethanol (2×1 mL) to get 498 mg of crude 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (76%, contains minor impurities by NMR). Crystallization from DMSO/H2O gave pure 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione as bright yellow microcrystals; mp: 352°-354° C. (dec.). IR (KBr, cm-1): 3387; 3256; 1756; 1700; 1537. NMR (1H, DMSO-d6): δ7.475 (s, 1H); 12.217 (s, 1H); 12.265 (s, 1H). HRMS: calcd for C8H3N3O4Br2 (M+) m/z: 362.8489; found: 362.8509.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:6][CH:5]=1)#[N:3]>C(O)C>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:8][CH:9]=1)#[N:3]
Reactant: N#Cc1ccc(C(=CCc2c[nH]cn2)c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(C(CCc2c[nH]cn2)c2ccc(C#N)cc2)cc1

Procedure:
4-[3,3-bis(4-cyanophenyl)-2-propenyl]-1H-imidazole hydrochloride is hydrogenated in ethanol using 10% Pd/C as a catalyst to give the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:29][CH2:28][CH2:27][NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A solution of 5-amino-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.48 mmol), N-2-pyridyl-1,2-ethanediamine (406 mg, 2.96 mmol) and triethylamine (0.410 mL, 2.94 mmol) in DMSO (2 mL) was stirred at 100° C. After 8 h, to the solution was added N-2-pyridyl-1,2-ethanediamine (102 mg, 0.744 mmol) and triethylamine (0.200 mL, 1.43 mmol) and stirred at 100° C. for another 8 h. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol. The resulting solid recrystallized by CH3CN, and dried to yield 5-amino-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (132 mg, 23%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:12][CH2:13]2)[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC1(c2cc(Br)cc(C=O)c2O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cc(Br)cc1C1(C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
step 3—To a solution of 130 (0.44 g, 1.7 mmol) in DMF (4 mL) was added K2CO3 (0.60 g, 4.4 mmol) and iodomethane (0.32 g, 2.3 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to RT and partitioned between water and Et2O. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated to afford 0.47 g (96%) of 5-bromo-2-methoxy-3-(1-methylcyclopropyl)benzaldehyde (132) as a light yellow solid.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:13]([OH:15])[CH3:14]>>[F:2][C:3]1[CH:4]=[N:5][N:6]([C:8]2([C:11](=[NH:12])[O:15][CH2:13][CH3:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: CCO
Reactant: N#CC1(n2cc(F)cn2)CC1
Agent: [Na]
Product: CCOC(=N)C1(n2cc(F)cn2)CC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Sodium metal (47 mg, 1.98 mmol) was added to anhydrous ethanol (4 mL) at room temperature. The mixture was stirred for 15 min. A solution of 1-(4-fluoro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (0.1 g, 0.66 mmol) in ethanol (2 mL) was added and the reaction mixture was heated to 70° C. for 90 min. The resulting solution was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C:49]1[N:50]=[C:51]([CH:54]2[CH2:59][CH2:58][N:57]([C:60](=[O:70])[CH2:61][C:62]3[CH:67]=[C:66]([CH3:68])[CH:65]=[CH:64][C:63]=3[CH3:69])[CH2:56][CH2:55]2)[S:52][CH:53]=1>C(#N)C>[CH3:69][C:63]1[CH:64]=[CH:65][C:66]([CH3:68])=[CH:67][C:62]=1[CH2:61][C:60]([N:57]1[CH2:56][CH2:55][CH:54]([C:51]2[S:52][CH:53]=[C:49]([NH:48][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:11])[N:50]=2)[CH2:59][CH2:58]1)=[O:70]
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(N)cs3)CC2)c1
Reactant: CC(C(=O)O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(NC(=O)C(C)c4ccccc4)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a solution of (rac.)-2-phenylpropionic acid (46 mg, 0.30 mmol) and diisopropylethylamine (0.15 mL, 0.9 mmol) in acetonitrile (2 mL) is added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (322 mg, 0.73 mmol) at RT. After stirring 30 min at RT, 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(2,5-dimethyl-phenyl)-ethanone (100 mg, 0.30 mmol) is added to the reaction mixture. After stirring overnight at RT, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (ethylacetate/cyclohexane 1:1) to give N-(2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-2-phenyl-propionamide (Compound No. I.g.141, 19 mg, 13.4%). 1H-NMR (400 MHz, CDCl3): δ=1.46-1.39 (m, 1H), 1.52 (d, 3H), 1.68-1.56 (m, 1H), 1.89-1.83 (m, 1H), 2.01-1.97 (m, 1H), 2.15 (s, 3H), 2.19 (s, 3H), 2.73-2.67 (m, 1H), 3.18-2.92 (m, 2H), 3.59 (s, 2H), 3.68-3.63 (q, 1H), 3.78-3.71 (m, 1H), 4.65-4.62 (m, 1H), 6.91-6.82 (m, 2H), 7.02-6.98 (m, 1H), 7.31-7.15 (m, 5H), 7.42 (s, 1H), 8.05 (br, 1H). MS: m/z=462 (M+1).
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.N.[H][H]>[Pd].CO>[N:13]1([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[CH:4]([NH2:3])[CH2:5][CH2:6]3)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CON=C1CCc2cc(N3CCCCC3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: NC1CCc2cc(N3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Piperidin-1-ylindan-1-one O-methyloxime (2.95 g, 12 mmol), 10% palladium on carbon (1.45 g), and 20% ammonia in methanol (80 ml), were placed in a Parr apparatus, which was charged with hydrogen to 60 psi. The mixture was shaken for 1 hour at ambient temperature and filtered. The filtrate was removed under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.53-1.60 (m, 2H), 1.65-1.79 (m, 4H), 2.42-2.53 (m, 1H), 2.69-2.81 (m, 1H), 2.86-2.96 (m, 1H), 3.12 (t, 4H), 4.31 (t, 1H), 6.82 (m, 2H), 7.20 (d, 1H); MS (DCI) 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:31])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NCCN1CCOCC1)C(=O)NC3=O
Agent: BrB(Br)Br
Product: O=C(CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O)NCCN1CCOCC1
Reaction time: 16 h
Yield: 64 %

