Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH:21]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[CH:20]3[C:19]=2[C:18]2[CH:17]=[C:16]([O:38][CH3:39])[CH:15]=[CH:14][C:13]1=2)(C(C)(C)C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.Cl>C1COCC1.CO>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[C:21]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:20]=3[C:19]=2[C:18]2[CH:17]=[C:16]([O:38][CH3:39])[CH:15]=[CH:14][C:13]1=2
Reactant: COc1ccc2c(c1)c1c(n2CCCO[Si](C)(C)C(C)(C)C)CC(c2ccccc2OC)C2C(=O)NC(=O)C12
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4OC)cc1n2CCCO)C(=O)NC3=O
Yield: 72 %

Procedure:
The reaction of 6-(3-{[tert-Butyl(dimethyl)silyl)oxy}propyl)-9-methoxy-4-(2-methoxyphenyl)-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-dione (IV; Ar=2-methoxyphenyl; R10═CH2CH2CH2OSiMe2t-Bu) prepared as described in example 52 with DDQ using the procedure described in example 70 followed reaction with 2N HCl in THF/methanol gave 6-(3-Hydroxypropyl)-9-methoxy-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-methoxyphenyl, R10═CH2CH2CH2OH) (100) in a 72% yield as an orange powder; mp 223–225° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 8.53 (d, 2.6 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.45–7.40 (m, 1H), 7.36 (dd, J=7.4, 1.7 Hz, 1H), 7.29 (dd, J=8.9, 2.7 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.06 (dd, J=7.2, 7.2 Hz, 1H), 4.63 (t, J=4.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.69 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 69.55; H, 5.31; N, 6.30. C25H22N2O5 requires C69.76; H, 5.15; N, 6.51.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16](N)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][NH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>C1COCC1>[CH3:37][N:38]([CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=1)=[O:17]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Reactant: CNC1CCN(C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N(C)C3CCN(C)CC3)cc21
Reaction time: 18 h
Yield: 3 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with methyl-(1-methyl-piperidin-4-yl)-amine (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-11 as an oil in 3% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24]=O)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]=[N:27][OH:28])[NH:3][C:2]=1[CH3:1])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1C#N
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.4 g), hydroxylamine hydrochloride (539.3 mg) and sodium acetate (752.3 mg) in acetic acid (15 ml) was stirred at room temperature for 55 minutes to form dimethyl-2-methyl-4-(2-cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (2.375 g), and the mixture was heated at 110° C. for 4 hours with stirring. The reaction mixture was concentrated and treated with water (30 ml). The resultant acidic solution was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, and evaporated to dryness under reduced pressure. The residue was kept overnight in a refrigerator for crystallization. The resultant crystals were collected by filtration and washed with small portion of cold methanol to give crystals of dimethyl 2-methyl-4-(2-cyanophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.71 g). Additional crop (0.9 g) was recovered from the mother liquor. The combined crystals (2.61 g) were recrystallized from methanol to give pure crystals (1.2 g), m.p. 166°-166.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13](O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([CH:16]=1)[C:13]([NH:6][C:4]1[CH:5]=[N:1][NH:2][CH:3]=1)=[O:14]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cn[nH]c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cn[nH]c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1H-pyrazol-4-amine (55.2 mg, 0.66 mmol) was added in one charge to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method D; 170 mg, 0.55 mmol), EDC (318 mg, 1.66 mmol) and HOBT (254 mg, 1.66 mmol) in N,N-dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (30 ml) was added, and the mixture was extracted with ethyl acetate (50 ml×2). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was washed with ethyl acetate yield the title compound as a brown solid. 180 mg.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([N+:15]([O-])=O)=[C:10]3[O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2]>[Pd].O1CCCC1>[NH2:15][C:11]1[CH:12]=[CH:13][C:14]2[N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:27][CH3:28])[N:7]=[C:8]3[C:20]4[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=4[O:18][C:10]=1[C:9]=23
Reactant: CCN(CC)CCn1nc2c3c(c([N+](=O)[O-])ccc31)Oc1ccc(OC)cc1-2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Oc1ccc(OC)cc1-2

