Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22]>CS(C)=O>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9](=[O:11])[NH:8][C:7]1=[O:12])#[N:22]
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: N#CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2CCCCCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a stirring slurry of 2.69 g 7-methylxanthine (16.2 mmol) (Aldrich, Milwaukee, Wis.) in 50 ml methyl sulfoxide was added 0.39 g sodium hydride (16.2 mmol). After 1 hour, 2.85 g of 6-bromocapronitrile (16.2 mmol) (Lancaster Synthesis, Inc., Windham, N.H.) was added neat and the reaction was stirred for 72 h at room temperature. The mixture was then quenched with 150 mL water and extracted five times with 35 ml methyl acetate. The combined extracts were washed two times with 40 ml saturated aqueous sodium bicarbonate solution and two times with 40 ml saturated aqueous sodium chloride solution and then dried over sodium sulfate. After concentration under vacuum, the residual white powder was recrystallized with ethyl acetate-hexane solution to yield 0.64 g 3-(cyanopentyl)-7-methylxanthine (15% yield) as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][C@@H:9]([O:42][C:43](=[O:45])[CH3:44])[C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([OH:24])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:25]([CH3:41])[CH2:26][CH:27]=[C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6]1)(=[O:3])[CH3:2].N1(C2C=CN=CC=2)CCCC1.[CH3:57][C:58]([CH3:64])([CH2:62][CH3:63])[C:59](Cl)=[O:60]>N1C=CC=CC=1.CCOCC.CCCCCC>[C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][C@@H:9]([O:42][C:43](=[O:45])[CH3:44])[C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24][C:59](=[O:60])[C:58]([CH3:64])([CH3:57])[CH2:62][CH3:63])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:25]([CH3:41])[CH2:26][CH:27]=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](OC(C)=O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H](C(C)CC=C(c3ccccc3)c3ccccc3)CC[C@@H]12
Reactant: CCC(C)(C)C(=O)Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2[C@@H]([C@H](OC(C)=O)C[C@@H]3C[C@H](OC(C)=O)CC[C@@]32C)[C@@H]2CC[C@H](C(C)CC=C(c3ccccc3)c3ccccc3)[C@@]12C
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 3α,7α-diacetoxy-12α-hydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (7.6 g), 4-pyrrolidinopyridine (0.184 g) and 2,2-dimethylbutyryl chloride (2.0 g) in pyridine (40 ml) is heated at 110° C. for about 1 hour, additional 2,2-dimethylbutyryl chloride (2.0 g) is added and heating is continued for about 16 hours. The mixture is cooled, diluted with 20% ether in hexane and the organic solution washed with 1.0M hydrochloric acid, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 30% ether in hexane to give the desired product.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: C[C@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (7.4 g, 0.05 moles) and (S)-(−)-2-methylpiperazine (5.0 g, 0.05 moles) in DMA (125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (20.75 g, 0.15 moles) to this mixture and stir at 135-140° C. for 56 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, and concentrate under vacuum to afford crude product as yellow liquid. Purify by flash column chromatography using CHCl3 to afford pyridylpiperazine derivative as yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(C2=CN3C(=NC(=O)C3(C)C)C=C2)c1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield according to the procedure described in Example 2, starting from 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one and 3-methoxyphenyl boronic acid. 1H NMR (CDCl3) δ 7.86 (dd, J=2.1 and 9.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.43-7.39 (m, 1H), 7.28-7.25 (m, 1H), 7.05 (m, 1H), 6.97-6.94 (m, 2H), 3.88 (s, 3H), 1.63 (s, 6H); MS (m/e): 269 (MH+).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.[OH-].[Na+]>FC(F)(F)S(O)(=O)=O.O>[CH2:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:16]1[O:18][CH2:17]1
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCCCO
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCOCC1CO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 114.3 %

Procedure:
Dodecanol (167.4 g) and 8.1 g of trifluoromethanesulfonic acid were heated to 95° C. while stirring. To the reaction mixture, 166.5 g of epichlorohydrin was added dropwise over 1 hour, followed by stirring for 8 hours. After completion of the reaction, the reaction mixture was cooled to 50° C. Over 1 hour, 75 g of a 48% aqueous solution of sodium hydroxide was added dropwise at a temperature maintained at 50° C. After stirring for 3 hours, 120 mL of water was added to the reaction mixture to cause separation. The water layer thus occurred was removed. The residue was then washed twice with 100 mL of water, whereby 249 g of crude dodecyl glycidyl ether was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH2:25])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([Cl:36])(=[O:35])=[O:34]>>[ClH:36].[ClH:36].[N:11]1([CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH:25][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:26])(=[O:35])=[O:34])[CH:17]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc(N)cc3ccoc23)CC1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2CCCNCC2)c2occc2c1
