Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[C:31]([CH:36]=O)=[N:32][CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2ncccc2-c2ccccc2)CC1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1-c1ccccc1)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B: Reaction of the above amine and 3-methyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridine-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 0.86 (q, 2H, J=10.8 Hz), 1.14 (q, 2H, J=11.1 Hz), 1.41 (s, 9H), 1.58 (d, 2H, J=11.7 Hz), 1.85 (s, 2H), 1.91 (s, 3H), 2.11 (s, 1H), 2.21 (s, 1H), 3.19 (br s, 1H), 3.80 (s, 2H), 3.84 (s, 2H), 4.23 (br s, 1H), 7.00 (dd, 1H, J=7.4, 5.1 Hz), 7.21-7.30 (m, 7H), 7.49 (dd, 1H, 7.8, 1.5 Hz), 8.25 (d, 1H, J=3.9 Hz), 8.53 (dd, 1H, J=4.8, 1.8 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 259 as a pale yellow solid. 1H NMR (D2O) δ 1.29-1.48 (m, 4H), 1.90 (d, 2H, J=10.2 Hz), 2.02 (d, 2H, J=9.6 Hz), 2.37 (s, 3H), 2.66 (br t, 1H, J=8.1 Hz), 3.09 (br s, 1H), 4.12 (s, 2H), 4.35 (s, 2H), 7.42 (d, 2H, J=4.5 Hz), 7.59 (s, 3H), 7.81 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.3 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.45 (d, 1H, J=7.8 Hz), 8.51 (d, 1H, J=5.7 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 14.56, 17.18, 25.80, 29.46, 49.67, 50.80, 51.86, 60.40, 126.08, 126.54, 129.68, 130.35, 133.97, 137.79, 138.70, 140.93, 141.18, 148.35, 148.41, 150.54, 151.18. ES-MS m/z 387 [M+H]+. Anal. Calcd. for C25H30N4.3.3HBr.2.2CH3OH: C, 45.12; H, 5.86; N, 7.74; Br, 36.42. Found: C, 45.22; H, 5.69; N, 7.97; Br, 36.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.Cl[CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccncc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (710 mg, 1.19 mmol), 4-(chloromethyl)pyridine hydrochloride (794 mg, 4.84 mmol), potassium carbonate (1.337 g, 9.67 mmol) in acetone (21 mL) and water (7 mL). Stir and heat at reflux for 24 h. Allow reaction mixture to cool to room temperature, and remove the acetone under vacuum. Add ethyl acetate, separate the organic layer and extract with saturated aqueous NaCl solution. Dry the organic layer over anhydrous Na2SO4, filter and concentrate in vacuo. Chromatograph the residue on silica gel eluting with 30% methanol/ethyl acetate to give the title compound: Rf=0.16 (silica gel, 20% methanol/ethyl acetate).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[CH2:26]([O:25][C:23]([C:22]([CH3:29])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:14]=1)[CH3:28])=[O:24])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 12-L 3-neck round-bottom flask was equipped with an overhead air-driven stirrer apparatus, condenser, nitrogen inlet, thermometer/thermocouple, and heating mantle. The flask was charged with ethyl acetate (450 mL) and 21% (wt.) sodium ethoxide in ethanol solution (3318 mL, 8.87 moles, 2 eq). The resulting mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux for 30 min. The mixture was then allowed to cool slightly below reflux, and 4-(4-hydroxyphenyl)butyric acid (800 g, 4.43 moles) was added. The flask contents were re-heated to reflux for 30 min, at which point ethyl 2-bromoisobutyrate (EBIB, 1954 mL, 13.32 moles, 3.0 eqs.) was added. After 1 h at reflux, the flask was equipped with a 2-L addition funnel, which was charged sodium ethoxide in ethanol solution (1660 mL, 4.43 moles, 1 eq.). The sodium ethoxide solution was added dropwise to the refluxing reaction over 1 h. After an additional 30 min at reflux, HPLC analysis showed the reaction was complete. The heat source was removed and the flask contents were cooled to 5-10° C. and then transferred to a 22-L bottom-outlet flask. While stirring, the mixture was quenched with dilute phosphoric acid (6000 mL), transferred to a 20-L Buchi flask, and concentrated in vacuo to remove ethanol. The resulting aqueous mixture of crystals and excess EBIB was refrigerated overnight. The crystals were then filtered and washed with water (2000 mL). The solids were removed from the funnel and placed in a 20-L Buchi flask equipped with an overhead stirring apparatus. After the addition of water (2000 mL), the solids were stirred at ambient temperature for 30 min, then filtered and washed with heptane (2×2500 mL)). The solids were then placed in the vacuum oven and dried at 45° C. to afford the title compound as an off-white solid (1247 g, 95.5%). 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3 H), 1.57 (s, 6 H), 1.92 (m, 2 H), 2.35 (t, 2 H), 2.60 (t, 2 H), 4.23 (q, 2 H), 6.76 (d, 2 H), 7.03 (d, 2 H). 13C NMR (CDCl3) δ 14.1, 25.4, 26.3, 33.3, 34.2, 61.4, 119.4, 129.1, 134.9, 153.7, 174.4, 179.7.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:13])[CH:11]=[CH2:12])=[C:4]([CH3:14])[CH:3]=1.CN(C)C=O.[NH:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:22][CH2:21]1>C(O)(C)C>[I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH2:11][CH2:12][N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:27](=[O:41])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][CH2:25]2)=[O:13])=[C:4]([CH3:14])[CH:3]=1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reactant: C=CC(=O)Nc1cc(C)c(I)cc1C
