Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][C:35]([O:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:36][C:30]=4[S:29](=[O:45])(=[O:44])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1.FC(F)(F)C(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][C:35]([O:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:36][C:30]=4[S:29](=[O:44])(=[O:45])[CH2:28][CH2:27]3)[CH:16]=2)[CH2:12][O:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4cc(Oc5ccccc5)ccc4C3)cc(NCC3(N)COC3)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.2 %

Procedure:
A mixture of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-8-phenoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (90 mg, 0.13 mmol), palladium hydroxide on carbon (40 mg) and trifluoroacetic acid (0.1 mL) in methanol (30.0 mL) was stirred at room temperature under hydrogen (2 bar) for 14 hours. Then the reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford 10.5 mg of the desired product as a white solid (yield was 15.2%). MS obsd. (ESI+) [(M+H)+] 531, 1H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J=8.34 Hz, 1 H), 7.69 (s, 1 H), 7.52 (d, J=2.53 Hz, 1 H), 7.45 (d, J=8.59 Hz, 1 H), 7.42-7.35 (m, 2 H), 7.31 (dd, J=8.46, 1.64 Hz, 1 H), 7.25-7.13 (m, 2 H), 7.06-6.97 (m, 2 H), 6.21 (s, 1 H), 5.14 (brs, 2 H), 4.70-4.46 (m, 6 H), 3.68 (s, 2 H), 3.60 (brs, 2 H), 2.44 (s, 3 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11](N)=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][O:34]C2C=CC(C(O)=O)=C(C3C=CC=CC=3)C=2)[CH:28]=1.[N+](C1C=CC(C(O)=O)=C(C2C=CC=CC=2)C=1)([O-])=O>>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH2:23][S:24][CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([O:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=C(O)c1ccc(OCc2cccnc2)cc1-c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OCc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared by according to the procedure used in step C of the preparation of compound 8, except substituting 4-(3-pyridylmethyloxy)-2-phenylbenzoic acid, prepared as in Example 240E, for 4-nitro-2-phenylbenzoic acid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].[NH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[N+:20]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[NH:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-:22])=[O:21]
Reactant: NCCCNC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
Triethylamine (9.3 mL, 67 mmol) was added to a mixture of 4-chloro-3-nitroquinoline hydrochloride (16.4 g, 67 mmol) and dichloromethane (400 mL). A solution of N-(3-aminopropyl)benzamide (11.9 g, 67 mmol) in dichloromethane (100 mL) was added all a once. The reaction mixture was stirred at ambient temperature for 1 hour and then heated on a steam bath for 1 hour. The resulting precipitate was isolated by filtration to provide 6 g of N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide as a yellow solid, m.p. 209-211° C. 1H NMR (500 MHz, DMSO-d6) δ 9.07 (broad s, I—H), 9.05 (s, 1H), 8.54 (t, J=6.0 Hz, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.55 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 3.69 (q, J=6.0 Hz, 2H), 3.35 (q, J=6.0 Hz, 2H), 2.00 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][NH:4][CH2:3]1.[BH3-][C:20]#N.[Na+].C=O.Cl>CO.O>[CH3:20][N:4]1[CH2:3][C:2](=[O:1])[C:14]2[C:13]3[C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5]1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C)C3
Reaction time: 2 h

