Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](F)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Si](Cl)(Cl)(Cl)[Cl:23]>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([Cl:23])=[O:7]
Reactant: O=C(F)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
1040 g of 3,5-bis(trifluoromethyl)benzoyl fluoride and 24 g of aluminum chloride were initially introduced and heated to 40° C. With stirring, 224 g of silicon tetrachloride were added dropwise over 3 hours, where the temperature was controlled and did not exceed 45° C. The mixture was then stirred until the evolution of gas had stopped (2 hours). 30 g of zeolite X133 were then added, and the mixture was filtered. This gave 1000 g of a cloudy filtrate, which was admixed with 5 g of triphenylphosphine and distilled at 12 mbar over a 70 cm column. This gave 623 g (83.6% of theory) of 3,5-bis(trifluoromethyl)benzoyl chloride which passed over at 68° C. (bath temperature: 80° C.).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: CCOC(=O)COc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-methoxy-2-nitrophenoxy)acetate 8 (1.0 g, 0.004 mol) in 10 mL dichloromethane cooled in an ice-bath was added aluminum chloride (1.6 g, 0.0133 mol) portion wise. The resulting mixture was gradually warmed to room temperature and then refluxed for 4 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was washed with saturated sodium bicarbonate solution and dried over sodium sulfate to give ethyl 2-(4-hydroxy-2-nitrophenoxy)acetate 9 which was purified by silica gel column chromatography using a gradient of hexane and ethyl acetate. White solid (0.28 g, 37%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=6.8 Hz, 3H); 4.27 (q, J=6.8 Hz, 2H); 4.71 (S, 2H); 6.32 (S, 1H); 6.90 (d, J=8.8 Hz, 1H); 6.99 (dd, J=3.2 Hz; 8.8 Hz, 1H); 7.30 (d, J=2.8 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@@H:11]([CH3:22])[C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[O:9])[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@@H:11]([CH3:22])[C:12]([OH:14])=[O:13])=[O:9])[CH2:3][CH2:2]1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To Pd/C (10%, 5.0 g) was added a solution of (S)-benzyl 2-(2-morpholinoacetamido)propanoate (20.0 g, 69.0 mmol) in MeOH (200 mL). The mixture was stirred under a hydrogen atmosphere at ambient temperature for 4 h, then it was filtered and rinsed with MeOH (200 mL). The filtrate and washings were combined and concentrated to dryness to afford crude product which was washed with EtOAc (2×100 mL) and dried under vacuum to afford (S)-2-(2-morpholinoacetamido)propanoic acid (12.8 g, 86% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (m, 1H), 4.25 (m, 1H), 3.70 (m, 4H), 3.08 (d, J=15.4 Hz, 2H), 2.40-2.55 (m, 4H), 1.30 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8](C)([CH2:47][CH2:48][CH3:49])[NH:7][C:6]=1O)=[O:4].[C:52](OCC)(=[O:54])C>C1COCC1.O=[Mn]=O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:47][CH2:48][CH3:49])=[N:7][C:6]=1[CH:52]=[O:54])=[O:4]
Reactant: CCOC(C)=O
Reactant: CCCC1(C)NC(O)=C(C(=O)OC)N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCCc1nc(C=O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A suspension of 10.00 g (14.82 mmole) of 5-methoxycarbonyl-4-hydroxy-methyl-2-propyl-1-[(2'-(N-trityltetrazol-5-yl)biphen-4-yl)methyl]imidazole (Example 101, Part A) in 200 mL THF was added to a stirring slurry of 12.88 g (148.2 mmole) of MnO2 at room temperature. The mixture was stirred at room temperature for 2 days. 3.22 g (37.0 mmole) of additional MnO2 was added to the mixture and stirred at room temperature for 5 hours after which TLC (ethyl acetate) showed no starting material. The product was filtered through Celite™, and the cake was washed with ethyl acetate and methylene chloride; the filtrate was evaporated under reduced pressure to give 8.10 g (81%) of the title compound as a light-yellow-colored solid. 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J=7.3 Hz, 3H); 1.74 (m, 2H); 2.58 (t, J=7.7 Hz, 2H); 3.81 (s 3H); 5.49 (s, 2H); 6.74-7.92 (m, 23H); 10.38 (s, 1H). MS (NH3 -DCI): m/z 673 (M+H, 10%); 617 (M+H--N44, 100 %); 243 (Tr, 20%). Calculated mass for C42H37N6O3 (M+H): 673.292714; found: 673.292470.
Reaction SMILES: [CH2:1]([S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:21](=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>C(O)C>[CH2:1]([S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[N:16]=[CH:21][C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCCSc1ccccc1N
Solvent: CCO
Product: CCCCCCCCCCCCSc1ccccc1N=Cc1ccccc1O
Yield: 97 %