Procedure:
A mixture of 5 g of N,N-diethyl-9-methoxy-5-nitro-2H-[1]-benzopyrano[4,3,2-cd]indazole-2-ethanamine, and 0.940 g of 10% palladium on carbon, in 250 ml of tetrahydrofuran was stirred under hydrogen atmosphere for 18 hours, filtered, and the filtrate concentrated to give 5-amino-N,N-diethyl-9-methoxy-2H-[1]benzopyrano[4,3,2-cd]indazole-2-ethanamine.
Reaction SMILES: [Br:1][C:2]1[CH:6]([CH3:7])[O:5][C:4]([CH3:9])([CH3:8])[C:3]=1[O:10]C(=O)C.BrBr>C(Cl)(Cl)Cl>[Br:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]([CH3:9])([CH3:8])[C:3]1=[O:10]
Reactant: CC(=O)OC1=C(Br)C(C)OC1(C)C
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CC1OC(C)(C)C(=O)C1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
To a solution of acetic acid 4-bromo-2,2,5-trimethyl-2,5-dihydrofuran-3-yl ester (19.14 g, 0.11 mol) (described in T. Hiyama et al. Bull. Chem. Soc. Jpn., 56, 3078-3087 (1983)) in anhydrous chloroform (75 ml) at −20° C. is added a solution of bromine (18.00 g, 0.11 mol) in anhydrous chloroform (200 ml) dropwise over 45 minutes. After stirring at this temperature for 30 minutes the reaction mixture was allowed to warm to room temperature, then further stirred for 1 hour. After dilution with chloroform (250 ml) the organic phase is washed with dilute aqueous sodium bicarbonate then brine, and the phases separated. Organics solvents are removed under reduced pressure to afford 4-bromo-2,2,5-trimethyldihydro-furan-3-one (23.50 g) as a dark orange oil. This material is used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH:33]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NC1CCc2ccccc21)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.95 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[NH2+:12].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:26][CH:27]([Cl:32])[C:28](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:26][CH:27]([Cl:32])[C:28]1[N:12]=[C:3]2[CH:4]=[CH:5][C:6]3[C:11]([N:2]2[N:1]=1)=[CH:10][CH:9]=[CH:8][N:7]=3
Reactant: COC(=O)C(Cl)Cl
Reactant: Nn1c(=[NH2+])ccc2ncccc21
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClC(Cl)c1nc2ccc3ncccc3n2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A suspension of 1-amino-1,5-naphthyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crude product from the previous step, 3.0 mmol), methyl 2,2-dichloroacetate (0.86 g, 6.0 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in EtOH (30 mL) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 2% v/v MeOH in DCM) to give the title compound as a purple solid (300 mg, yield 39%). ESI MS: m/z 253, 255 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[C:13]([C:14]([OH:16])=O)[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:4])[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:12]=[C:13]([C:14]([NH:26][CH2:27][C:28]3[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])=[O:16])[C:8]=2[C:7]([CH3:25])=[N:6]1)([CH3:1])[CH3:3]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: COc1ccc(-c2cc(C(=O)O)c3c(C)nn(C(C)(C)C)c3n2)cc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: COc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.206 mmol) in DMSO (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL), stirred for 10 min., and filtered. The contents were dried under high vacuum and collected as 71 mg (71%). LCMS E-S (M+H)=474.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (s, 9H), 2.12 (s, 3H), 2.25 (s, 3H), 2.39 (s, 3H), 3.33 (s, 1H), 4.38 (d, J=4.80 Hz, 2H), 5.88 (s, 1H), 7.10 (d, J=8.84 Hz, 2H), 7.61 (s, 1H), 8.16 (d, J=8.84 Hz, 2H), 8.70 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH3:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])c1ccc(Cl)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 157.7 %

Procedure:
A mixture of 11.0 g (41.9 mmol) of triphenylphosphine and 9.16 g (44.4 mmol) of 4-chlorobenzenesulfonate was allowed to react for 2 hr at 140° C. A total of 16.4 g (35.0 mmol, 83.5%) of the title product was obtained. It was further purified by recrystallization from 95:5 toluene-acetonitrile. Analyses: mp 123.2°-125.2° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.Cl.[F:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:22][CH2:21]1
Reactant: FCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (38.9 g, 195 mmol) and 1-(2-fluoroethyl)piperazine dihydrochloride (20 g, 97 mmol) were dissolved in 485 mL 1,2-DCE. TEA (81.5 mL, 585 mmol) was added and the reaction was stirred for 30 min. HOAc (8.4 mL, 146 mmol) was added and the reaction was stirred for an additional 30 min followed by the addition of sodium triacetoxyborohydride (49.6 g, 234 mmol). The reaction was stirred overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with DCM (1×) and EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was absorbed onto silica gel and purified by flash chromatography to give title compound of step C (28.95 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).
Reaction SMILES: [CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4]1)[CH3:2].[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([C@@:3]1([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
tert-Butyl [(1S,3R)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (0.39 g, 0.83 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (3.1 mL) and the solution was stirred at room temperature overnight. The reaction solution was evaporated to give the desired product as a yellow powder (0.36 g, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([F:10])[CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][CH2:20][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: BrCCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCBr)c(F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 51.2 %

