Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH3:26])=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:46]>O1CCOCC1>[ClH:46].[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4[CH3:26])=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1-methyl-1H-indazol-4-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (154 mg, 0.261 mmol) in dioxane (20 mL) was bubbled HCl gas until saturation and then stirred at room temperature for 4 hours. Reaction mixture was concentrated and the residue was triturated with methanol (1 mL) then decanted and dried to afford N-tert-butyl-2-(1-methyl-1H-indazol-4-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide hydrochloride (38 mg, 38%) as a white solid. LCMS: (M+H)+=349; 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 8.39 (s, 2H), 7.66-7.52 (m, 3H), 4.20 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>O1CCOCC1.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:82]3[CH2:86][CH2:85][CH2:84][CH2:83]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), pyrrolidine 0.23 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 6 ml dioxane, yielding title compound after HPLC purification.: LC-MSD, m/z for C22H20ClN3O3S [M+H]+: 442.1
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[C:22]([N+:23]([O-])=O)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)(C)(C)C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[O:5]=[C:6]1[NH:23][C:22]2[CH:21]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[N:14][C:13]=2[N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[CH2:7]1
Reactant: COC(=O)c1cnc(N2CCCC2CC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)CC1CCCN21
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
Methyl 6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate (1.79 g, 4.90 mmol) was dissolved in dichloromethane (Volume: 24.49 ml) and to this solution was added triphenyl phosphite (0.015 g, 0.049 mmol), ammonium metavanadate (0.034 g, 0.294 mmol) and Pt/C (5% wt.) (0.191 g, 0.049 mmol). The reaction mixture was hydrogenated at 100 psi at 25° C. for 3 h. The reaction mixture was filtered through a short plug of celite and the plug and precipitate were washed well with dichloromethane (30 mL). The combined filtrates were concentrated in vacuo and dissolved in AcOH (7 mL). This solution was heated to 90° C. for 10 min and concentrated in vacuo. The residue was crystallized with ethyl ether (20 mL) and sonicated until a fine suspension was obtained The precipitate was filtered off and dried in vacuum to afford methyl 6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepine-3-carboxylate (0.927 g, 3.55 mmol, 72.4% yield) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 1 H) 1.74-1.89 (m, 1 H) 1.89-1.99 (m, 1 H) 2.19 (d, J=5.81 Hz, 1 H) 2.59 (dd, J=14.78, 1.64 Hz, 1 H) 2.77 (dd, J=14.78, 9.98 Hz, 1 H) 3.56-3.67 (m, 1 H) 3.67-3.76 (m, 1 H) 3.78 (s, 3 H) 3.99 (td, J=9.85, 5.56 Hz, 1 H) 7.64 (d, J=2.02 Hz, 1 H) 8.40 (d, J=2.02 Hz, 1 H) 9.73 (d, 1 H) [M+H] calc'd for C13H15N3O3, 261; found, 261.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH:12]=[CH:11]N=[CH:9]2)=[O:7])=[C:4]([Cl:15])[CH:3]=1.CN[CH:18]1[CH2:23]CC[CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH:12]2[CH2:11][CH2:20][CH2:19][CH2:18][CH2:23]2)[CH3:9])=[O:7])=[C:4]([Cl:15])[CH:3]=1
Reactant: CNC1CCCCC1
