Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(O[N:33]1N=N[C:35]2C=CC=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:33][CH:34]([CH3:39])[CH3:35])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a solution of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid (69 mg, 0.21 mmol) and TBTU (76 mg, 0.24 mmol) in DMF (1.0 mL) was added DIPEA (183 μL, 1.07 mmol). Then isopropylamine (20 μL, 0.24 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (39 mg, 50%) as a light yellow solid after recrystallisation from ethyl acetate/heptane. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[C:8]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:7]=2[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: COc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(OC)c2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution, stirred at 0° C. under an inert atmosphere, of 165.5 g of 1,4-dimethoxybenzene and 218.7 g of 2,5dichloro-2,5 -dimethyl hexane, obtained in Example I(a), in 750 cm3 of anhydrous 1,2-dichloroethane, there are added, all at once, 31.9 g of powdered anhydrous aluminum chloride. The mixture is stirred for 1 hour at ambient temperature and then left to stand overnight. The next day after 4 hours stirring at this temperature, 600 cm3 of ice water are added. The organic phase is decanted and the aqueous phase is extracted three time with 400 cm3 of methylene chloride. The organic phases are combined, washed with water until neutral pH of the wash waters, then dried on sodium sulfate and concentrated. The resulting crude product is treated with animal charcoal in boiling ethanol, then recrystallized in this solvent. 195 g of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene are obtained in the form of white needles having a melting point of 195° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[N:3]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:4]=[N:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 2.8 %

Procedure:
A mixture of 4-methyl-1H-imidazole (25.5 g), 4-nitrobenzyl bromide (56 g), potassium carbonate (86 g) and N,N-dimethylformamide (500 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.6 g, 3%) as crystals from a fraction eluted with methanol-ethyl acetate (1:20, v/v). Recrystallization thereof from ethyl acetate-isopropyl ether gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:26][CH:27]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Yield: 23.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-4,4-dimethyl-6-ethynyl-1,2,3,4-tetrahydro-isoquinoline(Intermediate 27, 0.13 g, 0.571 mmol), 4-iodo phenyl acetic acid methyl ester (Reagent B, 0.16 g, 0.58 mmol), triethyl amine (0.5 mL), anhydrous tetrahydrofluran (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.05 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.01 g, 6%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[N:5]=[C:4]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:27][CH2:26][O:25][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][O:19]3)[CH:8]=2)[N:5]=[C:4]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:3]=1
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C#N)c1cc(N)n(-c2cccc(O)c2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To an ice cooled solution of Intermediate 20b (363 mg, 1.50 mmol), 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (329 mg, 305 μL, 2.25 mmol) and triphenylphosphine (786 mg, 3.00 mmol) in anhydrous THF (10 mL) was added dropwise diisopropyl azodicarboxylate (606 mg, 590 μL), and the ice bath removed and stirring continued under an Ar atmosphere. After 3 h, a further 1.0 eq of diisopropyl azodicarboxylate was added and the reaction stirred overnight. The reaction mixture was then concentrated in vacuo and subjected to FCC, eluting with 5-50% EtOAc in cyclohexane. The isolated product was repurified using FCC, eluting with 2.5-7.5% Et2O in DCM, to afford the title compound as a yellow oil (317 mg, 57%). LCMS (Method 3): Rt 3.67 min, m/z 393.3 [M+Na].
Reaction SMILES: [I-].[Na+].C(N(CC)CC)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C.CCCCC>[CH3:18][Si:17]([CH3:20])([CH3:19])[O:14][CH:13]=[CH:12][C:11]([CH3:15])=[CH2:10]
Reactant: CC(C)=CC=O
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: C=C(C)C=CO[Si](C)(C)C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To a suspension of 180 g of anhydrous sodium iodide in 300 ml of dry acetonitrile is added a solution of 112 g of triethylamine and 84 g of 3-methyl-2-butenal in 400 ml of pentane at room temperature. Added dropwise to the above solution is 109 g of chlorotrimethylsilane at 35°-38° C. and the mixture stirred for 4 hours at 40°-45° C. The resulting solid is filtered, washed with 400 ml of pentane and the solvent evaporated to a residue. The residue is distilled to afford 112 g of the desired product, B.P. 56°-60° C./35 mm, nD20 1.4496.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:36][C:33]1[C:34]2[CH:35]=[C:27]3[C:26]4[N:39]=[C:22]([C:21]5[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])=[CH:3][C:4]6[O:8][C:7]([C:9]7[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=7)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=6[CH:20]=5)[CH:23]=[CH:24][C:25]=4[O:38][CH2:37][N:28]3[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a mixture of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1000 mg, 1.914 mmol) and pyridine (1.548 mL, 19.14 mmol) in dichloromethane (30 mL), methylsulfonyl chloride (0.741 mL, 9.57 mmol) was added dropwise at 0° C. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was quenched with NaHCO3 and 20 mL dichloromethane was added. Solid crushed out, the mixture was filtered and washed with water. The crude solid was dried under vacuum and gave the crude product 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1100 mg, 96% yield).
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:11]([CH2:13][C:14](OCC)=O)=[O:12].[CH2:19](O)C>>[C:4]1([CH3:19])[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[N:9]=[C:11]([OH:12])[CH:13]=[CH:14][N:8]=2)[CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)CC=O
Reactant: N=C(N)c1ccccc1
Agent: [Na]
Product: Cc1cccc(-c2nccc(O)n2)c1