Product: Cl
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in Example 109, Step 2) and 2-methylbenzenesulfonyl chloride (23 μL, 0.16 mmol). The title compound (13 mg, 28%) was obtained as a colorless solid. HPLC 99%, RT=1.35 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.22 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.26-2.32 (m, 2H) 2.66 (s, 3H) 3.40-3.60 (m, 4H) 3.69-3.83 (m, 4H) 4.69 (s, 2H) 6.86 (d, J=2.26 Hz, 1H) 7.23-7.29 (m, 1H) 7.32-7.38 (m, 2H) 7.41-7.46 (m, 1H) 7.47 (d, J=2.26 Hz, 1H) 7.84-7.90 (m, 2H). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]1[CH2:48][CH2:47]1>CN(C=O)C.O>[CH:46]1([CH2:45][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:10]([NH:20][C:21]([NH:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]2=[O:19])[CH2:48][CH2:47]1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC3CC3)c3ncccc23)c1
Reaction time: 10 h
Yield: 78.8 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (400 mg, 0.85 mmol) in DMF (10 ml) were added potassium carbonate (141 mg, 1.02 mmol), potassium iodide (28 mg, 0.17 mmol), and (bromomethyl)cyclopropane (138 mg, 1.02 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1% methanol in chloroform), and crystallized from ether to give the title compound (354 mg, 0.67 mmol) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)[CH:18]([CH3:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH:18]([CH3:20])[CH3:19])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: Nc1cc[nH]n1
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(C)C
Product: CCOC(=O)C1=C(C(C)C)Nc2n[nH]cc2C1c1ccccc1OC

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.I[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:3]=[CH:4][C:5]=2[C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:10]=1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Ic1cnccn1
Reactant: Cc1nc(N)cs1
Product: Cc1ccc2c(-c3cnccn3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=335.4 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 2-iodopyrazine and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].N1C=CC=CC=1.[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>O1CCCC1>[C:11]([C:7]1[C:6]2[C:10](=[C:2]([NH:1][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:20]#[N:21])[CH:23]=3)(=[O:30])=[O:29])[CH:3]=[CH:4][C:5]=2[CH3:13])[NH:9][CH:8]=1)#[N:12]
Reactant: Cc1ccc(N)c2[nH]cc(C#N)c12
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NS(=O)(=O)c2cccc(C#N)c2)c2[nH]cc(C#N)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.4 %

Procedure:
To a solution of 7-amino-3-cyano-4-methyl-1H-indole (10 g, 58.4 mmol) in tetrahydrofuran (200 ml) were added pyridine (20 ml) and 3-cyanobenzenesulfonyl chloride (12.5 g), followed by stirring at room temperature for 3.5 hours. After further adding 2N hydrochloric acid (100 ml), extraction was performed with ethyl acetate. The organic layer was washed with water (twice) and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-3:2). A mixed solvent of ethanol-hexane (1:2) was added thereto, and after sonication, the precipitate was collected by filtration and washed with a mixed solvent of ethanol-hexane (1:3). The mixture was dried overnight under reduced pressure to give the title compound (9.33 g, 27.7 mmol, 47% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1COCCN1
Solvent: O
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
45.0 g (302.1 mmol) of 4,6-dichloropyrimidine are initially charged in 450 ml of water. 26.3 g (302.1 mmol) of morpholine are added, and the mixture is stirred at 90° C. for 16 h. The mixture is then cooled to 0° C., and the precipitate formed is filtered off. The precipitate is washed once with 50 ml of water and air-dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:19])[F:21])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1cccnc1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccnc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxypyridine and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 237.8–238.8° C. 1H NMR (DMSO-d6/300 MHz) 13.3 (br s, 1H), 8.42 (m, 2H), 7.87 (s, 1H), 7.83 (s, 1H), 7.48 (m, 2H), 6.72 (s, 1H), 5.93 (q, 1H, J=7.2 Hz). 19F NMR (DMSO-d6/282 MHz) −77.8 (d, J=7.2 Hz). FABLRMS m/z 372 (M+H). ESHRMS m/z 370.0083 (M−H, Calc'd 370.0094). Anal. Calc'd for C16H9ClF3NO4: C, 51.70; H, 2.44; N, 3.77; Cl, 9.54. Found: C, 51.49; H, 2.47; N, 3.70; Cl, 9.69.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:25])[CH3:24]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reaction time: 0.17 h
Yield: 0.6 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.72 mol) in anhydrous dichloromethane (10 mol) was treated with aluminum chloride (0.8 g, 6.8 mol) followed by acetyl chloride (0.4 mol, 6.08 mol). After 10 minutes, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with water, and dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.78 g, 67%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([CH2:5][OH:4])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cc2c(F)ccc(F)c2o1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