Procedure:
Into a 1-liter flask equipped with condenser, stirrer and thermometer, were placed 220 g (0.75 tool of 2-(dodecylthio)aniline, 200 g of ethanol, and 91.5 g (0.75 mol) of salicylaldehyde. The resultant solution was heated at reflux overnight. Upon cooling, solvent was removed at reduced pressure to afford 290 g (97%) of product as a dark yellow/brown oil.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:28]1(C)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.O>[C:28]1([C:2]2[C:14]3[C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[CH:7]=[N:6][C:5]=3[NH:4][N:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(-c4ccccc4)c23)C1
Temperature: 90 °C
Yield: 52 %

Procedure:
To a solution of tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.540 g, 1.53 mmol) in toluene (8 mL) and ethanol (4 mL) was added phenyl bronic acid (0.371 g, 3.07 mmol) followed by Na2CO3 (0.96 g, 9.18 mmol) as a solution in water (10 mL). The mixture was vortexed and 1,1-Bis(Di-t-butylphosphino)Ferrocene Palladium dichloride (BDtPFPdCl2, CAS#95408-45-0, 0.025 g) was added to the reaction mixture. The reaction was then purged with nitrogen and heated at 90° C. for 16 hours. On completion of the reaction, EtOAc (50 mL) and water (50 mL) was added. The organic layer was separated, washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. The crude product was purified using flash column chromatography (SiO2, 50% EtOAc in hexane) to give the pure desired product, tert-butyl 1-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.278 g, 52%) as a white foamy solid. M.p.=>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.72 (s, 1H), 8.38 (s, 1H), 7.73-7.62 (m, 2H), 7.56-7.42 (m, 3H), 4.65 (s, 2H), 3.54-3.45 (m, 2H), 2.88-2.8 (m, 2H), 1.44 (s, 9H); LCMS [M+H]: 351.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][CH2:13][CH2:14]Br.O>CS(C)=O>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH2:13][CH3:14]
Reactant: OCc1ccc(O)cc1
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1ccc(CO)cc1
Reaction time: 24 h
Yield: 95.2 %