Procedure:
A 92.3 g portion of 3-methylbenzamidine, hydrochloride [J. B. Ekeley, et al., J. Am. Chem. Soc., 57, 381 (1935)] was stirred with 200 ml of 5N sodium hydroxide and 400 ml of chloroform for 1/2 hour. When solution was complete the chloroform layer was separated and the aqueous layer extracted twice with 50 ml portions of chloroform. The chloroform solutions were combined, dried over sodium sulfate and evaporated, giving 69.3 g of free benzamidine. This benzamidine was taken up in one liter of absolute ethanol, 71.6 g of ethyl formylacetate sodium salt was added and the mixture was refluxed for 3 days. After cooling, the ethanol was evaporated and the residue dissolved in one liter of water and filtered. The pH of the filtrate was adjusted to 6 with 1N hydrochloric acid and the solid was collected and dried, giving 59.1 g of the desired intermediate as a white solid, mp 148°-149.5° C.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9]N=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:25])[N:14]=1.C1C2C(=CC=CC=2)CCN1>CS(C)=O>[CH2:11]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:9]=2)[CH2:6][CH2:7][N:1]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:25])[N:14]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1C
Agent: c1ccc2c(c1)CCNC2
Solvent: CS(C)=O
Product: CCOC(=O)c1c(C)nc(N2CCc3ccccc3C2)nc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (1.086 g, 7.15 mmol) was added to a mixture of 6b (1.02 g, 4.75 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.95 g, 7.13 mmol) in DMSO (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 6c (1.43 g, 4.5 mmol, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:43])=CC=3F)C=2)=CC=1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([NH:1][C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)=[O:43])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Product: NC(=O)c1cc(Oc2c(F)cc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 52 %

Procedure:
4-(4-Amino-2,6-difluorophenoxy)picolinamide (104 mg, 0.39 mmol) was converted to the title compound (91 mg, 52%) in a manner similar to the preparation of Compound D of Example 112. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.50 (d, 1H, J=5.6 Hz), 8.11 (br s, 1H), 7.72 (br s, 1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J=2.3 Hz), 7.23-7.31 (m, 3H), 7.11 (m, 2H), 3.69 (s, 2H); HRMS(ESI+), 445.1124 (M+H)+ calcd., 445.1117 (M+H)+ found.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:11][NH2:12]>C(O)C>[F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5]1[CH:6]=[C:7]([NH2:8])[NH:12][N:11]=1
Reactant: NN
Reactant: N#CCC(=O)C1CC1(F)F
Solvent: CCO
Product: Nc1cc(C2CC2(F)F)n[nH]1
Yield: 82.1 %