Procedure:
Demethylation of (120) prepared as described in example 233 with BBr3 using the procedure described in example 80 except that the reaction time was 16 h gave (121) as a yellow powder (64%), mp 143–148° C. (dec). 1H NMR δ [(CD3)2SO] 11.05 (s, 1H), 9.35 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.74 (t, J=5.6 Hz, 1H), 7.71 (s, 1H), 7.60–7.55 (m, 2H), 7.52–7.43 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 4.67 (t, J=6.3 Hz, 2H), 3.40 (t, J=4.7 Hz, 4H), 2.98 (m, 2H), 2.57 (t, J=6.3 Hz, 2H), 2.12 (t, J=4.7 Hz, 4H), 2.02 (t, J=6.7 Hz, 1H). Found: C, 62.37; H, 4.99; N, 9.82. C29H27ClN4O5.1/2H2O requires C, 62.64; H, 5.08; N, 10.08.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[Sn](Cl)Cl>>[CH3:15][N:2]([CH3:1])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Product: CN(C)CC#Cc1ccc(N)cc1

Procedure:
The reaction of 4-(3-dimethylaminoprop-1-ynyl)-nitrobenzene with tin dichloride analogously to Example 269 yields the following three products:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[Cl:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:29])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[Cl:38])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of racemic (2′R,3S,4′R)-6-chloro-2′-(2-chloro-5-fluoro-phenyl)-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (143 mg, 0.24 mmol) and CDI (78 mg, 0.48 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. Then to this solution was added a mixture of methanesulfonamide (475 mg, 5 mmol) and NaH (200 mg, 60%, 5 mmol) in DMF (5 mL), which had been stirred for 1 h at room temperature. After the resulting mixture was heated at 60° C. for 1 h, it was poured into water (5 mL) and the mixture was acidified by concentrated aqueous HCl, extracted with EtOAc twice. The combined extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (100 mg).
Reaction SMILES: [N:1]#[N:2].[C:3]([C@@:8]1([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:1]#[N:2].[C:3]([C@@:8]1([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][O:14][C:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)[C@@H:10]([OH:11])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 15 h

Procedure:
The tritylation procedure of Jones45 was modified such that no DMAP was used. To 3.37 g (10.0 mmol) of N2 -isobutyryl-2'-deoxyguanosine (that was first concentrated from dry pyridine) in 50 mL of dry pyridine, was added 4.06 g (12.0 mmol, 1.20 equiv.) of 4,4'-dimethoxytrityl chloride. The reaction was stirred for 15 h, and then concentrated. The residue was partitioned between CH2Cl2 and 0.5% aq. NaHCO3, shaken, and separated. The organic layer was washed with 0.5% aq. NaHCO3 and dried. The crude product was purified by flash chromatography.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:34])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:30]([N:13]([C:14]1[N:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][C:6]=1[Cl:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(C(=O)Nc1ccc(C(=O)O)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 2.2, 4-{3-butyl-3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-ureido}-3-chloro-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as colorless foam. MS: m/e=496.1 [M−H−].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[BrH:30].O1CCOCC1>O>[BrH:30].[BrH:30].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:29]=[CH:28][C:19]([O:20][C:21]([CH3:27])([CH3:26])[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1)C(=O)O
Temperature: 95 °C

