Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[CH3:17][O:18][C:19]([NH:21][C:22](=NC(OC)=O)OC)=[O:20].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][CH:2]([CH3:16])[CH2:3][N:4]1[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:22]1[NH:21][C:19](=[O:20])[O:18][CH3:17]
Reactant: COC(=O)N=C(NC(=O)OC)OC
Reactant: CC(C)CNc1c(N)cnc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cnc3cccnc3c2n1CC(C)C

Procedure:
A mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine (Gerster et al, U.S. Pat. No. 6,194,425, Example 30 Part A, 4.10 g, 19.0 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (7.21 g, 37.9 mmol), acetic acid (5.69 g, 94.8 mmol), and p-toluenesulfonic acid (3.60 g, 19.0 mmol) in methanol (50 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (150 mL). The solution was washed sequentially with water (150 mL), aqueous sodium carbonate (150 mL of 4% w/w), water (150 mL), and brine (150 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1.78 g of methyl [1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a white solid, mp 195-197° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:7].[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH2:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:21]=[O:22])=[CH:13][NH:14]2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus oxychloride (3.82 g) was added to N,N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 10 minutes. A solution of 6-ethylindole [Journal of the Chemical Society (J. Chem. Soc.), 7165 (1965)] in N,N-dimethylformamide (6 ml) was added to the reaction solution, and the mixture was stirred at room temperature for one hour. Ice (20 g) and then a 5N aqueous solution of sodium hydroxide (34 ml) were added to the reaction solution, and the mixture was heated under reflux for one hour. The reaction solution was ice-cooled, and the precipitated crystals were collected by filtration to give 6-ethylindole-3-carboxaldehyde (2.76 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:37]1([CH2:43][CH2:44][S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[OH:51][C:50]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[O:17][C:47](=[O:48])[C:46]=1[S:45][CH2:44][CH2:43][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccncc2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc(-c2ccc(OCc3ccncc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(4-pyridinylmethoxy)acetophenone (2.00 g, 8.81 mmol), trimethylsilyltriflate (2.04 mL, 10.57 mmol), triethylamine (2.45 mL, 17.62 mmol), methylene chloride (22 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 212° C.; 1H NMR (400 MHz, DMSO-d6) δ2.73 (t, 2 H), 2.88 (t, 2 H), 5.29 (s, 2 H), 6.48 (s, 1 H), 7.18 (m, 5 H), 7.45 (d, 2 H), 7.74 (d, 2 H), 8.90 (d, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1C=O.[CH2:35](N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:35][C:30]2[CH:31]=[CH:32][S:28][CH:29]=2)=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: O=Cc1cccs1
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Nc2ncc(Br)c(NCCCNCc3ccsc3)n2)c1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (1.0 g, 1.97 mmol) in THF (30 mL) was added 2-thiophenecarboxaldehyde (184 mg, 1.64 mmol, 0.8 equiv.), triethylamine (362 mg, 3-6 mmol, 1.8 equiv.) and sodium triacetoxyborohydride (688 mg, 3.25 mmol, 1.6 equiv.). The resulting mixture was stirred overnight at room temperature under N2. The reaction was quenched by satuarated sodium bicarbonate (30 mL) and was extracted with ethyl acetate (3×30 mL). The reaction mixture was concentrated. Purification by HPLC chromatography using acetonitrile/water gave the title compound (310 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([OH:18])=O)=[C:4]2[CH:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[C:28]([N:35]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:39][CH2:38][CH:37]([NH:40][C:16]([C:12]2[S:13][CH:14]=[CH:15][C:11]=2[NH:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[O:18])[CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (100 mg, 0.39 mmol), diisopropylethylamine (0.1 mL, 0.54 mmol), 1-BOC-3-aminopyrrolidine (143 mg, 0.77 mmol) in dimethylformamide (2 mL) was added HATU (176 mg, 0.463 mmol). The solution stirred at room temperature for 18 h then diluted with ethyl acetate and washed with aqueous 1% lithium chloride. The organic layer was dried, concentrated in vacuo and purified by ISCO Companion to provide 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (161 mg, 95%). LCMS (ESI) 428 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.24 (1H, s) 8.20 (1H, d, J=6.83 Hz) 8.02 (1H, d, J=5.47 Hz) 7.81 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.80 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.42, 1.85 Hz) 4.35-4.58 (1H, m) 3.47-3.65 (1H, m) 3.33-3.44 (1H, m) 3.26 (1H, t, J=9.08 Hz) 3.09-3.21 (1H, m) 1.99-2.14 (1H, m) 1.81-1.95 (1H, m) 1.39 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([OH:6])=[O:5].O=S(Cl)[Cl:19].[CH3:21]O>>[ClH:19].[NH2:1][CH2:2][C@H:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:4]([O:6][CH3:21])=[O:5]
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-1b (5.0 g, 21 mmol) in CH3OH (100 mL) at 0° C. was added SOCl2 (7.5 mL, 100 mmol) dropwise. The cooling bath was then removed and the solution stirred at ambient temperature for 20 h. Concentration and trituration with ether gave 2-2 as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[N:9]=[CH:8][C:7]=1[C:21]([NH:23][C:24]1[CH:25]=[N:26][C:27]([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)=[C:28]([CH3:30])[CH:29]=1)=[O:22].O>N1C=CC=CC=1>[C:1]([N:34]1[CH2:35][CH:36]=[C:31]([C:27]2[N:26]=[CH:25][C:24]([NH:23][C:21]([C:7]3[CH:8]=[N:9][N:10]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=4)[C:6]=3[CH3:5])=[O:22])=[CH:29][C:28]=2[CH3:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CC=C(c2ncc(NC(=O)c3cnn(-c4ccc(C(F)(F)F)cn4)c3C)cc2C)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Acetyl chloride (50 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg) described in Reference Example 170 in pyridine (3.4 ml), stirred at 40° C. for six hours. Acetyl chloride (50 μl) was added and stirred for two hours, and then, Acetyl chloride (50 μl) was added and stirred for six hours. Water was added to the reaction solution and the precipitated solid was washed with ethanol and water to give the titled compound (283 mg) as a pale yellow solid.
Reaction SMILES: C([O:4][C:5](=[O:38])[C:6]([CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])([NH2:29])[CH:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1)(C)C.C(N(C(C1C=CC=CC=1)C)C(=O)C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Li+]>CO.O>[CH2:22]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:12][CH:13]=1)[C:6]([CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31])([NH2:29])[C:5]([OH:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)OC(=O)C(N)(C(C)c1ccccc1)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CC(c1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(c1ccccc1)C(N)(C(=O)O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)cc1
Yield: 85 %

