Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1C1C2C(=O)N(CC(F)(F)F)C3C=CC=CC=3C=2N(C2CCCCO2)N=1.[Br:32][C:33]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][C:40]2[N:39]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:38](=[O:54])[C:37]3[CH2:55][N:56](C4CCCCO4)[NH:57][C:36]=3[C:35]=2[CH:34]=1.[ClH:64].O>O1CCOCC1>[ClH:64].[Br:32][C:33]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:41][C:40]2[N:39]([CH2:49][C:50]([F:52])([F:53])[F:51])[C:38](=[O:54])[C:37]3[CH:55]=[N:56][NH:57][C:36]=3[C:35]=2[CH:34]=1
Reactant: O=c1c2c(c3cc(Br)c(-c4ccccn4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Agent: Cl
Agent: O=c1c2c(-c3ccccn3)nn(C3CCCCO3)c2c2ccccc2n1CC(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=c1c2cn[nH]c2c2cc(Br)c(-c3ccccn3)cc2n1CC(F)(F)F
Yield: 94 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. by treating 8-bromo-7-(pyrid-2-yl-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 8-bromo-7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one with 4M HCl in dioxane, in the form of a white powder (hydrochloride, 0.4 H2O; yield 94%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: COc1ccccc1N(c1ccccc1)C(C)C
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (7.8 mL) in methylene chloride (125 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(2-methoxy-phenyl) aniline, prepared as in Part A, (14.51 g, 87.9 mmol) in methylene chloride (125 mL) and triethylamine (12.3 mL) and the resultant mixture is allowed to attain RT overnight. After 18 h an additional 2.0 mL of bromoacetyl bromide is added and the resultant reaction mixture stirred at RT for 4 h. The reaction mixture is washed with 1N hydrochloric acid (3×100 mL), water (2×100 mL), brine (100 mL), dried, (MgSO4) and concentrated in vacuo to afford N-Isopropyl-N-(2-methoxy-phenyl) bromoacetamide(20.3 g) as a dark mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ7.45 (dt, 1H, J=7.8, 1.4), 7.20 (dd, 1H, J=7.8, 1.4), 7.04 (m, 2H), 4.90 (m, 1H, J=6.8), 3.85 (s, 3H), 3.60 (dd, 2H, J=32.9, 11.5), 1.20 (d, 3H, J=6.8), 0.97 (d, 3H, J=6.8).
Reaction SMILES: [OH-].[Na+:2].O.[CH3:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][S+:15]([O-:27])[C:16]2[NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22][C:23]=3[N:24]=2)=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12]>CO>[CH3:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][S+:15]([O-:27])[C:16]2[N-:17][C:18]3[CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22][C:23]=3[N:24]=2)=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 31 °C
Yield: 52.6 %

Procedure:
50 ml of methanol was taken into a round bottom flask and a mixture of 12.75 g sodium hydroxide and 11 ml of water was added to it and stirred for clear dissolution at 31° C. 110 g of esomeprazole was dissolved in 550 ml of methanol and the solution was added to the above methanolic sodium hydroxide solution. The mass was subjected to stirring at a temperature of 30° C. for 40 minutes, followed by the addition of 5.5 g of carbon with simultaneous stirring. The reaction mass was filtered through a Celite bed, and washed with 550 ml of methanol. The filtrate was subjected to distillation at a temperature of 30° C. under a vacuum of 200 torr. The residue was co-distilled with 1650 ml of acetone in three equal lots at 35° C. To the obtained residue, 220 ml of acetone was added and stirred for one hour. The separated solid was filtered and dried at 34° C. for 12 hours to afford 61.5 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:24].C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([O:20][CH3:21])=[CH:8][C:9]3[O:14][C:13](=[O:15])[C:12]4[CH2:16][CH2:17][CH2:18][C:11]=4[C:10]=3[CH:19]=2)[CH2:36][CH2:37]1)[CH3:24]
Reactant: CCOc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCOc1ccccc1N1CCN(CCCOc2cc3c4c(c(=O)oc3cc2OC)CCC4)CC1
Yield: 72 %