Procedure:
A mixture of methyl 2-[4-[2-[4-(4-pyridyl)piperazin-1-yl]-acetyl]phenoxy]isobutyrate (50 mg), 48% w/v hydrobromic acid (0.74 ml), dioxane (1 ml) and water (3 ml) was heated at 95° C. for 4 hours. The solution was cooled, diluted with water and freeze-dried to give the title compound, 40 mg, as a pale yellow solid: m.p. 163°-167° C.; NMR (D2O) δ 8.40 (2H, d), 8.16 (2H, d), 7.40 (2H, d), 7.21 (2H, d), 5.21 (2H, s), 4.32 (4H, b), 3.89 (4H, bt), 1.86 (6H, s); m/e 384 (M+H)+ ; calculated for C21H25N3. 2HBr.2H2O: C, 43.3; H, 5.3; N, 7.2. found: C, 43.6; H, 5.3; N, 7.3%.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@@H]1CC[C@@H](c2cccnc2)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 91 °C
Reaction time: 7 h
Yield: 16.3 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (1.00 g, 3.61 mmol), (1R,3R)-3-(3-pyridyl)cyclopentylamine (702 mg, 4.33 mmol) and diisopropylethylamine (1.38 mL, 7.94 mmol) in anhydrous DMSO (18 mL) was stirred at 91° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[(1S,3S)-3-(3-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (247 mg, 16%) as a yellow powder.
Reaction SMILES: C(OC(=O)[N:7]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[C:19]([Cl:27])=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[ClH:26].[O:34]1[C:33]2[CH:38]=[CH:39][C:30]([CH2:29][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=5)[C:19]([Cl:27])=[CH:18][C:17]4=[O:28])[CH2:12][CH2:13]3)=[CH:31][C:32]=2[O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(Cl)cc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1cc(Cl)c2ccc(Cl)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Yield: 133.7 %

Procedure:
To 1 mL of an ethyl acetate solution containing 104 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4,7-dichloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature. The resulting solid was filtered to give 62 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4,7-dichloroquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].I[C:8]1[C:9]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1N2CCN(CC2)C1>[N:18]1([C:9]2[C:8](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=[C:11]([C:14]([F:17])([F:15])[F:16])[N:10]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: FC(F)(F)c1ccc(I)c(N2CCCCC2)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1N1CCCCC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
70 μl (1.0 mmol) methyl acrylate was added to a mixture of 237 mg (0.66 mmol) 3-iodo-2-(piperidin-1-yl)-6-(trifluoromethyl)pyridine, 3 mg (0.01 mmol) Pd(OAc)2, 2.2 mg (0.02 mmol) DABCO and 91 mg (0.66 mmol) K2CO3 in 3 ml DMF under a nitrogen atmosphere. The reaction mixture was stirred in a sealed tube at 80° C. for 24 h. The mixture was cooled to RT, filtered through celite with EtOAc eluation. The organic phase was washed with water, dried and concentrated. Flash chromatography (SiO2, Pet. Ether/EtOAc 8/1) afforded 196 mg (94%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:21])[NH:12][C:13]=3[C:17]([O:19]C)=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1.CNC>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:21])[NH:12][C:13]=3[C:17]([OH:19])=[O:18])[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: COC(=O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Agent: CNC
Solvent: CO
Product: O=C(O)c1[nH]c(=O)c(O)c2c1CCN(Cc1ccc(F)cc1)C2=O
Temperature: 130 °C

Procedure:
To methyl 6-(4-fluorobenzyl)-4-hydroxy-3,5-dioxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (0.178 g, 0.514 mmol) in wet methanol was added N,N-dimethylamine in MeOH (4.0 eq.). The reaction mixture was put in a microwave reactor where it was heated at 130° C. for 1.5 hours, after which the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a solid. Alternatively, the starting material can be treated with LiOH in 1:1:1 THF/MeOH/H2O to give the product.