Procedure:
To the above mixture of crude product 15 and N-benzyl-N-(1-phenyl-ethyl)-benzamide in methanol (30 mL) and water (15 mL) was added lithium hydroxide (831 mg, 34.7 mmol). The resulting suspension was heated to reflux for 48 hours. After cooled downed, the mixture was concentrated to remove methanol. The water layer was taken up with CH2Cl2 (30 mL×3). The organic layer was dried and concentrated. The residue was purified by silica gel column using hexane and ethyl acetate (2:1) as eluent to give 1.406 g white solid, in 85% yield for two steps. 1H NMR (400 MHz, CDCl3): δ7.44 (d, J=8.52 Hz, 2H), 7.37-7.22 (m, 12H), 6.55 (brs, 1H), 4.43 (dd, J1=4.46 Hz, J2=11.32 Hz, 1H), 4.15 (q, J=6.87 Hz, 1H), 3.98 (d, J=13.68 Hz, 1H), 3.64 (d, J=13.68 Hz, 1H), 2.92 (dd, J1=11.34 Hz, J2=16.94 Hz, 1H), 2.41 (dd, J1=4.48 Hz, J2=16.96 Hz, 1H), 1.54 (s, 9H), 1.28 (d, J=6.88 Hz, 3H); 13C NMR (100 MHz, CDCl3): 174.39, 152.82, 141.25, 138.44, 137.70, 132.56, 129.22, 128.80, 128.62, 128.60, 128.19, 127.81, 127.53, 118.52, 80.86, 57.96, 57.82, 50.61, 36.29, 28.34, 15.68. mp 93-95° C. IR v (Diamond, cm−1): 3307, 1699, 1594, 1081, 698. MS (ESI) m/z found 475.6 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH2:33][CH3:34])=[N:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:33]([C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[CH:29][CH:28]=[C:27]([N+:30]([O-:32])=[O:31])[N:26]=1)[CH3:34]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (863 mg, 4.15 mmol), 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 3.19 mmol), K2CO3 (1.322 mg, 9.57 mmol) and Pd(PPh3)4 (184 mg, 0.159 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT and stirred for 24 h. The mixture was treated with EtOAc, washed with satd. NaHCO3 (1×), then brine (1×), dried over Na2SO4 and concentrated to dryness to afford 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) as a thick oil. Material carried on to the next step without purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[C:22]1(C)C=CC=CC=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[CH:22][O:4][CH3:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][N:13]=1
Reactant: Cc1ccccc1
Reactant: CCCCCCC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCC(=COC)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Methoxymethyl)triphenylphosphinium chloride (6.5 g, 20.0 mmol) is suspended in anhydrous toluene (50 mL) and potassium tert-butoxide (2.24 g, 20.0 mmol) carefully added. The solution is allowed to cool and stir at room temperature for 1 h. 1-(6-Chloro-pyridin-3-yl)-heptan-1-one (3.0 g, 13.3 mmol) is then dissolved into anhydrous toluene (50 mL) and added to the reaction mixture by syringe. The reaction is allowed to stir at room temperature for several hours and is monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully quenched with saturated ammonium chloride solution, extracted with diethyl ether, washed, dried, and concentrated. The 2-chloro-5-(1-methoxymethylene-heptyl)-pyridine is purified using flash column chromatography.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22].[C:30](#N)C>>[CH2:21]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH2:10][CH3:30])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:26]1)[CH3:22]
Reactant: CC#N
Reactant: CCNCC1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCC4CC)C1