Reactant: Nc1ccc(C(=O)n2ccnc2)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc(N)cc1Cl)C1CCCCC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 15 gm of N-(4-amino-2-chloro-benzoyl)-imidazole (m.p. 122°-127° C) and 150 ml of N-methyl-cyclohexylamine was stirred at 130° C for 4 hours. Subsequently, chloroform was added to the reaction mixture, and the resulting mixture was extracted twice with 300 ml of water. The organic phase was dried with sodium sulfate and evaporated. The oily residue was purified by chromatography on a silicagel column with chloroform/methanol (6:1), and the combined eluate fractions containing the desired product were evaporated. The residue was crystallized from isopropanol, yielding 4-amino-2-chloro-N-cyclohexyl-N-methyl-benzoic acid amide, m.p. 166°-170° C.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][O:11][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1.[O-]CC.[Na+].C(O)C.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)=[O:33]>O>[CH:46]1([CH2:45][O:44][C:36]2[CH:35]=[C:34]([C:32](=[O:33])[CH2:31][CH:14]([C:13](=[O:20])[CH2:12][O:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:39]=[CH:38][C:37]=2[O:40][CH:41]([F:43])[F:42])[CH2:48][CH2:47]1
Reactant: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CCOC(=O)CC(=O)COCc1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1)C(=O)COCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To 460 ml of an ethanol solution containing 13.5 g (50.7 mmol) of ethyl 4-(4-methoxybenzyloxy)-3-oxobutyrate (see WO 2004060890) was added 18.9 ml (50.6 mmol) of 21% sodium ethoxide-ethanol solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Then, to the above mixture was added dropwise 300 ml of ethanol solution containing 16.5 g (42.3 mmol) of 2-bromo-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone obtained in Reference example 45-(a) under ice-cooling, and the mixture was further stirred at 10° C. or lower for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1→7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 14.0 g of the title compound as a pale yellowish oil. (Yield: 63%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33](O)=[O:34])=[C:31]([CH3:39])[N:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:34])=[C:31]([CH3:39])[N:30]=1
Reactant: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-pyridin-3-ylmethyl-amine (0.78 g, 2.12 mmol) was dissolved in DCM (10 mL). 6-Chloro-2,4-dimethyl-nicotinic acid (474 mg, 1.2 eq.), HOBT (430 mg, 1.5 eq.), DIPEA (760 μL, 2 eq.), and EDCI (612 mg, 1.5 eq.) were added sequentially. The mixture was stirred at room temperature for 6 h, and then quenched with saturated NaHCO3 (20 mL). The pH of the equilibrated aqueous was adjusted to 8 with 1N HCl, and the mixture was extracted with DCM (200 mL in 5 extracts). The combined organic was dried (Na2SO4) and concentrated. The residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent to give 6-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.88 g, 77%) as light brown foam. 1H NMR (δ, CDCl3): 8.66 (1 H, d, br, J=5.7 Hz), 8.51 (1 H, s), 8.44 (1 H, d, J=4.8 Hz), 7.61 (1 H, d, J=8.1 Hz), 7.20 (1 H, dd, J=7.8, 4.8 Hz), 7.01 (1 H, s), 6.73 (2 H, d, J=9.0 Hz), 6.62 (2 H, d, J=9.0 Hz), 3.88 (2 H, s, an overlapping 1H, m), 3.71 (3 H, s), 3.33 (2 H, pentet, J=13.5 Hz), 2.80 (3 H, m), 2.51 (3 H, s, an overlapping 1 H, m), 2.30 (3 H, s), 2.12 (1 H, t, J=11.4 Hz), 1.82-1.66 (3 H, m), 1.60-1.46 (1 H, m), 1.11 (1 H, qd, J=12.3, 3.6 Hz), 0.99 (3 H, d, J=6.6 Hz), 0.92 (1 H, qd, J=12.0, 3.0 Hz); 13C NMR (δ, CDCl3): 167.2, 155.4, 152.9, 150.2, 148.9, 148.1, 147.5, 142.5, 135.7, 134.8, 123.3, 122.5, 117.8, 114.6, 60.5, 58.1, 55.6, 52.1, 47.5, 43.6, 40.1, 30.7, 29.4, 22.1, 18.8, 13.4; ES-MS m/z 536.5 (M+1). Anal. Calcd. for (C30H38N5ClO2) 0.2(H2O): C, 66.76; H, 7.17; N, 12.98; Cl, 6.57. Found: C, 66.80; H, 7.00; N, 12.86; Cl, 6.55.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=C)[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@](CC=O)(CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
