Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15](=[O:32])[CH2:14][CH2:13]1.[Cl-].[Ce+3].[Cl-].[Cl-].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:32])[CH2:14][CH2:13]1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(C)(C)C2C1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)CCC2(C)C
Temperature: 15 °C
Yield: 10.1 %

Procedure:
To a suspension of 2.61 g of 2-methoxyphenylmagnesium bromide in 10 cm3 of tetrahydrofuran, cooled to 15° C., is added, dropwise and with stirring, a solution of 1.3 g of (3aRS,7aRS)-7,7-dimethyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone in 30 cm3 of tetrahydrofuran, followed by 2 g of anhydrous cerium chloride. The reaction mixture is stirred at room temperature for 18 hours, treated with 80 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3.6 cm, height 22 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cm3 fractions. Fractions 47 to 54 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is crystallized in 1 cm3 of acetonitrile. 0.177 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolol is obtained, in the form of white crystals melting at 187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[N:27])[N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3([CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]3)[C:6]=12.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:26]#[N:27])[N:5]2[C:6]=1[C:7]1([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=1
Reactant: Cc1cc(C#N)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)n2c1C1(CCNCC1)Oc1ccccc1-2

Procedure:
To a solution of 3′-methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (10 mg, 0.027 mmol) in MeOH (159 μL) was added K2CO3 (7.7 mg, 0.056 mmol) in one portion at 25° C. Water was added (35 mL), and the organics were removed under vacuum and the aqueous layer was extracted with dichloromethane (3×100 ml). The organic phases were combined, dried, filtered, concentrated to a white solid, which was used directly in the next step without further purification (7 mg, 93%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccccc1
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
Following General Procedure A (120° C., 30 hours), phenyl acetylene (84 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol) to give 95% yield 1,1′-ethyne-1,2-diyldibenzene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: c1csc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1cccs1

Procedure:
The title compound, white solid, m.p. 97° C. and MS: m/e=312.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-2-yl-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [C:1]([O:9]/[C:10](/[C:32]([O:34][CH3:35])=[O:33])=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl>[C:1]([O:9][C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:14]([CH3:26])[C:13]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])[C:32]([O:34][CH3:35])=[O:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Reactant: [H][H]
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)OC(=O)c1ccccc1

Procedure:
(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-yl benzoate (20.00 g, 41.4 mmol) in dichloromethane (120.00 ml) was added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate (280.00 mg, 0.424 mmol) under nitrogen atmosphere. The reaction mixture was hydrogenated at 60 psi pressure of hydrogen for 12 h. The solvent was removed and crude product was carried to the next step as such. MS (ESI) 508 (M+H); Rf=2.53.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][CH3:9])=[O:7])=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21]([O:23][CH3:24])=[O:22])C=CC=CC=1>ClCCl>[CH3:9][NH:8][C:6]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CNC(=O)c1cccc(C=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CNC(=O)c1cccc(/C=C/C(=O)OC)c1
Yield: 96.8 %

Procedure:
A solution of 3-formyl-N-methylbenzamide (2.9 g, 17.77 mmol) and methyl 2-triphenylphosphoranylideneacetate (8.91 g, 26.66 mmol) in dichloromethane (85 mL), was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford impure product. Re-purified by silica column chromatography, eluting with a gradient of 50 to 100% EtOAc in hexanes. Pure fractions were evaporated to dryness to afford (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=[O:5].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:18][CH:19]2[CH2:20][CH2:21]2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)=[O:5]
Reactant: O=C(NCC1(CC2CC2)CCC2(CC1)OCCO2)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1

