Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)=O.CC(C)=O.C([Li])CCC.CCCCCC.[CH2:19]([C@@H:26]1[C@@H:34]([O:35][CH2:36][CH2:37][C:38](=O)[CH3:39])[C@H:33]([CH3:41])[O:32][C:31](=[O:42])[C@@H:30]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:29][O:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:19]([C@@H:26]1[C@@H:34]([O:35][CH2:36][CH2:37][C:38]([CH3:1])=[CH2:39])[C@H:33]([CH3:41])[O:32][C:31](=[O:42])[C@@H:30]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:29][O:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C=O
Reactant: CC(=O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 22 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (346 mg, 0.969 mmol, 1.40 equiv) in anhydrous THF (7 mL) at −78° C. (dry ice/acetone) was added a 2.5 M solution of n-butyllithium in hexane (n-BuLi; 332 μL, 0.830 mmol, 1.20 equiv). The flask was removed from the cold bath for 25 min and then re-cooled to −78° C. In a separate vessel, tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(3-oxobutoxy)-1,5-dioxonan-3-yl)carbamate (311 mg, 0.692 mmol, 1.00 equiv) was dissolved in anhydrous THF (7 mL), cooled to −78° C., and transferred via cannula to the phosphonium ylide solution prepared above. The resulting light yellow suspension was stirred at −78° C. for 50 min and then transferred to a −50° C. bath (deficient dry ice/acetone) and stirred for 45 min. The suspension was slowly warmed to −20° C. over 1 h and then warmed to 0° C. (ice water bath) and stirred for 20 min. The reaction was quenched with ½ sat'd aq. ammonium chloride (NH4Cl; 20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a colorless oil. Purification by automated silica gel column chromatography (2-25% acetone in hexanes) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-8-((3-methylbut-3-en-1-yl)oxy)-2-oxo-1,5-dioxonan-3-yl)carbamate (68 mg, 22%) as a sticky oil: IR (ATR) 2977, 2933, 2875, 1750, 1712, 1497, 1454, 1367, 1326, 1250, 1202, 1163, 1080, 1042, 1023 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 2H), 7.23-7.10 (m, 3H), 5.16 (d, J=8.2 Hz, 1H), 4.95 (dq, J=9.2, 6.4 Hz, 1H), 4.80 (s, 1H), 4.77-4.69 (m, 1H), 4.59 (q, J=7.4 Hz, 1H), 3.88 (dd, J=11.5, 7.3 Hz, 1H), 3.83-3.71 (m, 1H), 1.57-1.46 (m, 3H), 3.65 (dt, J=8.7, 7.0 Hz, 1H), 3.50-3.31 (m, 2H), 3.25 (dd, J=11.4, 7.3 Hz, 1H), 3.20-3.02 (m, 2H), 2.32 (t, J=6.9 Hz, 3H), 1.91 (s, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.27, 154.98, 142.31, 139.91, 129.15, 128.43, 126.12, 111.99, 85.31, 80.06, 75.48, 72.79, 72.30, 71.29, 52.93, 47.28, 38.33, 35.19, 28.28, 22.88, 18.80; HRMS-ESI (m/z) [M+Na]+ calc'd for C25H37NO6Na, 470.2513. found, 470.2522.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:42]([O:41][C:39]([C@@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([CH2:13][CH2:12][O:11][CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:34]1)=[O:40])[CH3:43]
Reactant: Cc1cccc(C(=CCOCCO)c2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(C)c2)C1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
A mixture of 2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethanol (16 g, 60 mmol) and triethylamine (15.1 g, 149 mmol) in dry toluene (75 ml) kept under a nitrogen atmosphere was cooled to 5° C. and a solution of methanesulphonyl chloride (13.7 g, 119 mmol) in dry toluene (75 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1.5 h at 5° C. Water was added (100 ml) and the mixture was stirred at room temperature for 0.5 h. The phases were separated and the aqueous phase was extracted with a small portion of toluene. The combined organic extracts was washed with brine, dried over sodium sulphate and filtered. To the filtrate was added ethyl (R)-3-piperidinecarboxylate (10.3 g, 66 mmol) and potassium carbonate (9.9 g, 72 mmol) and the mixture was heated at reflux temperature for 6 days. Another portion of ethyl (R)-3-piperidinecarboxylate (5.3 g) was added and the mixture was heated at reflux temperature for another 24 h. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic extracts was washed with a sodium citrate buffer solution (2×100 ml, pH 5) and then extracted with a 5% aqueous citric acid solution (4×100 ml). Toluene (120 ml) was added to the combined acidic extracts and sodium hydroxide pellets was added to the mixture until the pH was measured at 8.5. The phases were separated and the organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo to give 9.4 g (39%) of (R)-N-(2-(3-(3-methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.50 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:49])[N:30]([C@H:40]3[CH2:45][CH2:44][C@H:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]3)[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:49]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:5][N:14]=3)=[CH:22][CH:23]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:41]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](C(N)=O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexanecarboxamide (0.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.31 g, 82%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].O.[OH-].[Li+:19]>O1CCCC1.C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[Li+:19]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc2ncc(C(=O)[O-])n2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
Ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (13.9 g, 65 mmol) and lithium hydroxide monohydrate (2.7 g, 65 mmol) were dissolved in tetrahydrofuran/ethanol/water (1:2:1, 150 mL:300 mL:150 mL). After stirring for 16 hours at ambient temperature, the solvent was removed under vacuum to give lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (12.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=O)[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33].S1C=CC=C1>C1COCC1.[Pd].CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[CH:26]([NH:33][CH:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH3:31])[CH3:27])[C:21]4=[O:30])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Pd]
Agent: [Ti]
Solvent: c1ccsc1
Solvent: C1CCOC1
Solvent: CCCCO
Product: CC(NC(C)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.05 mol) and (+)-(R)-α-methyl-benzenemethanamine (0.1 mol) in THF (500 ml) was hydrogenated at 50° C. for 48 hours with Pd/C 10% (10 g) as a catalyst in the presence of titanium(IV) n-butoxide (28.4 g) and thiophene solution (10 ml). The catalyst was filtered off. Pd/C 10% (10 g) was added again. Hydrogenation was continued at 50° C. for 48 hours. After uptake of H2, the mixture was cooled, then the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in CH2Cl2 (500 ml) and H2O (50 ml) was added. The mixture was acidified with a concentrated HCl solution, alkalized with a concentrated NH4OH solution and filtered over dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 23.5 g (91%) of [(R*,R*)(R)+(R*,S*)(R)]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[2-[(1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1ccc(OC)c(OC)c1
Yield: 63.7 %