Procedure:
Method B (40 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxycyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-ethoxyphenyl)piperazine hydrochloride; yield 72%; fusion point 169°-170° C. (from isopropanol). Fumarate: method E; yield 85%; fusion point 159°-161° C. (from acetone).
Reaction SMILES: C(OC(=O)[N:10]([CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30](=[O:43])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH2:42])[CH:33]=1)[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.C=O.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH:42][CH3:48])[CH:33]=1)=[O:43])[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(NC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamic acid benzyl ester (83 mg, 0.13 mmol, see procedure 12c) in 1,2-dichloroethane (2 mL) was charged with formaldehyde (0.008 mL of a 37% aq. solution, 0.10 mmol), stirred for 20 min at RT, and then charged with sodium triacetoxyborohydride (69 mg, 0.33 mmol). The reaction was stirred at RT for 40 min, quenched with water, and extracted with EtOAc (2×). The organic extracts were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). This solution was charged with 5% Pd/C, Degussa style (7 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=509.3.
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[C:16]1([NH:22][C:23](=[S:26])[NH:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:25][NH:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[S:26])[C:6]2=[O:14]
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Reactant: NNC(=S)Nc1ccccc1
Agent: Cl
Solvent: O
Product: O=c1c(=NNC(=S)Nc2ccccc2)c(=O)c2cc(O)ccc12

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenyl thiosemicarbazide hydrochloride, reflux for 2 hours.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].O.[Cl-].[Na+]>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]1([N:3]=[C:2]=[S:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N=NC1(N=C=S)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 91.5 grams (1.05 moles) of sodium thiocyanate in 450 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 203.2 grams (1.0 moles) of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 900 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 173 grams (75% crude yield) of a yellow liquid. The product had a broad band at approximately 2040 cm-1 in its infrared spectrum which is indicative of the isothiocyano band in these compounds. There was no band at 2170 cm-1 (thiocyano band).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1(C)C=CC=CC=1>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([N:21]2[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]3[N:7]=[C:6]([NH2:30])[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=3)[CH3:16])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:39])[CH:32]=1
Reactant: O=C=Nc1cccnc1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)Nc4cccnc4)CC3)nc(N)c2cc1OC

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (340 mg) in dichloromethane (5 mL) was slowly added dropwise with stirring a dilute solution of 3-pyridylisocyanate in toluene. The progress of the reaction was monitored by TLC. After completion of the reaction, aq. sodium carbonate was added and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid pyridin-3-ylamide 15, MS: 528 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 242 mg of the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 6-Chloro-nicotinic acid (3.00 g, 19.0 mmol) in 30 mL dimethylformamide was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (10.9 g, 20.9 mmol), 1-methylpiperazine (2.30 g, 22.1 mmol). and triethylamine (2.18 g, 21.5 mmol). After stirring for 18 hours, this was partitioned between ethyl acetate and water. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with 3% methanol/dichloromethane) to yield (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.50 g, 9.33 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([OH:21])[CH3:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:22])=[C:17]([CH:19]([O:21][C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[CH3:20])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C(C)Oc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.46 mmol), 4-methanesulfonyl-phenol (0.08 g, 0.46 mmol) and PPh3 (0.14 g, 0.55 mmol) in THF (5 mL) was added DEAD (0.1 g, 0.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H, q, J=6 Hz), 4.2-4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s), 2.86-2.72 (2H, m), 2.39 (3H, s), 2.04-1.96 (2H, m), 1.67 (3H, d, J=6 Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:17]=1
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NCc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (190 mg, 1.15 mmol) and 6-chloro-N4-(phenylmethyl)-2,4-pyrimidinediamine (300 mg, 1.28 mmol) into a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (74 mg, 0.064 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were filtered, then washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The material (367 mg) was carried on as is into the next reaction.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])=O)[CH:40]=[CH:39][N:38]=1.[CH3:61][C:62]([CH3:67])([CH3:66])[C:63](=[S:65])[NH2:64]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:65][C:63]([C:62]([CH3:67])([CH3:66])[CH3:61])=[N:64][C:44]=2[C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Yield: 17 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (10 g, 27.2 mmol) NBS (5.08 g, 28.6 mmol) and 2,2-dimethylpropanethioamide (3.51 g, 29.9 mmol) the title compound of Step A was obtained (2.15 g, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (br. s., 1H), 8.67 (d, J=5.3 Hz, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.27 (t, J=8.9 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 5.89-6.01 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.4 Hz, 1H), 4.60 (d, J=5.3 Hz, 2H), 1.45 (s, 9H); MS (ESI): 464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:25]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[N:16]=[CH:15][N:14]([CH3:25])[C:13]=3[C:12](=[O:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1
Reactant: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
4-[(4-Chlorophenyl)methyl]-6,7-dihydro-3H-imidazo-[1,2-a]purin -9(4H)-one (Procedure 3), 6.02 g. (0.02 mole), is dissolved with warming in a mixture of 100 ml. of water and 15 ml. of ethanol containing 1.0 g. (0.25 mole) of sodium hydroxide. Approximately 3 ml. (approximately a molar equivalent) of methyl iodide was added and the mixture was stirred for about 48 hrs. at room temperature. The precipitated solid was collected, air dried, and recrystallized from isopropanol, m.p. 182.5°-184.5°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:32])[CH2:27][NH:28]CCO)[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[BH-](OC(C)=O)(OC(C)=O)[O:44][C:45]([CH3:47])=O.[Na+].C=O>CO>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:32])[C:27]([CH3:2])([NH2:28])[CH2:47][CH2:45][OH:44])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:33][C:34]([C:36]2[NH:37][CH:38]=[C:39]([C:41]#[N:42])[N:40]=2)=[O:35])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CNCCO)CC3)cc2C2=CCCCC2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCO)C(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 113.8 %