Procedure:
2,4-Dichloro-N-[(8-cyclopropylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)methyl]benzamide (11 g; 27.6158 mmol) was dissolved in THF (80 ml) and HCl (2M; 80 ml) and the solution stirred at ambient temperature for 18 hours. The solution was adjusted to pH 9 with 10N NaOH solution and extracted with DCM (2×75 ml). The combined organics were dried (MgSO4) filtered and evaporated to give an oil which was crystallised from EtOAc isohexane as a white solid (8.0 g) 1H NMR δ (ppm)(CDCl3): 7.67 (1H, d, J=8.3 Hz), 7.44 (1H, d, J=2.0 Hz), 7.34 (1H, dd, J=2.0, 8.3 Hz), 6.37 (1H, s), 3.72 (2H, d, J=6.4 Hz), 2.57-2.49 (2H, m), 2.39-2.31 (2H, m), 1.92-1.80 (4H, m), 1.43 (2H, s), 0.77-0.69 (1H, m), 0.58-0.54 (2H, m), 0.11 (2H, q, J=5.0Hz). MS (m/e)=354.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq) and N,N-diisopropylethylamine (0.26 mL, 3 eq) in anhydrous dichloromethane (10 mL) at room temperature was added dropwise cyclopropane carbonyl chloride (0.26 mL, 3 eq). After the reaction mixture was stirred at ambient temperature for two hours, it was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (with 10% THF added). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a white powder in amount of 51 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:26]=[N:27][NH:28][N:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3nn[nH]n3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3nn[nH]n3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1>CN(C=O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH:15]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[C:14](=[O:25])[N:13]([CH3:26])[C:11]2=[O:12])=[CH:2]1
Reactant: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2c[nH]c3ccccc23)C(c2c[nH]c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (14 mg, 0.04 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) in DMF (1 mL) was added a small amount of 10% palladium-carbon and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(1H-indol-3-yl)-1-methy-2,5-dioxopyrrolidine (12.9 mg, 91.7%) as a mixture of two isomers (A:B=2.7:1.0) as pale red solids.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[Cl:35][C:36]1[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[C:37]=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:46][S:43]([C:37]3[C:38]([CH3:42])=[N:39][N:40]([CH3:41])[C:36]=3[Cl:35])(=[O:45])=[O:44])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1nn(C)c(Cl)c1S(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)c3c(C)nn(C)c3Cl)cnn12
Yield: 85.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 39, step 2 and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide (0.18 g, 0.88 mmol), the title compound (0.10 g, 90%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:27])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)=[O:2].S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)=[CH:40][N:39]=[CH:38]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1c(-c2ccccc2-c2cnco2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
13 mg of 3-(2-formylphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of methanol. To the mixture were added 11 mg of tosylmethylisocyanide and 8 mg of potassium carbonate, followed by heating under reflux overnight. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. It was filtered through NH silica gel and silica gel, and the filtrate was evaporated. The resulting precipitates were washed with ether and dried, to give 9 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.C1C=[N:26][C:25]2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.CN.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([NH:26][CH3:25])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Temperature: 25 °C

Procedure:
To a solution containing 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid (0.57 g, 1.9 mmol), HOAT (0.28 g, 2.1 mmol), diisopropylethylamine (2.3 mL, 13.2 mmol), methylamine hydrochloride (0.20 g, 2.8 mmol) and dichloromethane (20 mL) was added EDCI (0.51 g, 13.2 mmol). The solution was maintained at room temperature for 6 h, diluted with additional DCM (20 mL), washed with water (20 mL), washed with aqueous HCl (2×20 mL, 0.1 N), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3-carboxamide which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.30 (d, J=4.27 Hz, 1H), 7.90 (d, J=8.85 Hz, 1H), 7.60 (dd, J=8.70, 5.34 Hz, 2H), 7.34 (t, J=8.85 Hz, 2H), 7.16 (d, J=2.14 Hz, 1H), 7.07 (dd, J=8.85, 2.44 Hz, 1H), 3.81 (s, 3H), 2.74 (d, J=4.58 Hz, 3H). LCMS: retention time: 2.513 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 316 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CO[CH:10](OC)[CH2:11][CH:12]=O.[OH-].[Na+]>>[CH3:7][C:5]1[C:6]2[C:2](=[N:1][CH:10]=[CH:11][CH:12]=2)[NH:3][N:4]=1
Reactant: COC(CC=O)OC
Reactant: Cc1cc(N)n[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1n[nH]c2ncccc12
Temperature: 100 °C
Yield: 2.3 %