Procedure:
A mixture of 4-cyano-2-fluorophenol (8.5 g, 0.0620 mol; see Preparation D(iv) above), anhydrous K2CO3 (17.14 g, 0.124 mol) and 1,3-dibromopropane (37.7 mL, 0.372 mol) in dry DMF (80 mL) was stirred at 60° C. for 3 days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 4% ethyl acetate in petroleum ether, as eluent, to yield 8.2 g of the sub-title compound as a white solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:62][CH:63]3[CH2:65][CH2:64]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[C:52]([O:54]CC5C=CC=CC=5)[N:51]=[CH:50][N:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:82][C@H:83]([CH3:87])[C:84](O)=[O:85])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:82][C@@H:83]([C:84]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:62][CH:63]3[CH2:64][CH2:65]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[N:49]=[CH:50][NH:51][C:52](=[O:54])[CH:53]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1)=[O:85])[CH3:87]
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(OCc5ccccc5)ncn4)n3n2)CC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H](N)C(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(=O)[nH]cn4)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
BOP (129 mg, 0.292 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (50.0 mg, 0.097 mmol), DIEA (0.068 mL, 0.39 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (36.8 mg, 0.195 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min and concentrated. TFA (0.450 mL, 5.84 mmol) was added, and the reaction mixture was heated at 70° C. for 1 hr. The reaction mixture was diluted in methanol and purified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(6-oxo-1,6-dihydro-4-pyrimidinyl)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (26 mg, 0.053 mmol, 54.0% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.393 (M+H=495.16).). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.56 (1H, br. s.), 11.73 (1H, s), 8.29 (1H, d, J=7.78 Hz), 8.18 (1H, s), 8.06 (3H, d, J=4.27 Hz), 7.90-8.00 (1H, m), 7.61 (1H, s), 7.05 (1H, s), 7.00 (1H, d, J=7.78 Hz), 5.96 (1H, s), 3.68-3.92 (2H, m), 3.46-3.69 (1H, m), 2.10 (2H, d, J=10.54 Hz), 1.82 (2H, d, J=2.51 Hz), 1.43-1.69 (2H, m), 1.16-1.43 (5H, m), 0.69-0.86 (2H, m), 0.51-0.70 (2H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:11]([CH2:12]O)=[CH:10][C:9]([CH3:14])=[CH:8][N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[C:11]([CH2:12][Cl:3])=[CH:10][C:9]([CH3:14])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc(Cl)c(CO)c1
Solvent: ClCCl
Product: Cc1cnc(Cl)c(CCl)c1
Reaction time: 6 h
Yield: 92 %

Procedure:
Thionyl chloride (2.73 g, 0.023 moles) was added slowly to a well-stirred solution of 2-chloro-3-hydroxymethyl-5-methylpyridine (1.2 g, 0.0076 moles) in methylenechloride (20 ml) at 0° C. temperature over a period of 20 minutes. The reaction mass was further stirred for 6 hours at the same temperature. The solvent and excess thionylchloride was removed under reduced pressure and the mass was quenched with water (25 ml). The mass was extracted with methylene chloride (2×50 ml) and the layers separated. The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure. The residue so obtained was subjected to chromatographic purification on silica gel to give 2-chloro-3-chloromethyl-5-methylpyridine as a solid in 92% yield.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[NH:32][C:33](=[O:35])[CH3:34]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([NH:32][C:33](=[O:35])[CH3:34])[CH:19]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(C)=O
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: COc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1NC(C)=O
Yield: 25 %

Procedure:
N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.170 g, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide according to the general procedure of Example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH3:13][C:11]([CH3:12])([CH3:14])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:1][C:40]2[CH:41]=[CH:42][C:37]([C:36]([F:45])([F:44])[F:35])=[CH:38][CH:39]=2)[N:8]=1)=[O:15]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
N-(6-Hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.625 g), triphenylphophine (0.786 g) and 4-trifluoromethyl-phenol (0.486 g) in toluene was treated at RT under an argon atmosphere with diisopropyl azodicarboxylate (0.67 g). The mixture was stirred for 2 h, partitioned between ice water and AcOEt, the layers were separated, the aqueous layer twice extracted with AcOEt. The combined organic layers were washed with water and saturated aqueous NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100 to 85%) to give 2,2-dimethyl-N-[6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-yl]-propionamide (0.98 g) as a yellow oil. MS (ESI): 353.2 (MH+).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2ccc(C#N)cc2n1
Product: CC(C#N)(Cn1nc2ccc(C#N)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-cyano-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 21, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.46 g, 81%). Rf=0.45 (1:1 EA/heptane). MS (ES): M/Z [M+H]=431. 1H NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 5.46-5.59 (m, 2H), 7.76 (dd, J=8.9, 1.3 Hz, 1H), 7.84-7.93 (m, 4H), 8.18 (d, J=8.9 Hz, 1H), 8.78 (br s, 1H) and 9.01 (br s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).