Procedure:
Prepared according to the procedure of Example 50 using 3,4-dimethoxybenzaldehyde (1.94 g, 11.6 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.8 g, 11.6 mmol), acetic acid (0.69 g, 11.5 mmol), and sodium triacetoxyborohydride (2.6 g, 11.7 mmol) to afford the product (2.9 g); m.p. 187-188° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH2:1]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1CCC=C(c2csc(N)n2)C1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCN1CCC=C(c2csc(NC(C)=O)n2)C1

Procedure:
Seven grams of the 4-(1,2,5,6-tetrahydro-1-pentyl-3-pyridinyl)-2-thiazolamine obtained in Example 6 was dissolved in 100 ml of acetic anhydride with 10 g of anhydrous sodium acetate. The solution was heated at reflux under a nitrogen atmosphere for three hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 150 ml dichloromethane and 150 ml 10% sodium bicarbonate solution. The organic layer was concentrated in vacuo and the residue was chromatographed on silica gel using 2% ammonium hydroxide in ethyl acetate as the eluent. The title compound was obtained as 4.10 g of a beige solid, mp 117°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl>[Cl:15][CH2:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:19]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hours, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as an oil. MS: 202.1 (M+H+)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH:27]([CH3:29])[CH3:28])/[C:9]1=[O:30])=O)(C)(C)C.[CH3:31][C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])=[CH2:33]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:30])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH:27]([CH3:29])[CH3:28])[CH2:37][C:36](=[O:38])[NH:35][CH:34]3[C:32]([CH3:33])=[CH2:31])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(C)C=NC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OC(C)C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 63.3 %

Procedure:
In a manner similar to the method described in Example 41b, E/Z-6-Chloro-3-(5-chloro-2-isopropoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2 g, 4.47 mmol) was reacted with 1-(1-methyl-ethenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (22.37 mmol) in toluene to give title compound as a white solid (1.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23].[CH2:34](N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]2[N:21]=[C:34]([S:23][CH3:22])[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)nc1N
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc2nc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.1 %