Procedure:
4-hydroxybenzyl alcohol (12.4 g: 100.0 mmol) was dissolved in 100 ml of dimethylsulfoxide (DMSO), and an aqueous solution of potassium hydroxide (KOH/H2O: 6.6 g/15 ml) was added to the mixture. After the resultant mixture was dissolved homogeneously by stirring, n-propyl bromide (12.3 g:100.0 mmol) was added thereto, and the reaction was carried out at a room temperature for 24 hours. The reaction mixture was poured into 1 L of an iced water and a solid was formed by stirring. The resultant solid was collected by filtration, dried, and recrystallized from toluene to provide 15.8 g (95.2 mmol) of 4-n-propyloxybenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH3:9])=[N:4][C:3]1=[O:20].[OH-:29].[K+].Cl>CC(O)(C)C>[CH3:1][C:2]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:29])=[CH:27][CH:28]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:17])([F:18])[F:19])[CH3:9])=[N:4][C:3]1=[O:20]
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(N)=O)cc2)S1)c1ccccc1C(F)(F)F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 4-(5-methyl-4-oxo-2-((S)-1 -(2-(trifluoromethyl)phenyl) ethylamino)-4,5-dihydrothiazol-5-yl)benzonitrile (0.080 g, 0.20 mmol), prepared according to Example 1, and potassium hydroxide (0.14 g, 2.6 mmol) and t-BuOH (2 mL) was gradually heated to 85° C. After 1 h, 2N HCl was added to the reaction mixture until the pH reached 7-8. The reaction mixture was extracted with CH2Cl2 three times (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo. The crude product was purified by preparative TLC: 10% MeOH—CH2Cl2. The product (3a) was obtained as a white solid. MS (ESI, pos. ion) m/z: 422 (M+1), 420 (M-1). 1H NMR (CDCl3, 400 MHz): δ1.73-1.77 (m, 3H), 1.98, 2.08 (s, 3H), 5.04 (q, J=8 Hz, 1H), 6.17-6.39 (m, 2H), 7.36-7.42 (m, 2H), 7.52-7.75 (m 4H), 7.80-7.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of [4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester (2 g, 9.50 mmol) and Raney Ni (˜0.600 g) in MeOH (40 mL) is stirred for 4 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated to afford the title compound as a grey solid: ES-MS: 258.0 [M+H]+; tR=2.30 min (System 1); Rf=0.15 (Hexane/EtOAc, 1:1).
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1)[CH3:2]
Reactant: CC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 3-acetylpyrrolidine-1-carboxylate in methanol (10 mL) was added sodium borohydride (114 mg, 3.0 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours then quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound for the next step.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[C:18]1[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)CCC>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(C#N)cc1C1=NNC(=O)CC1
Solvent: CCCCO
Product: CC(C)(C)NCC(O)COc1ccc(C#N)cc1-c1ccc(=O)[nH]n1

Procedure:
A mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5cyanophenyl]-4,5-dihydro-3(2H)-pyridazinone and chloramil was heated under reflux in n-butanol to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-cyanophenyl]-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]1=[O:17].[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:3]1=[O:17])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1N(N2CCOCC2)c2ccccc2C1(O)Cc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(Cc2ccccn2)C(=O)N(N2CCOCC2)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of alcohol from Example 26 (63 mg, 0.194 mmole) 4-dimethylaminopyridine (78 mg, 0.639 mmole), acetic anhydride (0.06 ml, 0. 639 mmole) in dichloromethane (10 ml) was stirred at 0° C. for 8 hours. The volatiles were removed and the crude mixture applied directly to a silica gel column and eluted with 5% methanol in chloroform (Rf =0.34). The product slowly crystallized from hexane-ethyl acetate at 0° C. to give 41 mg of colorless cubes, m.p. 107°-110° C. after filtration. IR (KBr): 1702 cm-1. High Res. Mass Spec. Calcd. for C20H21N3O4 : 368.1610 (M+H). Found: 368. 1611.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][NH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>C1COCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][N:41]([C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][CH3:13])[N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COC(C(=O)O)c1ccc(F)cc1
Reactant: COc1ccc(-c2cc[nH]n2)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccn(C(=O)C(OC)c3ccc(F)cc3)n2)cc1OC
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-methoxyacetic acid (0.11 g, 0.61 mmol) in anhydrous THF (2 mL) at room temperature was added DCC (0.14 g, 0.67 mmol) in one portion. After stirring for 10 min, 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.14 g, 0.67 mmol) was added in one portion. After 48 hrs, the reaction mixture was diluted with EtOAc and the solids removed via filtration. The filtrate was concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) gave the product as an oil (0.12 g, 46% yield). MS: m/z 371.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NS(C)(=O)=O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 150 mg, 0.326 mmol) was dissolved in pyridine (4 mL) and methanesulfonyl chloride (50 μL, 0.652 mmol) was added. The reaction mixture was stirred at RT for 18 hrs then at 60° C. for 3 hrs. A further quantity of methanesulfonyl chloride (50 μL) was added and the mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool then water was added and the mixture was extracted with EtOAc. The organic extract was washed with 1 M HCl followed by water and then saturated brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound as a tan solid (85 mg).
Reaction SMILES: C(OC(=O)[N:7]([CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)(C)(C)C.Cl[C:27]1[N:28]=[C:29]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:42][CH2:41][N:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:39][CH2:38]3)[S:33][C:31]=2[N:32]=1>>[CH3:24][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:27]2[N:28]=[C:29]([N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[C:30]3[CH:35]=[C:34]([CH2:36][N:37]4[CH2:38][CH2:39][N:40]([S:43]([CH3:46])(=[O:44])=[O:45])[CH2:41][CH2:42]4)[S:33][C:31]=3[N:32]=2)=[CH:10][N:9]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cc1C