750 mg of 2-trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate were dissolved in 30 ml of THF. 852 mg of sodium periodate and 10 ml of water were added. The mixture was then stirred at room temperature for 3 h and filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 2 with 1 N HCl solution. The phase were separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][Si:11]([CH3:27])([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][Si:11]([CH3:26])([CH3:27])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[N:19]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]2
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2cccc([Si](C)(C)C)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cccc([Si](C)(C)C)c2n1Cc1cccc(F)c1
Yield: 63.2 %

Procedure:
0.42 ml (3.44 mmol) of 3-fluorobenzyl bromide is added, slowly at ambient temperature, to a suspension of 0.75 g (2.87 mmol) of ethyl 7-trimethylsilyl-1H-indole-2-carboxylate, obtained according to the protocol described in stage 5.1, and of 1.18 g (8.61 mmol) of potassium carbonate in 50 ml of dry acetonitrile, maintained under an inert atmosphere. The reaction mixture is stirred at reflux for 18 h. After this period of time, the cooled suspension is filtered through a frit and then rinsed with acetonitrile. The reaction crude obtained after evaporation of the filtrate under reduced pressure is purified by flash chromatography on a silica gel column, elution being carried out with a gradient of 10 to 50% of dichloromethane in heptane. 0.67 g of the expected ethyl 7-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate is thus isolated.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=O)=[CH:11][CH:10]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:17]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[N:4]=1
Reactant: CSC(=N)NN
Reactant: O=CC(=O)c1ccc(F)cc1
Solvent: O
Product: CSc1nncc(-c2ccc(F)cc2)n1
Yield: 63.1 %

Procedure:
3-(Methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 69%) was prepared from methyl hydrazinecarbimidothioate (4.51 g, 43.0 mmol) and 4-fluorophenylglyoxal monohydrate (6.60 g, 43.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1.[CH3:28][Mg]Br.C(OCC)C>O1CCCC1.[NH4+].[Cl-]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])([CH3:28])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(N)nc(C)n2)cc1F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ncc(Nc2ncc(C(C)(C)O)nc2-c2cc(N)nc(C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of 1-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)ethanone (11 mg, 0.030 mmol) and methylmagnesium bromide, 3.0 M solution in diethyl ether (10.65 μL, 0.089 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (1 mL) was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic extracts were washed with saturated NaCl 5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give 2-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)propan-2-ol (8.5 mg, 0.022 mmol, 74.1% yield). 1F1 NMR (300 MHz, CDCl3) δ 1.63 (s, 6H) 2.66 (s, 3H) 3.66 (s, 1H) 4.03 (s, 3H) 5.01 (s, 2H) 7.45 (s, 1H) 8.11 (d, J=1.90 Hz, 1H) 8.22 (dd, J=12.13, 2.05 Hz, 1H) 8.39 (s, 1H) 12.66 (s, 1H). m/z (ESI, +ve ion) 386.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1.Cl>C(OCC)(=O)C.O.CN(C)C=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:11]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCC(F)(F)F)s1
Reaction time: 4 h
Yield: 18.3 %

Procedure:
To an N,N-dimethylformamide solution (30 mL) of 2,2,2-trifluoroethanol (1.50 g, 15.0 mmol), sodium hydride (655 mg, 15.0 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.91 g, 10.0 mmol) were added and the resultant mixture was stirred at 65° C. for 6 hours, at room temperature for 15.5 hours, and at 65° C. for 4 hours. After completion of the reaction, water and 1 M hydrochloric acid were added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (464 mg, yield 18%).