Procedure:
0.75 g (2.7 mmole) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile and 1.03 g (8.00 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. The reaction mixture was cooled in an ice bath and then filtered. The precipitate was washed with ethanol/ether (4:1), and then with ether until dry to give 0.86 g of 10-[3-[(ethylamino)-methyl]-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-ethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 221°-224° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:38])=[C:30]([CH:37]=2)[O:31][C@@H:32]([CH3:36])[C:33]([OH:35])=O)[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:44][C:33](=[O:35])[C@@H:32]([O:31][C:30]1[CH:37]=[C:26]([CH:27]=[CH:28][C:29]=1[Cl:38])[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:40])=[C:20]1[CH3:39])[CH3:36]
Reactant: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(N)=O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 89.3 %

Procedure:
A solution of (S)-2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 560/561/562 [MH]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Br[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CS(C)=O.O>[C:1]1([N:7]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccccn2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of 2-(N-phenylamino)pyridine (5.0 g) in DMSO (15 ml) was added to a suspension of sodium hydride (0.78 g) in DMSO (20 ml). The mixture was stirred and slowly heated under nitrogen to 85° C. After the evolution of hydrogen had ceased, the mixture was cooled to room temperature and a solution of N-(3-bromopropyl)phthalimide (7.88 g) in DMSO (15 ml) added dropwise. The mixture was allowed to stand overnight and then poured into water. The aqueous phase was made acid to a pH between 2 to 4 and extracted with ether. The extracts were dried (MgSO4), the ether evaporated and the residue crystallised from ethanol to give N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide, 3.69 g (35%) m.p. 103°-105° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:22]2[C:7](=[O:8])[N:6]=[C:4]([C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])[O:5][C:23]2=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Product: O=c1nc(-c2c(F)cccc2F)oc(=O)n1-c1ccc(Cl)c(Cl)c1
Temperature: 120 °C