Procedure:
Methyl-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 361. NMR: (CDCl3): 2.54-2.58 (4H, m), 2.72 (3H, s), 3.04-3.07 (3H, m), 3.18-3.21 (4H, m), 3.72 (2H, s), 3.78-3.80 (4H, m), 3.85-3.88 (4H, m), 4.40 (1H, s, NH), 7.031 (1H, s, Ar), 8.16 (1H, s, Ar) and 9.09 (1H, s, Ar). MS: (ESI+): MH+=518.24
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][OH:28])=[CH:26][C:4]=2[N:3]=1>CS(C)=O.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:4]=2[N:3]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(CO)ccc4c3c2)c(C)c1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reaction time: 2.5 h

Procedure:
To a solution of (5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)methanol (2-1), 1.0 equiv. in DMSO (0.15 M) at room temperature was added IBX (1.5 equiv.). The reaction was stirred for 2.5 hours and then diluted with water. The aqueous layer was extracted with 2% MeOH/DCM (4×). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.[OH-].[NH4+]>ClC(Cl)Cl>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[N:6]=[N:7][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=4)[CH2:25][CH2:26]3)=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCc1ccc(Oc2ccc(Cl)nn2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Oc2ccc(N3CCN(c4cccc(C)c4)CC3)nn2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of 4 parts of 6-chloro-3-(4-ethylphenoxy)pyridazine and 6 parts of 1-(3-methylphenyl)piperazine was stirred and heated for 3 hours in an oil bath at 110° C. The whole was alloWed to stand overnight. Concentrate ammonium hydroxide and trichloromethane were added. The precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7 parts (27%) of 3-(4-ethylphenoxy)-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 106.6° C. (compound 221).
Reaction SMILES: C[N:2]([CH3:22])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:19][CH:20]=[CH2:21])[C:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1)=O.NC1[C:28]([C:29]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[O:30])=[CH:27][NH:26][N:25]=1>C(O)(=O)C>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:29]([C:28]1[CH:27]=[N:26][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH2:19][CH:20]=[CH2:21])[C:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:22]=12)=[O:30]
Reactant: C=CCN(C(=O)OCC)c1cccc(C(=O)C=CN(C)C)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Solvent: CC(=O)O
Product: C=CCN(C(=O)OCC)c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1

Procedure:
A mixture of 0.01 mole of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propenylcarbamic acid, ethyl ester and 0.01 mole of 3-amino-4-furoylpyrazole in 50 ml of glacial acetic acid is refluxed for 12 hours and the solvent removed in vacuo. The residue is partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is separated, dried over anhydrous sodium sulfate and passed through a 2-3 cm thick layer of hydrous magnesium silicate. The filter cake is washed with 2-3 volumes of additional dichloromethane and the filtrate concentrated. Addition of hexane and concentration gives the desired product.