Reaction SMILES: [B-]C#N.[Na+].[F:5][C:6]1([F:26])[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:10][CH2:9][NH:8][CH2:7]1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.C(O)(=O)C>CO>[F:26][C:6]1([F:5])[CH2:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]([F:24])([F:25])[F:23])=[N:20][N:21]=3)[N:18]=2)[CH2:10][CH2:9][N:8]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:7]1
Reactant: FC1(F)CNCCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Reactant: O=Cc1ccc(F)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC(F)(F)C2)cc1
Temperature: 21 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
Sodium cyanotrihydroborate (58.5 mg, 0.93 mmol) was added to a stirred mixture of 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 0.62 mmol), 4-fluorobenzaldehyde (93 mg, 0.75 mmol) and acetic acid (71.1 μl, 1.24 mmol) in methanol (10 mL) at room temperature. The resulting mixture was stirred at 21° C. for 20 hours. The reaction mixture was concentrated to dryness, diluted with methanol and a few drops of 7M ammonia in methanol were added. The mixture was concentrated to dryness, the residue was diluted with DCM and the salts were filtered off. The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% acetonitrile in DCM. Product-containing fractions were concentrated to give to give 6-[6,6-difluoro-4-(4-fluorobenzyl)-1,4-diazepan-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (154 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[C:48]([CH:51]1[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH2:52]1)(=[S:50])[NH2:49]>C1COCC1.O1CCOCC1.Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:49]=[C:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[S:50][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: Cl
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3sc(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 36 %

Procedure:
The 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.250 g, 0.790 mmol, Preparation #K.1) was dissolved in THF (4 mL) then pyridinium tribromide (0.253 g, 0.790 mmol) was added in one portion. Within about 2-3 min, a solid started forming. The mixture was stirred at ambient temperature for about 1.5 h then DCM (20 mL) and water (10 mL) were added. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and then tert-butyl 4-carbamothioylpiperidine-1-carboxylate (0.290 g, 1.19 mmol) was added. The mixture was stirred overnight at ambient temperature, then concentrated under reduced pressure, and partitioned between EtOAc and water. The organic layer was concentrated under reduced pressure and then the residue was purified by flash chromatography with EtOAc as an eluent. Concentration of the desired fractions gave an oil which was dissolved in 1,4-dioxane (3 mL) and 6 N HCl (1 mL). The mixture was heated at about 60° C. in an oil bath for about 30 min then concentrated and purified by RP-HPLC (Table 1, Method d). Concentration of the appropriate fractions followed by basification with 1 N NaOH gave a turbid solution that was extracted with EtOAc (3×25 mL). The organic extracts were combined, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was then suspended in water and lyophilized to give the title compound (0.125 g, 36% yield: LC/MS (Table 1, Method a) Rt=1.54 min; MS m/z: 441.2 (M+H)+; 1H NMR (DMSO-d6) δ 1.33 (d, 6H), 1.63 (m, 2H), 2.05 (m, 2H), 2.62 (m, 2H), 3.04 (m, 2H), 3.17 (m, 1H), 3.37 (m, 1H), 7.13 (m, 1H), 7.24 (m, 1H), 7.36 (m, 1H), 7.70 (m, 1H), 8.26 (d, 1H); Anal. calcd. for C22H22F2N6S: C, 59.98; H, 5.03; N, 19.08. found C, 59.66; H, 4.72; N, 19.05.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])([O-])=O.[H][H].[S]>C(O)C.[Ni]>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=1
Reactant: [H][H]
Reactant: CSc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: CSc1ccc(N)c(C(F)(F)F)c1

Procedure:
2-Nitro-5-methylthiobenzotrifluoride (190 g, 0.85 mole) in ethanol (1 l.) is reduced over Raney nickel at about 45 psi of hydrogen gas. After hydrogen uptake is complete the catalyst is deactivated with elemental sulfur, the mixture is filtered, and the filtrate evaporated under reduced pressure to afford the desired product as an oil. IR 2.9μ (strong NH band).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:17][CH3:18])[CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:4]([CH2:3][C@@H:2]([CH3:1])[CH2:17][CH3:18])[CH2:5][C:6]3[NH:7][C:8](=[O:16])[C:9]4[CH2:15][O:14][CH2:13][CH2:12][C:10]=4[N:11]=3)=[O:34])[CH2:30][CH2:31]2)=[O:25])=[CH:36][CH:37]=1
Reactant: CC[C@H](C)CNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC[C@H](C)CN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (38.2 mg) from (S)-2-((2-methylbutylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C27H35FN4O4 498.6. found 499.7 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.88-8.15 (m, 2H) 7.20 (t, J=8.59 Hz, 2H) 4.44-4.68 (m, 4H) 4.09-4.25 (m, 1H) 3.85-3.99 (m, 2H) 3.80 (d, J=11.12 Hz, 2H) 3.42 (d, J=7.58 Hz, 2H) 3.22-3.36 (m, 2H) 3.17 (br. s., 1H) 2.66-2.76 (m, 1H) 2.20 (br. s., 3H) 1.26-1.47 (m, 1H) 1.06-1.25 (m, 1H) 0.93 (ddd, J=6.82, 3.79, 3.54 Hz, 4H) 0.78-0.90 (m, 2H).