Procedure:
To a stirring suspension of 5.0 g (51.5 mmol) of 3-Amino-5-methyl pyrazole in 10.1 g (61.8 mmol, 1.2 equiv) of malonaldehyde dimethyl acetal is added approx. 8 g of polyphosphoric acid, and the resulting mixture is heated to 100° C. for 2 h. The resulting black oil is poured onto crushed ice and made basic by the addition of 3N NaOH, then extracted with EtOAc (2×100 mL). The organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 160 mg of 3-Methyl-1H-pyrazolo[3,4-b]pyridine as a white solid: 1H NMR (CDCl3, 400 MHz) δ8.57 (dd, 1H, J=1.1, 4.7), 8.04 (dd, 1H, J=1.1, 8.0), 7.12 (dd, 1H, J=4.7, 8.0), 2.60 (s, 3H); low resolution MS (FAB)m/e 134 (MH+).
Reaction SMILES: ClC1C=CC2N(C(C(C3C=[C:15]4[C:19](=CC=3F)[N:18]([CH3:23])[N:17]=[CH:16]4)=O)=CN=2)N=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([C:34]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]([CH3:47])[N:41]=[CH:40]4)(O)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C[Mg]Br>C1COCC1.CCOC(C)=O>[F:46][C:45]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH3:47])=[CH:38][C:37]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:15]3[CH:16]=[N:17][N:18]([CH3:23])[CH:19]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethanol (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone (Stage 278.3, 3.7 g, 11.22 mmol) was dissolved in THF (250 mL) with heating under Argon. The solution was let to cool down and methylmagnesium bromide (3 M, 7.48 mL) was added. The mixture was stirred at rt for 1 h. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 120 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 20 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound (tR 1.14 min (conditions 2), MH+=346)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
4-(7-Azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (1.9 g, 3.55 mmol) was suspended in dichloromethane (60 ml) and trifluoroacetic acid (2 ml) added dropwise. All solid dissolved at this point giving an orange solution which was stirred for 3 hours at ambient temperature. More trifluoroacetic acid (4 ml) was added and the mixture stirred overnight. The mixture was concentrated under reduced pressure and the residue concentrated from dichloromethane (×3) and toluene to remove trifluoroacetic acid. The residue was dissolved in methanol, placed on an Isolute SCX column, washed with methanol and then eluted with 7N ammonia in methanol. The product was then purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5 followed by 93/7) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (660 mg, 43%) as a white foam.
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH2:10][C@@H:5]2[CH2:4][CH2:3][NH:2]1.I[CH2:16][CH2:17][CH3:18].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:2]1[CH2:3][CH2:4][C@H:5]2[CH2:10][O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C@H:6]2[CH2:1]1)[CH2:17][CH3:18]
Reactant: c1ccc2c(c1)OC[C@@H]1CCNC[C@H]21
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCN1CC[C@H]2COc3ccccc3[C@H]2C1

Procedure:
A solution of 0.235 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[4,3-c]pyridine in 5 ml toluene is refluxed with 200 mg iodopropane and 3 ml saturated NaHCO3 solution for 2 hours. The organic phase is separated, dried over Na2SO4, filtered, concentrated in vacuo, and flash chromatographed with CH2Cl2 /ammonia saturated methanol (95:5)to give the title compound; m.p. HCl salt 245°-247°.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9]([Cl:23])=[N:10][C:11]([S:21][CH3:22])=[N:12][C:13]=1[NH:14][CH:15]1[CH2:18][C:17]([F:20])([F:19])[CH2:16]1)(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:23][C:9]1[C:8]2[CH2:7][CH2:6][N:14]([CH:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)[C:13]=2[N:12]=[C:11]([S:21][CH3:22])[N:10]=1
Reactant: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(NC2CC(F)(F)C2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c2c(n1)N(C1CC(F)(F)C1)CC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 2-{4-chloro-6-[(3,3-difluorocyclobutyl)amino]-2-(methylsulfanyl)pyrimidin-5-yl}ethyl methanesulfonate (922 mg, 2.38 mmol) in DMF (23 mL) was added DBU (0.725 mL, 4.75 mmol). The mixture was stirred at 80° C. for 1 h, whereupon the reaction mixture was diluted with EtOAc (40 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give 649 mg (94%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.44-4.33 (m, 1 H), 3.75 (t, J=8.5 Hz, 2 H), 3.13-2.99 (m, 2 H), 2.98-2.92 (m, 2 H), 2.91-2.81 (m, 2 H), 2.42 (s, 3 H). m/z (APCI+) for C11H12ClF2N3S 292.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Br[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1CCCC1=O.[Cu]Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Temperature: 120 °C
Yield: 45.3 %

Procedure:
A mixture of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (4.0 g, 20.6 mmol), 1,3-dibromo-5-fluorobenzene (15.71 g, 61.9 mmol), cesium carbonate (8.05 g, 24.7 mmol), copper (I) chloride (1.02 g, 10.3 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (0.95 g, 5.15 mmol) in 1-methyl-2-pyrrolidinone (40 mL) is heated to 120° C. for 7 hours under N2. The reaction is cooled and quenched with 1 N HCl (40 mL). The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/ethyl acetate to afford 3.43 g (45%) of the title compound. Rf=0.38 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C17H16O3BrF 366, found 384 and 386 (M+NH4, 100%).