252 mg of 2-acetoxymethyl-4,7-difluorobenzofuran was dissolved in 5 ml of methanol and 455 mg of potassium carbonate was added to the solution at room temperature. The resulting mixture was stirred at the same temperature for 2 hours, followed by the addition of ethyl acetate thereto. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel chromatography (developer: 5% ethyl acetate/n-hexane) to give 161 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:8][CH:9]=[CH:10][C:11]=1[Cl:12])(=[O:3])[CH3:2].N12CCCN=C1CCCC[CH2:27]2.[C:37](OCC)(=O)C>C(=O)(OC)OC>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:13]2[N:17]([CH3:27])[C:16]3[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[N:8][CH:9]=[CH:10][C:11]=1[Cl:12])(=[O:3])[CH3:2].[C:1]([O:4][CH2:5][C:6]1[C:7]([C:13]2[N:14]([CH3:37])[C:15]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:16]=3[N:17]=2)=[N:8][CH:9]=[CH:10][C:11]=1[Cl:12])(=[O:3])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Reactant: CC(=O)OCc1c(Cl)ccnc1-c1nc2ccc(C(C)(C)C)cc2[nH]1
Solvent: COC(=O)OC
Product: CC(=O)OCc1c(Cl)ccnc1-c1nc2cc(C(C)(C)C)ccc2n1C
Product: CC(=O)OCc1c(Cl)ccnc1-c1nc2ccc(C(C)(C)C)cc2n1C
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 160h (500 mg, 1.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (212 mg, 1.4 mmol) in dimethyl carbonate (100 mL) was stirred at 140° C. for 3 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluting with petroleum ether:ethyl acetate=3:1) to afford (2-(6-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methyl acetate 160i and (2-(5-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methyl acetate 160j as a mixture of regioisomers (480 mg, 92%). MS-ESI: [M+H]+ 372.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:19].[CH:21](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:17]3[N:18]=[CH:21]2)=[CH:7][C:6]=1[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)Cc1ccc(Nc2ncccc2N)cc1C
Product: COC(=O)Cc1ccc(-n2cnc3cccnc32)cc1C
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of [4-(3-amino-pyridin-2-ylamino)-2-methyl-phenyl]-acetic acid methyl ester (1.92 g, 7.08 mmol) and triethyl orthoformate (30 mL, 181 mmol, 26 equiv) is stirred for 3 h at 150° C. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound: ES-MS: 282.1 [M+H]+; tR=3.39 min (System 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16][C:17]1[N:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH3:15])[N:22]=3)=[CH:29][CH:28]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1nccc(Oc2ccc(N)cc2)n1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A solution of 4.81 g (21.7 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 100 ml THF was added within 45 min. drop by drop at 0° C. to a solution of 5.06 g (21.7 mmol) 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and leached with 100 ml dichloromethane. The precipitate was isolated and dried to give 8.53 g (86%) 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(OC([NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27]2[CH:28]=[C:29]([N:39]([CH:49]3[CH2:51][CH2:50]3)CC3C=CC(OC)=CC=3)[C:30]3[N:31]([C:33]([C:36](O)=[O:37])=[CH:34][N:35]=3)[N:32]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C>[C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:1][C:36]([C:33]2[N:31]3[N:32]=[C:27]([NH:26][C@H:23]4[CH2:24][CH2:25][C@H:20]([NH2:19])[CH2:21][CH2:22]4)[CH:28]=[C:29]([NH:39][CH:49]4[CH2:51][CH2:50]4)[C:30]3=[N:35][CH:34]=2)=[O:37])[CH:7]=[CH:6][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)O)cnc23)C2CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(NC(=O)c2cnc3c(NC4CC4)cc(N[C@H]4CC[C@H](N)CC4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(3-aminophenyl)acetamide (4.09 mg, 0.027 mmol), 83C (10 mg, 0.018 mmol) and DIEA in DMF (0.5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16.06 mg, 0.036 mmol) and the reaction was stirred at room temperature overnight. One mL of TFA was added to the reaction mixture and heated at 60° C. After 1 hr, the reaction mixture was concentrated under reduced pressure and purified using preparative HPLC containing TFA to isolate N-(3-acetamidophenyl)-6-((trans)-4-aminocyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (4 mg, 5.02 μmol, 27.6% yield) as a white solid. 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=1.3 minutes. [M+H]=463.23. 1H NMR (500 MHz, METHANOL-d3) δ ppm 10.99 (1H, s), 7.92 (1H, d, J=1.83 Hz), 7.62 (1H, d, J=8.25 Hz), 7.37 (2H, t, J=8.25 Hz), 7.16 (1H, d, J=8.25 Hz), 6.08 (1H, s), 3.80 (1H, t, J=4.35 Hz), 3.09-3.26 (1H, m), 2.51-2.72 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.35 (2H, d, J=10.08 Hz), 2.11-2.24 (3H, m), 1.98-2.14 (2H, m), 1.67-1.89 (2H, m, J=12.72, 12.43, 12.43, 3.21 Hz), 1.37-1.53 (2H, m), 1.20-1.38 (1H, m), 0.82-1.00 (2H, m), 0.58-0.76 (2H, m).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(O[CH:15](OCC)[N:16]([CH3:18])[CH3:17])C>>[CH3:15][N:16]([CH:18]=[C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2]1)[CH3:17]
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCOc2ccccc21
Product: CN(C)C=C1COc2ccccc2C1=O

Procedure:
The 3-(dimethylaminomethylene)-chroman-4-one starting material was prepared from 4-chromanone (5.0 g, 33.7 mmol) and N,N-dimethylformamide diethyl acetal (15 ml, 87.5 mmol) to give the desired product as orange crystals (4.3 g) m.p. 135.8°. MS (ES+) 204 (100%).