Procedure:
Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.04 g, 0.016 mmol) and NaCNBH3 (2.4 mg, 0.04 mmol) were added to a round bottomed flask, which were then dissolved in MeOH (2 mL), and treated with 0.5 mL of a 27% solution of formaldehyde in water. This mixture was stirred for 2 h, after which, 2N HCl (2 mL) was added, followed by stirring for 15 min. The mixture was taken to pH=11 by addition of concentrated, aqueous NaOH and extracted with methylene chloride (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.Br[C:17]1[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[CH:19][CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Cl:25][C:21]1[C:22]([CH:23]=[O:24])=[C:17]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])[CH:18]=[CH:19][N:20]=1
Reactant: O=Cc1c(Br)ccnc1Cl
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1ccnc(Cl)c1C=O)C3=O
Temperature: 97 °C
Yield: 64 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 107e (612 mg, 3.0 mmol), 4-bromo-2-chloronicotinaldehyde (2.0 g, 9.0 mmol), Pd2(dba)3 (275 mg, 0.30 mmol), XantPhos (347 mg, 0.60 mmol), cesium carbonate (1.95 g, 6.0 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 97° C. overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 1:2 ethyl acetate/petroleum ether to afford 329a as a yellow solid (660 mg, 65%). MS-ESI: [M+H]+ 344.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH3:29][O:30][CH2:31][C:32]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:33]
Reactant: COCC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) in THF (4 mL) was added triethylamine (0.12 mL, 0.85 mmol). The mixture was cooled in an ice bath and a solution of methoxyacetyl chloride (0.092 mL, 0.85 mmol) in THF (1 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (5 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound (180 mg, 73%) as a white solid. MS: m/e=355.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34](O)=[O:35])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:44][CH:45]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:46]#[N:47].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]12[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]1)[CH2:14][N:13]1[C:32](=[O:33])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([C:34](=[O:35])[NH:44][CH:45]([C:46]#[N:47])[CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[N:11]=[C:12]21)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)O)c(OCc2ccccc2)c1=O)OCc1ccccc1
Reactant: N#CC(N)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CC(Cc1ccc(F)cc1)NC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (180 mg, 0.368 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (0.051 mL, 0.588 mmol) followed by 1 drop of DMF. After stirring for 2 h, the mixture was concentrated under reduced pressure. The crude acid chloride was then diluted with dichloromethane (2 mL) and added to a stirred solution of 2-amino-3-(4-fluorophenyl)propanenitrile HCl (81 mg, 0.404 mmol) and triethylamine (0.205 mL, 1.471 mmol) in CH2Cl2 (2 mL) and the resulting solution was stirred at room temperature. After 16 h at room temperature, the reaction mixture was poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane) to afford the title compound (145 mg, 62% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.82 (brs, 1H), 7.28-7.49 (m, 10H), 7.06-7.17 (m, 2H), 6.96 (t, 2H, J=8.39 Hz), 6.63 (brs, 1H), 5.27-5.40 (m, 2H), 5.00-5.14 (m, 2H), 4.07-4.14 (m, 3H), 2.77-2.92 (m, 2H), 2.64-2.78 (m, 2H), 2.49 (brs, 1H), 1.87-2.02 (m, 4H), 1.63-1.75 (m, 2H). LCMS (M+H)=636.19.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.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>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:13]1[CH:12]=[C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)Cc1cccc(Br)c1
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: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1cccc(-c2ccccc2)c1
Yield: 78.8 %

Procedure:
A mixture of phenylboronic acid (1.000 g, 8.20 mmol), methyl 3-bromophenylacetate (1.691 g, 7.38 mmol), Na2CO3 (1.738 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.474 g, 0.41 mmol), toluene (30 mL), and water (5 mL) was heated under reflux for 20 h. The reaction mixture was diluted with water (20 mL) and the volatiles were removed in vacuo. The aqueous solution was washed with EtOAc (4×20 mL). The organic solutions were combined, washed with 1N NaOH (15 mL) followed by water (15 mL). The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography (79:1 hexanes:EtOAc to 39:1 hexanes:EtOAc) provided biphenyl-3-yl-acetic acid methyl ester (1.316 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)cn1

Procedure:
5-Aminopyridine-2-carboxylic acid (1.60 g, 11.6 mmol) was dissolved in MeOH (100 mL) and concentrated sulfuric acid (1.7 mL, 12.8 mmol) was added and the mixture was heated to 80 C for 5 hours. The reaction mixture was concentrated under vacuum, neutralised by adding 1M aq. sodium bicarbonate and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound as a pale yellow solid (1.813 g, quant.). Method B HPLC-MS: MH+ requires m/z=153 Found: m/z=153, Rt=0.35 min (by MS).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38]>C1COCC1>[Cl:29][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])[N:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:33])([F:32])[F:31])[CH:4]=1)=[O:10]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)c2)n1
Reactant: NCCCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.145 mmol) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[2-chloro-4-(2-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea, 23 mg (0.30 mmol) 3-amino-propan-1-ol and 2 ml THF was stirred at r.t. for 12 h. The reaction mixture was evaporated and the residue purified by chromatography on silica (dichloromethane/ethanol 96:4). Yield 21 mg (28%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.B(O)O.C(=O)(O)[O-].[Na+]>C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:24]4[CH:23]=[CH:22][C:27]([Cl:28])=[CH:26][CH:25]=4)[CH:18]=3)[N:13]([C:21](=[O:30])[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: OBO
Solvent: O
Product: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 201.6 %

