Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:7]1[C:2]2[N:3]([N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Br
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1cccn2nc(-c3ccccc3)nc12
Temperature: 130 °C
Yield: 60 %

Procedure:
A mixture of 2-amino-3-bromopyridine (2.00 g, 11.2 mmol), copper (I) bromide (240 mg, 1.64 mmol), 1,10-phenanthroline monohydrate (336 mg, 1.68 mmol) and benzonitrile (25 mL) was heated in a 50-mL 3-necked flask to 130° C. During 4 d a gentle flow of (O2/N2 5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 8-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.85 g, 60%) as a light brown solid with 97.5% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:21](Cl)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: N#Cc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1

Procedure:
The title compound was prepared as described in Example A (route 1), starting from 2-amino-5-cyanopyridine and 3,5-bis(benzyloxy) benzoyl chloride, 1H NMR δ (d6-DMSO): 5.19 (4H, s); 6.89 (1H, m); 7.26-7.46 (12H, m); 8.27 (1H, dd); 8.33 (1H, d); 8.84 (1H, s); 11.23 (1H, br s); m/z (LCMS; ESI+) 436 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1>>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]4[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=4[CH3:19])=[CH:13][CH:14]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccc3c(c2)OCO3)cc1

Procedure:
Compound (28) was prepared from compound (20) and (3,4-methylenedioxyphenyl)-boronic acid by adapting the procedure of Example 24A. LC/MS System B; Rt=1.76 mins, m/z (ES−)=351 (M−H for C20H16O6).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.[BH3-]C#N.[Na+]>CO>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:30])[F:31])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([S:33][CH3:32])=[CH:35][CH:36]=3)[N:5]=2)[CH:26]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CNCCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)cc1
Reaction time: 2 h

Procedure:
To a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (130 mg, 0.29 mmol) in methanol (5 mL) was added 4-(methylsulfanyl)benzaldehyde (66.3 mg, 0.44 mmol). The mixture was stirred for 2 hr, then NaBH3CN (27.5 mg, 0.44 mmol) was added. The resulting solution was stirred at room temperature overnight and quenched with water (1 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 37.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 39.6 mg (23%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)phenyl]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=584.2, RT=2.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.59 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.31-7.27 (m, 3H), 7.18 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=73.6 Hz), 4.25 (t, 2H, J=5.2 Hz), 3.70 (s, 2H), 2.95-2.92 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:6](=[O:25])[N:5]([CH3:26])[C:4]=2[N:3]=1.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:24][CH:22]([CH3:23])[CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:2]([O:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([O:29][C:28]([F:27])([F:37])[F:38])[CH:31]=3)=[N:3][C:4]=2[N:5]([CH3:26])[C:6]1=[O:25]
Reactant: CC(O)CCn1c(=O)c2c(nc(Br)n2COCC[Si](C)(C)C)n(C)c1=O
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a solution of 8-bromo-1-(3-hydroxybutyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1 g, 2.2 mmol) in DNF (10 mL) was added 3-(trifluoromethoxy)phenol (0.6 g, 3 mmol) followed by potassium carbonate (0.6 g, 4.4 mmol). The reaction was stirred at 80° C. for 4 h. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated to give 1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.1 g, 91.8% yield) as yellow syrup. LCMS retention time 2.036 min; LCMS MH+ 545.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[S:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:8]=1.[C:25](=[O:28])([O-])O.[Na+].NCC1S[C:34](C2C=CC(OC)=CC=2)=[C:35]([C:37]2C=CC(OC)=CC=2)[N:36]=1>ClCCl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:8]=[C:4]([CH2:3][NH:2][C:25]([NH:36][CH:35]([CH3:37])[CH3:34])=[O:28])[S:5][C:6]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:14][CH:13]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2nc(CN)sc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nc(CNC(=O)NC(C)C)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Aminomethyl-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.00 g) was added to a mixture of dichloromethane and saturated aqueous sodium hydrogencarbonate, and 2-aminomethyl-4,5-bis(4-methoxyphenyl)thiazole was extracted with dichloromethane. The separated organic layer was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo and the resulting residue was dissolved with tetrahydrofuran (20 ml) and methanol (7 ml). N-Isopropyl isocyanate (0.38 ml) was added thereto, and the reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was evaporated in vacuo, and the resulting powder was triturated with isopropyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(3-isopropylureidomethyl)thiazole (1.04 g).
Reaction SMILES: C[Al](C)C.[C:5]1([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O:23][C:24]([C:26]1[C:31]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)=[CH:30][CH:29]=[C:28]([CH:39]2[CH2:41][CH2:40]2)[N:27]=1)=O)C.O>O1CCOCC1.ClCCl.CO>[C:5]1([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:24]([C:26]4[C:31]([NH:32][C:33]5[CH:38]=[N:37][CH:36]=[N:35][CH:34]=5)=[CH:30][CH:29]=[C:28]([CH:39]5[CH2:40][CH2:41]5)[N:27]=4)=[O:23])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nc(C2CC2)ccc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Trimethylaluminum (2M solution in toluene, 0.26 ml) was added to a stirred suspension of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 111 mg) in dioxane (5 ml), and the mixture was stirred for 2 h at RT. 6-Cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (50 mg) was then added in one portion, and the mixture was heated to 100° C. for 17 h. Upon cooling, water (0.5 ml) was added, followed by small amounts of methanol and dichloromethane to get an almost clear solution. Some Mg504 was added, the mixture was stirred for 15 min, and filtered. The filtrate was concentrated, and the title compound (44 mg, 56%) was isolated from the residue by column chromatography (silica gel, dichloromethane/methanol gradient), followed by trituration (methanol). MS (m/e)=449.2 [M+H+].
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[CH2:19]([NH:22][C:1](=[O:2])[O:3][CH2:4][CH:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:20]#[CH:21]
Reactant: C#CCN
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of Fmoc chloride (25.00 g, 96.64 mmol, 1.05 eq.) in DCM (150 mL) was added dropwise to a solution of propargylamine 8 (5.89 mL, 92.04 mmol, 1.0 eq.) and triethylamine (15.4 mL, 110.4 mmol, 1.2 eq.) in DCM (200 mL) at −78° C. The reaction mixture was allowed to stir at room temperature, and after 16 hours the solution was washed with water (300 mL), 0.1 N aqueous citric acid (300 mL), saturated aqueous NaHCO3 (300 mL) and brine (200 mL). The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide an amorphous white powder. Sonication in cold hexane (200 mL) followed by filtration afforded the product as a white solid (24.316 g, 95%). LC/MS (2.758 min (ES+)). m/z: 300.0 [M+Na]+. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 2H, J=7.6 Hz), 7.57 (d, 2H, J=7.4 Hz), 7.41-7.37 (m, 2H), 7.30 (dt, 2H, J=7.5, 1.2 Hz), 4.93 (br s, 1H), 4.41 (d, 2H, J=6.9 Hz), 4.21 (t, 1H, J=6.4 Hz), 3.99 (d, 2H, J=3.3 Hz), 2.24 (t, 1H, J=2.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[O:30][C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([N:17]([CH2:19][C@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[O:30][C:11]2=[CH:12][CH:13]=[C:14]3[C:18]([N:17]([CH2:19][C@H:20]([OH:22])[CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)CC(C(=O)OC(C)(C)C)O3)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc3c(c21)CC(C(=O)OC(C)(C)C)O3
Yield: 115.6 %