Procedure:
A solution of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg, 0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)3BH (39.5 mg, 0.19 mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture was stirred at room temperature for 5.5 h, and the solvents were removed in vacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile in water with 0.1% TFA over 30 min) afforded the title compound (19.5 mg, 47%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.4 Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m, 1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 2.32-2.24 (m, 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS (ESI, m/z): Calcd. for C27H34N6O3 491.3 (M+H), found 491.2.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C=O)cn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-methoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-methoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C[Si](Cl)(C)C.[I-:34].[Na+].[OH-].[Na+]>C(#N)CC>[I:34][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1-c1nc2ccnc(Cl)c2c(=O)n1CCc1ccccc1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: COc1ccccc1-c1nc2ccnc(I)c2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 5-chloro-2-(2-methoxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one (300 mg, 0.766 mmol), trimethylsilyl chloride (0.097 mL, 0.766 mmol) and sodium iodide (344 mg, 2.297 mmol, 3 equiv.) in propionitrile (7.66 mL) was heated to reflux under nitrogen in the dark for 4 hours. TLC showed no starting material remaining. The reaction mixture was cooled to ambient temperature and poured into 1N NaOH (30 mL). The resulting suspension was extracted with ethyl acetate (3×20 mL), the combined extracts were washed with water, brine and dried, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by column chromatography using 10% ethyl acetate in dichloromethane to provide 235 mg (64%) of product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:29]Br>C(O)(=O)C.O>[Br:29][C:13]1[CH:12]=[CH:11][C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:20])[CH3:18])=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:22])[F:23])[N:8]=2)[CH:14]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ccnc(C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ccnc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
3 g N-[2-[2-(trifluoromethyl)4-pyrimidinyl]phenyl]-2,2-dimethylpropanamide was dissolved in 30 mL glacial acetic acid, 5 g anhydrous sodium acetate was added, and a solution of 2.8 g bromine in 5 mL acetic acid was added dropwise with stirring over 1 h. The reaction mixture was stirred at room temperature overnight, after which it was diluted with water. The precipitate was collected by filtration, washed well with water, then with hexane, and was dried in a vacuum oven overnight to yield 3.3 g of the title compound melting at 153°-157° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 7.40-8.4 (6H), 10.6 (s,1H,NH).