Procedure:
Compound 5 (900 g; 1.7 mol) compound 6 (375.8 g; 1.4 mol), sodium bicarbonate (302.6 g; 2.1 mol) followed by 3-methyl-THF (9 L) and water (4.5 L) were added to the 20 L reactor and the mixture was purged with nitrogen at least for 1 h. Bis-triphenylphospino-palladium (II) chloride (60.8 g; 0.086 mol) was added and the reaction mixture was heated to 70-75° C. and stirred for 2 h. The reaction mixture was cooled and filtered over celite pad. The organic layer of the filtrate was separated, washed with water, and concentrated under vacuum. The precipitated solid was isolated by filtration and dried to provide compound 7 (953.9 g) as a brown solid (Purity=95.1%; Yield=˜100%). 1H NMR (DMSO-d6): δ (ppm) 8.75-8.76 (d, J=2.2 Hz, 1H), 8.59 (m, 1H), 8.52 (s, 1H), 7.80-7.82 (d, J=8.6 Hz, 1H), 7.69-7.71 (m, 3H), 7.54-7.56 (d, J=8.6 Hz, 2H), 6.99-7.07 (m, 2H), and 5.36 (s, 2H). MS (ESI) [M+H+]+=556.1 and 558.1.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH3:15])=[CH:8][N:7]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[CH3:15][C:9]1[CH:8]=[N:7][C:6]2[O:5][CH2:4][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1
Reactant: COC(=O)COc1ncc(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Product: Cc1cnc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
In a 250 ml round flask, (5-methyl-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester (5.47 g, 23.9 mmol) and tin tetrachloride (18.1 g, 95.6 mmol) were dissolved in 24 ml of concentrated hydrochloric acid, and then stirred at 800 for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% NaOH solution, and extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=19:1. The resulting solid was recrystallized from dichloromethane/methanol/tetrahydrofuran to obtain 7-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one as pale-brown solid (2.65 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5](CC)[C:4]2[CH:13]=[CH:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:3]1=2>Cl>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[NH:5][C:4]2[CH:13]=[CH:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:3]1=2
Reactant: CCOc1cc2c(=O)cc(C(=O)O)n(CC)c2ccc1=O
Agent: Cl
Product: CCOc1cc2c(=O)cc(C(=O)O)[nH]c2ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-6-ethoxy-1-ethyl-1H-cyclohepta[b]pyridine-2-carboxylic acid (5.3 g, described in Example 13) and 19% hydrochloric acid (50 ml) is refluxed for 1 hr and cooled to room temperature. The precipitate is collected and washed with water to give the title compound, mp > 280° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]([OH:19])[CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.[CH3:23][N:24]1[C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1.O>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][N:9]1[CH2:8][CH:7]([OH:19])[CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]3[N:26]=[CH:25][N:24]([CH3:23])[C:28]=3[CH:29]=2)[CH:3]=1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3cccc(OCC(O)CN4CCc5ccccc5C4)c3)cc21
Temperature: 120 °C
Yield: 26.4 %