Procedure:
A stirred mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example 153, 1.00 g, 3.54 mmol), thiocarbonyldiimidazole (1.28 g, 7.1 mmol) and triethylamine (0.72 g, 7.1 mmol) in tetrahydrofuran (12 mL) was heated to 80° C. in sealed tube. After 24 hours, the mixture was cooled and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with dichloromethane/methanol (95:5) to give the title compound (0.60 g, 53%) as a beige solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[C:10]([Cl:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:40]=[N+:41]=[N-:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:40]=[N+:41]=[N-:42])[CH3:15])=[C:10]([Cl:17])[CH:9]=1
Reactant: [N-]=[N+]=N
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl

Procedure:
To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0° C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446: Wiley, N.Y.) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([CH3:13])[CH3:12])C1C=CC=CC=1.CCO>[Pd].O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]([NH2:10])([CH3:12])[CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C(C)(C)NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cccc(C(C)(C)N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A flask was charged with [1-(3-methoxy-phenyl)-1-methyl-ethyl]-carbamic acid benzyl ester (D100) (1 g, 3.34 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 100 mg, 10% w/w), NH4COOH (2.1 g, 33 mmol, 10 equiv), EtOH (40 ml) and H2O (8 ml). The resulting mixture was stirred at 80° C. for 2 h, cooled to room temperature and the catalyst was filtered off using a pad of celite. Most of the EtOH was removed in vacuo and the residue was diluted with 1N HCl aqueous solution. The aqueous phase was extracted with AcOEt then basified to pH 13 and extracted twice with AcOEt. These combined organic layers were dried over MgSO4 and concentrated in vacuo to yield 1-(3-methoxy-phenyl)-1-methyl-ethylamine (F15) (290 mg, 53%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.Br.Br.[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][NH:30][CH2:29]2.N12CCCN=C1CCCCC2>C(#N)C>[C:28]12[CH2:35][NH:34][CH2:33][C:32]=1[CH2:31][N:30]([C:7]1[C:2]([F:1])=[C:3]3[C:4]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:18]3[CH:13]=[CH:14][C:15]([F:21])=[CH:16][C:17]=3[F:19])=[CH:5][C:6]=1[F:8])[CH2:29]2
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
1-(2,4-Difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.07 g), 3,7-diazabicyclo [3.3.0] oct-1(5)-ene dihydrobromide (1 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 2 ml) were dissolved in acetonitrile (30 ml) and refluxed for 7 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered and then suspended in methanol (10 ml) and sonicated for 30 minutes. The insoluble product was collected by filtration to give the title compound (1 g, yield 74%).
Reaction SMILES: [CH2:1](Br)[CH3:2].[Br:4][C:5]1[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:4][C:5]1[C:12]([O:13][CH2:1][CH3:2])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CCBr
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(OC)ccc(C=O)c1Br
Temperature: 35 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
Ethyl bromide (2.88 g, 26.4 mmol) was added to a mixture of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (5.08 g, 22 mmol) and potassium carbonate (4.56 g, 33 mmol) in anhydrous DMF (50 mL) at room temperature under nitrogen. The reaction mixture was stirred at 35° C. for 18 h, diluted with EtOAc (150 mL), washed with water (2×50 mL), brine, dried over Na2SO4 and concentrated to give crude product as a white solid. Purification by silica column chromatography (eluant: 30% EtOAc in Hexanes) to generate 5.65 g (99% yield) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 10.26 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.95 (s, 3H), 1.46 (t, J=7.0 Hz, 3H); MS (ESI) m/z=261 (M+1, positive).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 223.1 using 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide and 3-fluoropyridine-5-boronic acid pinacol ester. The crude product was dissolved in DCM (20 mL) and treated with n-hexane. The resulting solid was filtered off, washed with n-hexane and dried to afford the title product as a beige solid. UPLC-MS (Condition 3) tR=1.13 min, m/z=412 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=[CH:23]1)=O.CNC>O1CCCC1>[OH2:6].[Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([N:22]([CH3:23])[CH3:20])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0155 mole), and 1,1'-carbonyldiimidazole (2.52 g, 0.0155 mole) in dry tetrahydrofuran (100 ml) was stirred at room temperature for two hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (40.6 ml of a 2.29M solution, 0.093 mole) was added, and the resulting solution was heated at 45° C. overnight under a nitrogen atmosphere. The reaction mixture was evaporated to a solid which was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered, and allowed to cool to room temperature. Addition of water caused a precipitate to form which was collected by filtration, rinsed with water, and dried at high vacuum to give 3.16 g (58%) of title compound, mp 182°-185° C.