Procedure:
A mixture of freshly prepared 2,6-difluorobenzoyl isocyanate (1.85 g) and 3,4-dichlorophenyl isocyanate (1.89 g) is heated at 120° C. for a period of 16 hours, and then cooled. Recrystallisation of the solid which was obtained from ethyl acetate yielded 3-(3,4-dichlorophenyl)-6-(2,6-difluorophenyl)-3,4-dihydro-2H-1,3,5-oxadiazin-2,4-dione, white crystals, m.p. 196°-197° C.
Reaction SMILES: O.[C:2]([OH:5])(=[O:4])[CH3:3].CC1O[N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:39]=[CH:40][CH:41]=2)[O:15][CH:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)=[O:18])[N:8]=1>CO>[C:9]([C:12]1[CH:13]=[C:14]([CH:39]=[CH:40][CH:41]=1)[O:15][CH:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])=[CH:24][CH:25]=1)=[O:18])(=[NH:8])[NH2:10].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: CC(=O)O
Reactant: Cc1nc(-c2cccc(OC(C(=O)Nc3ccc(N4CCCCC4=O)cc3)c3ccccc3)c2)no1
Solvent: O
Solvent: CO
Product: CC(=O)[O-]
Product: N=C(N)c1cccc(OC(C(=O)Nc2ccc(N3CCCCC3=O)cc2)c2ccccc2)c1
Reaction time: 18 h

Procedure:
200 mg of water-moist Raney nickel and 0.2 ml of acetic acid are added to a solution of 122 mg (0.253 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-N-[4-(2-oxopiperidin-1-yl)phenyl]-2-phenylacetamide in 5 ml of methanol, and the mixture is hydrogenated at room temperature and atmospheric pressure for 18 hours. The reaction mixture is filtered, and the residue is evaporated, giving 2-(3-amidinophenoxy)-N-[4-(2-oxopiperidin-1-yl)phenyl]-2-phenylacetamide, acetate (EMD 388547), ESI 443; IC50(Xa)=3.2×10−8 M; IC50(VIIa)=1.4×10−8 M.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([OH:45])=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1.[O:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54]O)[CH2:48][CH2:47]1>C(Cl)Cl>[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][C:39]([O:45][CH2:54][CH2:53][CH2:52][N:49]3[CH2:50][CH2:51][O:46][CH2:47][CH2:48]3)=[C:40]([O:43][CH3:44])[CH:41]=2)[N:36]=[CH:35][CH:34]=1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
Diethyl azodicarboxylate (120 μl, 0.76 mmol) was added dropwise to a solution of triphenylphosphine (200 mg, 0.76 mmol), 4-chloro-7-hydroxy-6-methoxyquinoline (100 mg, 0.47 mmol), 3-morpholino-1-propanol (75 mg, 0.52 mmol), (Tet. Lett. 1994, 35, 1715), in methylene chloride (5 ml). The mixture was stirred for 4 hours at ambient temperature, the solvent was removed by evaporation to dryness and purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (105 mg, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH2:19](COC)[O:20]C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:19][OH:20])[C:12]([OH:15])=[C:11]([CH3:17])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COCCOC
Reactant: Cc1cc(O)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(OCc2ccccc2)cc(CO)c(O)c1C
Temperature: 130 °C

Procedure:
To 684 mg (3 mmol) of 4-benzyloxy-3-methyl-phenol in 10 mL toluene and 1.5 mL DME (dimethoxyethane) in a sealable tube was added paraformaldehyde (1.8 g, 60 mmol). The tube was flushed with argon and sealed. It was heated to 130° C. for 48 h under stirring. After cooling to room temperature, the solid was filtered off and washed with 1:1 hexane/EtOAc and the liquid was concentrated. The residue was chromatographed to afford 4-benzyloxy-6-hydroxymethyl-2,3-dimethyl-phenol, as a light brown solid (640 mg). 1H-NMR (300 MHz, CDCl3/CD3OD)) δ (ppm): 7.43-7.29 (m, 5H), 6.55 (s, 1H), 4.95 (s, 2H), 4.70 (s, 2H), 2.18 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z: 241 (M-OH−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]=1[N:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1)[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:39][CH2:40][CH3:41])[C:33]([N:34]4[CH:38]=[CH:37][CH:36]=[CH:35]4)=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow foam. MS: 548.4 (MH+).