Procedure:
Crude 3-(2,2-difluorocyclopropyl)-3-oxo-propionitrile (2 g) was dissolved in ethanol (18 mL) and treated with hydrazine (2.5 mL, 0.050 mol) at reflux for 24 hours. The reaction mixture was concentrated, diluted with brine and extracted into ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel chromatography eluting with 1-15% methanol in methylene chloride to afford 3-(2,2-difluorocyclopropyl)-1H-pyrazol-5-amine (1.8 g, 54% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28](OC)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH:37][CH2:38][CH2:39][OH:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:32])[C:28]([N:37]([CH2:38][CH2:39][OH:40])[CH3:36])=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CNCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)CCO
Yield: 56 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (205 mg, 0.43 mmol) was reacted with 2-methylaminoethanol (326 mg, 4.3 mmol) to give the title compound as a white solid (124 mg, 56%) except that the reaction mixture was heated at 45° C. for 24 hours and the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum (2 rotamers) 1.59-1.62 (m, 3H), 3.18 and 2.93 (s, 3H), 3.53-3.65 (m, 4H), 5.00 and 4.74 (t, 1H), 5.71 (s, 2H), 5.90 and 5.81 (q, 1H), 7.05-7.07 (m, 3H), 7.30-7.37 (m, 3H), 7.71-7.77 (m, 2H), 7.82-7.88 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 and 8.58 (s, 1H), 11.10 (br s, 1H); Mass spectrum MH+ 515.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:21])[N:15]=[C:16]([CH3:20])[C:17]=1SC)[CH3:2].[C:23](=O)([O-])O.[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:39]([O-:42])([O-])=[O:40].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:21])[N:15]=[C:16]([CH3:20])[C:17]=1[S:39]([CH3:23])(=[O:42])=[O:40])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(SC)c(C)nn(C)c1=O
Reactant: O=S([O-])[O-]
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 20 ml volume two-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone ((2-4)-(1)-39) (0.18 g), chloroform (1.0 ml), and sodium hydrogen carbonate (0.20 g) were added thereto under a nitrogen atmosphere. Meta-chloroperbenzoic acid (0.32 g) was added thereto at room temperature, and then the mixture was stirred for 4 hours. After stirring, to the reaction mixture was added saturated aqueous sodium sulfite solution, and extracted with tert-butyl methyl ether. Then, the organic layer was concentrated under reduced pressure. Then, the residue was subjected to column chromatography (silica gel 10 g, chloroform: ethyl acetate=15:1) to give 0.12 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[O:28][C:29]([CH2:32][N:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[O:28][C:29]([CH2:32][N:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)o1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)o3)c(=O)[nH]2)o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.29 g) and 2-nitroamino-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone in pyridine (15 ml) was heated under reflux for about 20 hr. The pyridine was evaporated at reduced pressure. The last traces of pyridine were removed by azeotroping with water and water removed by azeotroping with n-propanol. The oily residue was chromatographed on a silica gel column eluting with methanol in ethyl acetate (10% v/v). Evaporation of the eluant yielded 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone as an oil which was converted to its trihydrochloride using an excess of ethanolic HCl. The salt was recrystallised from isopropanol yielding a white solid (0.72 g) m.p. 181°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH2:14][C:15]#[N:16])[S:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:12][CH:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: N#CCc1nc(-c2cc(F)cc(F)c2)cs1
Reactant: BrCCOCCBr
Product: N#CC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1
Yield: 59 %

Procedure:
This compound was synthesized from 2-(4-(3,5-difluorophenyl)thiazol-2-yl)acetonitrile using 2-bromoethyl ether as described in example 1 step 2 (1.0 g, yield 59%). MS (ESI) m/z: Calculated for C15H12F2N2OS: 306.06. found: 307.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[N:25]=[C:26]=[O:27]>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:15]([CH3:16])[C:26]([NH:25][C:19]3[C:18]([CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:24])=[O:27])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(Nc2cccc(Cl)c2)ncn1
Reactant: Cc1cccc(C)c1N=C=O
Solvent: COCCOCCOC
Product: Cc1cccc(C)c1NC(=O)N(C)c1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
A solution of N-(3-chloro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (Example 124A, 94 mg, 0.4 mmol) and 2,6-dimethylphenyl isocyanate (74 mg, 0.52 mmol) in diglyme was stirred at 80° C. for 18 h. The solvent is evaporated in vacuo, and the residue is purified by column flash chromatography on silica gel (ethyl acetate/hexane 1:2) to afford title compound (29 mg, 19
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6](Cl)[C:7]#[CH:8].Cl[C:11]([O:13][CH3:14])=[O:12]>CCOCC>[C:11]([O:13][CH3:14])(=[O:12])[C:3]#[C:2][CH2:1][CH2:8][CH:7]=[CH2:6]
Reactant: C#CCCl
Reactant: COC(=O)Cl
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCCC#CC(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A solution of allylmagnesium bromide (1M, 150 mL, 150 mmol) in ether under a nitrogen atmosphere was cooled to −10° C., and propargyl chloride (5.4 mL, 75 mmol) was added dropwise. The solution was stirred for 24 h at room temperature, and then cooled to 0° C. Methyl chloroformate was added dropwise, and the solution was allowed to stir at room temperature for 4 h. The reaction was quenched by cautious addition of satd aq NH4Cl (100 mL) at 0° C. The organic layer was washed with brine, dried, and evaporated to a residue. Chromatography on silica gel provided the title compound (4.5 g, 44%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[CH3:24][O:25][C:26]([C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:31]([C:28]3([C:26]([O:25][CH3:24])=[O:27])[CH2:30][CH2:29]3)=[O:32])=[C:16]2[N:15]=1
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 43 mg, 0.14 mmol), 1-(methoxycarbonyl)cyclopropanecarboxylic acid (24 mg, 0.16 mmol), and HATU (62 mg, 0.16 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water, brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a yellowish foamy powder (36 mg, 60% yield). MS (apci) m/z=442.2 (M+H).