Procedure:
To a solution of 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.55 mmol) in a mixed solution (Dioxane/H2O=4/1 mL) were added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (214 mg, 0.83 mmol), Pd(dppf)Cl2 (40 mg, 0.06 mmol) and Cs2CO3 (360 mg, 1.10 mmol). The reaction mixture was heated at 120° C. under microwave condition for 40 min. The solvent was removed by concentration and the residue was dissolved in ethyl acetate, washed with water. The separated organic layer was concentrated and the crude product was purified by preparative HPLC separation to give the title compound (60 mg, yield 26%) MS (ESI+) e/z: 414.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 9.45 (s, 1H), 8.21 (s, 1H), 8.00-7.93 (m, 2H), 7.50-7.24 (m, 7H), 7.10-7.07 (m, 1H), 4.76-4.70 (m, 1H), 4.62-4.49 (m, 2H), 4.24 (s, 3H), 4.22-4.19 (m, 2H), 3.98-3.94 (m, 1H), 3.60-3.51 (m, 3H), 3.41-3.21 (m, 2H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@@H:18]2[C@@H:13]([C:14]3[C:22]([O:23][C:24]4[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C>ClCCl>[CH3:30][C:27]1[N:26]=[N:25][C:24]([O:23][C:22]2[C:14]3[C@@H:13]4[C@H:18]([CH2:17][CH2:16][C:15]=3[CH:19]=[CH:20][CH:21]=2)[NH:9][CH2:10][CH2:11][CH2:12]4)=[CH:29][CH:28]=1.[ClH:1]
Reactant: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2CC3)nn1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN[C@H]2CC3)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrochloric acid (4 mol/L in 1,4-dioxane, 0.7 mL) is added to a solution of cis-10-(6-methyl-pyridazin-3-yloxy)-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.13 g) in dichloromethane (5 mL) at room temperature. The solution is stirred at room temperature for 2 h and then concentrated to give the crude title compound as its hydrochloric acid salt that is used without further purification. Yield: 0.12 g (crude); LC (method 1): tR=1.90 min; Mass spectrum (ESI+): m/z=296 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:9][O:8][C@@H](C(C)(C)C)[N:6]1C(OC(C)(C)C)=O)=[O:4].Cl>CO>[CH3:1][O:2][C:3](=[O:4])[C@@:5]([NH2:6])([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH2:9][OH:8]
Reactant: COC(=O)[C@@]1(Cc2cccc(Cl)c2)CO[C@@H](C(C)(C)C)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@](N)(CO)Cc1cccc(Cl)c1
Yield: 95 %

Procedure:
Under N2, to a solution of crude of 11 (1 mmol) in dried MeOH (5 mL) was added dropwise conc.HCl (2 mL) over 1 hr then stirred for overnight. After concentration, the residue was basified with NaHCO3 at 0° C. The mixture was extracted with CH2Cl2 (5×20 mL). The combined extraction were dried over MgSO4, filtered and concentrated. The crude was submitted to silica gel column chromatography (CH2Cl2:MeOH:NH4OH=500:9:1-100:9:1) to give 12 (95%, from 10). [α]D−3.6 (c 1.45, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.75 (d, J=13 Hz, 1H), 3.05 (d, J=13 Hz, 1H), 3.56 (d, J=10 Hz, 1H), 3.73 (s, 3H), 3.87 (d, J=10 Hz, 1H), 7.02 (m, 1H), 7.13 (m, 1H), 7.22-7.27 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ 41.5, 52.4, 63.6, 67.7, 127.4, 128.0, 129.8, 129.9, 134.3, 137.5, 175.3; IR (film): 3359, 3300, 3180, 1736, 1083 cm−1; Mass (ESI) 244.02 ([MH]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1.[CH3:17]I>C(O)(C)(C)C>[CH3:16][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:17])([C:12](=[O:15])[CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: CI
Reactant: CCC(=O)C1CCC(C)(C)c2ccccc21
Solvent: CC(C)(C)O
Product: CCC(=O)C1(C)CCC(C)(C)c2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
5.6 g of potassium tert.butylate are placed in 42.5 ml of tert.butanol and 10.8 g of 1,1-dimethyl-4-propionyl-tetralin are added dropwise thereto. The mixture is stirred for 1 hour, cooled to 5° C. and 8.5 g of methyl iodide are added. The mixture is stirred for a further 3 hours, a further 4.2 g of methyl iodide are added, the cooling source is removed and the mixture is stirred for a further 15 hours. The bulk of the tert.butanol is then removed by evaporation, the residue is taken up in ether, washed neutral with water, dried over sodium sulphate, evaporated and distilled. There are obtained 6 g of 1,1,4-trimethyl-4-propionyl-tetralin of boiling point 79° C./0.05 mmHg; nD20 =1.5249; yield 52%. Odour: fruity, woody.