Procedure:
To a mixture of the product from Step C (0.46 g, 1.06 mmol) in THF (50 mL) was added tetrabutylammnium fluoride (1 N in THF, 2.13 mL, 2.13 mmol). The mixture was combined with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 20% to 70% ethyl acetate in hexane) gave an oil (0.39 g): LC/MS (+ESI) m/z 319 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[C:20]1([S:19]([C:16]2[CH:17]=[CH:18][C:13]([N:4]3[N:3]=[C:2]([Br:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]3=[O:12])=[CH:14][CH:15]=2)=[O:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=c1c2ccccc2c(Br)nn1-c1ccc(S(=O)c2ccccc2)cc1

Procedure:
4-Bromo-2-(4-phenylsulfanyl-phenyl)-2H-phthalazin-1-one (0.095 g, 0.23 mmol) and MCPBA (0.052 g, 0.23 mmol) were stirred at RT in DCM (1 ml) for 1 h. The title compound was obtained after evaporation of the solvent in vacuum and subsequent purification of the raw product by chromatography over silica gel with heptane:DCM (1:1 until 0:1) (0.031 g, 31% yield). 1H-NMR: (400 MHz, CDCl3) 8.49 (1H, d), 7.80-7.99 (5H, m), 7.76 (2H, d), 7.69 (2H, d), 7.48 (3H, m); MS (ESI+)=427.22 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:45][C:46]([F:57])([F:56])[CH2:47]OS(C(F)(F)F)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:14]([Cl:34])=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][C:23]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH2:47][C:46]([F:57])([F:56])[F:45])[CH2:32][CH2:33]5)=[O:27])=[CH:24][CH:25]=4)=[CH:17][C:18]=3[Cl:19])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCN(CC(F)(F)F)CC1
Yield: 43.6 %