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1I
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a solution of N-(4-iodo-2,5-dimethylphenyl)acrylamide (32.2 g, 107 mmol) in a 6:1 v/v mixture of N,N-dimethylformamide and isopropanol (700 mL) was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (36.3 g, 123 mmol). The resulting mixture was heated at 50° C. for 24 hours and then at 80° C. for 24 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in dichloromethane (1 L) and this solution was washed with 1N aqueous hydrochloric acid (500 mL), water (500 mL), brine (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Ethanol (400 mL) was added and the resulting mixture was concentrated under vacuum to a volume of about 400 mL, at which time a precipitate had formed. The precipitate was filtered and dried to afford biphenyl-2-ylcarbamic acid 1-[2-(4-iodo-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (59.6 g, 84% purity, 79% yield). m/z: [M+H+] calcd for C29H32IN3O3 598.49; found 598.5.
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+].C(O)(=O)C>O.C(O)C>[OH:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:27]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NC(=O)CC(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred solution of ethyl 3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate (which was obtained in Example 371) (0.23 g, 0.43 mmol) in distilled water (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL). The reaction was stirred at room temperature for 1 hr. The reaction mixture was made acidic (pH 6) with glacial acetic acid, concentrated, triturated with water, ether, ethyl acetate to give the title compound as a light yellow solid (0.13 g, 59%); 1H NMR (300 MHz, DMSO-d6) δ 1.30-1.45(m, 2H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.90 (s, 2H), 2.91(s, 3H), 3.45-3.60 (m, 2H), 4.48-4.53(m, 1H), 6.80-6.90(m, 3H), 7.00(d, J=8.3 Hz, 1H), 7.18 (d, J=1.6 Hz, 1H), 7.38(d, J=9.0 Hz, 2H), 11.50-11.60(m, 1H); MS (ES) m/z: 505.3 (M−H)−; HRMS Calcd. for C23H31N4O7S(MH+): 507.1908. Found: 507.1895.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([NH:1][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CCC(=O)[O-]
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 27 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 41 mg (0.21 mmol) of 4-toluenesulfonyl chloride. After recrystallization from methanol, 23 mg (28%) of 4-oxo-8-(4-toluenesulfonylamino)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8](OC)[CH:9]([F:12])[C:10]=2[CH:11]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[CH:8]=[N:7][C:6]=2[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Solvent: CC#N
Product: Fc1cnc(Cl)c2ncc(Cl)cc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
A vial was charged with 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (7.5 g, 32.5 mmol), acetonitrile (130 mL) and phosphorus oxychloride (9.09 mL, 98 mmol), and the mixture was stirred at 75° C. for 15 hours. The mixture was concentrated, and the crude material was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in heptanes, to provide the title compound (5.57 g, 25.7 mmol, 79% yield) as a white solid. LC/MS (ESI+) m/z=217(M+H)+.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28](F)[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]([O:42][C:43]([C:45]1([C:48]([OH:50])=O)[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.[F:58][P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[C:24]([F:58])=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43]([O:42][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[O:44])[CH2:47][CH2:46]4)=[O:50])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Reactant: F[P-](F)(F)(F)(F)F
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1nccc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2)c1F
Reaction time: 8 h
Yield: 95 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (678 mg) was dissolved in N,N-dimethylformamide (25 ml). 1-(benzyloxycarbonyl)cyclopropanecarboxylic acid (815 mg), triethylamine (0.516 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.64 g) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1) to provide the titled compound as a colorless oil (928 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.COC1C=C2C(=CC=1)C(=O)NC(C#N)=C2C1C=CC=CC=1[F:43]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:43])=[C:4]([C:20]#[N:21])[N:3]=1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3F)c2c1
Product: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3F)c2c1

Procedure:
Following the procedure for 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 6-methoxy-1-oxo-4-(2-fluorophenyl)-1,2-dihydroisoquinoline-3-carbonitrile in place of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([OH:31])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 5-bromopentanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.03 (q, 2H), 3.98 (t, 2H), 3.91 (s, 3H), 2.36 (t, 2H), 1.80-1.60 (m, 4H), 1.15 (t, 3H); MS (ESI): 480.9.
Reaction SMILES: [C:1]([C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:12].C(N(CC)CC)C.[Cl-]>CN(C=O)C.C(Cl)Cl>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[C:12][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(=O)c1cccnc1Br
Reactant: C#Cc1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1cccnc1C#Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
750 mg 3-Acetyl-2-bromopyridin, 550 μL 2-ethynyl-pyridine, 765 μL triethylamin, 255 mg triphenylphosphinpalladium(II) chlorid, 17 mg Cu(I)I were suspended in 10 mL DMF under argon atmosphere and stirred for 2 h at 25° C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and saturated NH4Cl solution. The organic phase was concentrated and the mixture separated via FCC (100 g SiO2, cyclohexane→cyclohexane/ethylacetate 35:65) to yield 455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone as solid. Analysis: HPLC-MS: Rt=0.88 min (method E) M+H=223.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)=[CH:10][CH:9]=1)[C:11]([O:13][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=1)=[O:12]
Reactant: Fc1cccc(CBr)c1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1cccc(F)c1)c1ccc(OCc2cccc(F)c2)cc1C(=O)OCc1cccc(F)c1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27.5 mmol), 3-fluorobenzylbromide (31.14 g, 164.7 mmol) and potassium carbonate (15.18 g, 109.8 mmol) in THF:water (1:1, 200 mL) was heated under reflux for 72 h. After cooling to RT, the mixture was then half evaporated and the residue extracted with ethyl acetate (100 mL). The organic layer was then washed with brine, dried over sodium sulfate, filtered and evaporated. The mixture was then heated in a Kugelrohr apparatus (160° C. at 15 mmHg) to remove the excess 3-fluorobenzylbromide to leave the title compound (13.1 g, 94%) as a light yellow liquid. MS m/e=506.1 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=3[N:35]=[C:34]2[CH:44]([F:46])[F:45])[N:22]=1.C(O)(=O)C>C1COCC1.O>[F:46][CH:44]([F:45])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:9][C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=2[N:35]=1
Reactant: COc1ccc(N)nn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)nn1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To 0.216 g (1.73 mmol) of 6-methoxy-3-pyridazinamine (J. Med. Chem. 2006, 49, 4409-4424) in THF (3 mL) was added 0.97 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 10 min. A solution of 0.233 g (0.59 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) was added and the resulting mixture was stirred for 10 min. The resulting mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, dried, and concentrated. Recrystallization from ethanol/CH2Cl2 gave 0.086 g (30% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-methoxy-3-pyridazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 256-259° C.; 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 7.99 (t, JHF=52.6 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.84-3.79 (m, 4H), 3.72 (s, 4H); Anal. Calcd. For C21H21F2N9O30.5H2O: C, 51.1; H, 4.5; N, 25.5. Found: C, 51.4; H, 4.6; N, 25.0%.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[C:15]([Si:19]([CH3:22])([CH3:21])[O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CCO)CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol as a colorless oil (2.7 g, 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:41])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]3[C:21](=[CH:22][C:23]([CH3:41])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Reaction time: 4 h

Procedure:
To a solution of 5 g 4-{2-[(4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 50 ml ethanol and 150 ml DMF were added under argon 732 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (5 bar) for 4 h. The suspension was filtered over a plug of Celite® and washed with ethanol and DMF. The crude product was obtained after evaporation of the solvent. Yield: 4.1 g.
Reaction SMILES: CO[Mg][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-].[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].[CH2:19]([O:21]CC)C>>[F:11][C:12]([F:18])([F:17])[C:13]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[O:21][CH3:19])=[O:14]
Reactant: CCOCC
Reactant: CO[Mg]c1ccccc1
Reactant: COC(=O)C(F)(F)F
Agent: [Br-]
Product: COc1ccccc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
2 Methoxy Phenyl magnesium bromide (35 ml) was added slowly to a solution of methyl trifluoroacetate (5.0 g) in diethyl ether (100 ml) @ −78° C. The reaction mixture was warmed to room temperature over 12 hrs and the quenched with saturated ammonium chloride solution (100 ml). The mixture was then partitioned between ethyl acetate (500 ml) and water (250 ml) The organics were separated and dried over magnesium sulfate filtered and concentrated in vacuuo. The crude residue was purified by column chromatography on silica gel eluting with 100% hexanes, 90:10 and 80:20, hexanes:ethyl acetate, to afford title compound as a yellow oil. (4.0 g). 1H NMR (CDCl3): δ 3.57 (s, 3H), 7.00 (m, 2H), 7.35 (m, 1H), 7.63, (d, J=2.54 Hz 2H).