Procedure:
Treat a solution of 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.182 g, 0.35 mmol) and N,N-diisopropyl ethyl amine (0.32 g, 2.47 mmol) in THF (10 mL) with trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (0.41 g, 1.77 mmol) and heat to reflux for 3 hours under N2. Add more N,N-diisopropyl ethyl amine (0.13 g, 1.03 mmol) and trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (0.24 g, 1.03 mmol) and continue to heat at reflux for 2 more hours. Cool the reaction to room temperature, dilute with ethyl acetate and wash with saturated sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by reverse phase HPLC to afford 91 mg (43%) of the title compound: MS (m/z): 596 (M+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([OH:24])(=O)=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][S:21]([Cl:27])(=[O:24])=[O:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CS(=O)(=O)Cl)CC1
Temperature: 42 °C
Reaction time: 1 h

Procedure:
To a mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonic acid (34 mg, 0.092 mmol) in methylene chloride (0.30 mL) was added 1 drop of DMF and thionyl chloride (33 μL, 0.46 mmol). The resulting mixture was stirred at 42° C. for 1 h, then the solvents were evaporated to give the crude {trans-4-[(6-Nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanesulfonyl chloride. To the crude sulfonyl chloride made above was added 2.0 M methylamine in THF (0.30 mL, 0.60 mmol). The mixture was stirred at room temperature for 30 h. LCMS showed a small amount of starting material remaining More 2.0 M methylamine in THF (0.15 mL) was added and stirred for 30 min, to give a complete reaction. The solvents were evaporated and the resultant residue was dried in vacuo to give the crude product which was used in the next step without further purification. LCMS calculated for C15H21N4O4S2 (M+H)+: m/z=385.1. Found: 385.1.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(4-fluorobenzoyl) benzyl bromide (645 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (371 mg, yield 43%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]([OH:41])[C:30]3[O:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:34]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]([OH:41])[C:30]3[O:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:34]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1C(O)c1ncc(-c2ccccc2)o1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2C(O)c2ncc(-c3ccccc3)o2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step (B) (200 mg, 0.305 mmol) in 10.2 ml of CH3CN, Me3SiCl (199 mg, 1.83 mmol) was added and followed by NaI (274 mg, 1.83 mmol). The mixture was stirred at room temperature for 1 hr. Additional Me3SiCl (199 mg, 1.83 mmol) and NaI (274 mg, 1.83 mmol) were added in three portions and the reaction was stirred for additional 5.5 hr. The mixture was added to 5 ml H2O and 50 ml EtOAc. The organic layer was washed with sat. Na2S2 O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 27% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 73% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (65 mg, 37%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.COC(C1N=NC(NCC2C(C3C=CC=CC=3)=NOC=2C)=CC=1)=O.[CH:51]1([NH2:54])[CH2:53][CH2:52]1>>[CH:51]1([NH:54][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:53][CH2:52]1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: NC1CC1
Agent: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC2CC2)nn1
Yield: 75 %

Procedure:
As described for example 67e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (106 mg, 0.3 mmol) was converted, instead of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester, using cyclopropylamine instead of aminomethylcyclopropane, to the title compound (83 mg, 75%) which was obtained as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: NN.O=[C:4]1[C:12]2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1>C(O)C>[CH:4](=[N:5][O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1)[CH3:12]
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)c3ccccc3)c12
Agent: NN
Solvent: CCO
Product: CC=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrazine (0.481 mL, 15.3 mmol) was added, to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]benzamide (prepared as described in Part B of Example 89, 2.86 g, 5.11 mmol) in ethanol (50 mL). The reaction was stirred overnight and then was concentrated under reduced pressure. Methanol (25 mL) was added and the mixture was cooled to 0° C. Acetaldehyde (2.9 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated partially under reduced pressure, then 1 M aqueous sodium hydroxide (50 mL) was added and the mixture was sonicated for 1 minute. The solid was isolated by filtration, washed with water, and dried under vacuum at 70° C. to provide a 3:1 ratio of oxime isomers of N-{4-[8-({[ethylideneamino]oxy}methyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=[S:34])[NH2:33])[CH2:28][CH2:27]1)=O)(C)(C)C>C(O)C>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]2[CH:6]=[C:5]([C:3]3[N:33]=[C:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[S:34][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21

Procedure:
6.12 g (12.28 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 3 g (12.28 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester were suspended in 50 ml of ethanol and refluxed overnight. The reaction mixture was cooled and evaporated. The residue was slurried using a little EA and PE, digested and filtered off with suction. The solid was suspended in 180 ml of EA, washed with 60 ml of a saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated.