Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:15]1([C:21]2[S:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:21]2[S:25][C:24]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of sodium carbonate (799 mg), tetrakis(triphenylphosphine)palladium(0) (218 mg), 3-bromopyridin-2-amine (652 mg) and 5-phenylthiophen-2-ylboronic acid (1000 mg) in water (10 ml) and 1,2-dimethoxyethane (50 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (579 mg) as a dark yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([F:13])[C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: O=C1COc2c(ccc(F)c2F)N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(ccc(F)c2F)N1CCCCl
Yield: 93.2 %

Procedure:
7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol), Cs2CO3 (0.314 g, 0.96 mmol) and 3-chloro-1-iodopropane (0.144 g, 0.70 mmol) were mixed according to GP5 giving the crude title compound (0.156 g); 1H NMR (CDCl3) δ 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.18-2.10 (m, 2H); 13CNMR (CDCl3) δ 163.5, 147.7 (q, J=245.6 Hz, J=10.4 Hz), 141.0 (q, J=249.4 Hz, J=15.7 Hz), 135.5, 126.2, 109.9 (d, J=18.4 Hz), 108.6 (q, J=7.6 Hz, J=4.2 Hz), 67.8, 42.3, 39.4, 30.0.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18]([NH:19][C:20](=[O:28])[CH2:21][CH2:22]1)=[CH:17][CH2:16]3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[C:29]([N:19]1[C:20](=[O:28])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C:18]1=[CH:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]1[CH2:13][CH2:14][C@@H:9]2[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 17β-t-butyldimethylsilyloxy-4-azaandrost-5-en-3-one (2 g) in pyridine (5 ml) at 5°-10° C. was added benzoyl chloride (2 ml) in CH2Cl2 (10 ml) dropwise. After the addition, the mixture was stirred at 60° C. for 3 hours and poured onto ice-water. The mixture was extracted with methylene chloride, and dried (Na2SO4). Removal of solvent gave the crude product which was recrystallized from CH2Cl2 -hexane to afford the title product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12]/[C:11]/2=[N:31]/[C:30]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6-phenoxy-2-phenylchroman-4-one (316 mg, 1. mmol) in anhydrous DCM (7.8 mL) was added TiCl4 (1 M solution in DCM, 2 mL, 2 mmol) dropwise within 15 minutes at room temperature. After addition, the mixture was stirred for 1 h. To this mixture was added bis-trimethylsilylcarbodiimide (0.41 g, 0.49 mL, 2.2 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][CH2:56]2)=[N:49][CH:50]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=O)[CH3:16])=[CH:4][CH:3]=1.[OH-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[C:15]([CH3:16])[N:14]=[C:9]3[C:8]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:3]=1
Reactant: CC(=O)Nc1ccccc1-c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccccc2c2ccc(F)cc12
Temperature: 120 °C
Reaction time: 48 h
Yield: 93.3 %

Procedure:
N-(4′-Fluorobiphenyl-2-yl)-acetamide (18.5 g, 80.7 mmol) was mixed with polyphosphoric acid (250 g) and then heated to 120° C. with vigorous stirring for 48 hours. The hot reaction mixture was poured onto ice and stirred vigorously until homogeneous. Concentrated ammonium hydroxide was added until the pH >9. A white precipitate formed. The mixture was filtered and the white solid was dissolved in ethyl acetate (250 mL) and filtered. The filtrate was washed with saturated, aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and reduced in vacuo to a brown solid. The solid was purified by recrystallization from ethyl acetate-hexane to afford 8-fluoro-6-methylphenanthridine as white crystals (15.9 g, 94% ), m.p. 92-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:4][C:3]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26].[Cl:29][CH2:30][C:31](N1CCCC1)=O.ClCC(N(C)C)=O>>[ClH:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:11][C:12]([N:14]2[CH2:15][CH2:31][CH2:30][CH2:16]2)=[O:13])=[CH:4][C:3]=1[O:23][CH2:24][C:25]([F:26])([F:27])[F:28]
Reactant: O=C(CCl)N1CCCC1
Reactant: CN(C)C(=O)CN(CCc1ccc(F)c(OCC(F)(F)F)c1)CC1CCOC1
Agent: CN(C)C(=O)CCl
Product: Cl
Product: O=C(CN(CCc1ccc(F)c(OCC(F)(F)F)c1)CC1CCOC1)N1CCCC1
Yield: 74 %

Procedure:
This compound was obtained as a brown solid in 74% yield following the same procedure described in Scheme 21 for the synthesis of 2-[[2-[4-fluoro-3-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl]-(tetrahydrofuran-3-ylmethyl)amino]-N,N-dimethyl-acetamide, using 2-chloro-1-pyrrolidin-1-yl-ethanone as the reagent instead of 2-chloro-N,N-dimethyl-acetamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23](=O)[C:24]#[C:25][CH3:26])[CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][NH:14][CH:23]([C:24]#[C:25][CH3:26])[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
To a solution of tert-butyl (2-(((6-chloro-3-pyridinyl)sulfonyl)(2-oxo-3-pentyn-1-yl)amino)ethyl)carbamate (1.0 g, 2.40 mmol) in CH2Cl2 (40 mL) at 0° C. was added TFA (4.0 mL, 51.9 mmol). After 20 min, additional TFA (4.0 mL, 51.9 mmol) was added and the cooling bath was removed. After 50 min at room temperature, solid sodium triacetoxyborohydride (2.1 g, 9.91 mmol) was added. The mixture was stirred at room temperature for 20 min then MeOH (5 mL) was added. The mixture was concentrated to about ⅕ its original volume and then saturated aqueous NaHCO3 (20 mL) was added. The pH of the aqueous layer was adjusted to about 8 with NaOH (1 N) and then the mixture was extracted with CHCl3 (containing 10% iPrOH) (3×10 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated. The resulting orange oil was purified by chromatography on silica gel using (1 to 5% MeOH in EtOAc) to give 1-((6-chloro-3-pyridinyl)sulfonyl)-3-(1-propyn-1-yl)piperazine as a light-yellow solid (0.39 g)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:20]1([CH2:19][CH2:18][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCC1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2cn(CCN3CCCC3)cn2)c1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (20 mg, 0.10 mmol), 1-(2-chloroethyl)pyrrolidine hydrogen chloride (34 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) in 2 mL DMF was heated at 120° C. for 2 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-100%). 1H NMR (400 MHz, DMSO-d6): δ 1.77 (4H, m), 2.67 (4H, m), 2.74 (2H, t, J=6.2 Hz), 3.92 (3H, s), 4.17 (2H, t, J=6.2 Hz), 7.62 (1H, dd, J=1.3 Hz and 5.0 Hz), 7.79 (1H, s), 7.87 (1H, s), 8.30 (1H, s), 8.69 (1H, d, J=4.9 Hz). [M+H] Calc'd for C16H20N4O2, 301. Found, 301.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1sccc1-c1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2-c2ccc3c(c2)OCO3)c1Br
Yield: 60 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)-phenyl]thiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p. 183-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[CH:13]1([CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:33]([N:19]([CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)=[O:34])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Fc1ccc(NCC2CCCC2)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Temperature: 60 °C

Procedure:
To a solution of (2-amino-thiazol-4-yl)-acetic acid ethyl ester (1.0 mmol) and cyclopentylmethyl-(3,4-difluoro-phenyl)-amine (1.0 mmol) in dry toluene (10 mL) was added CDI (1.5 mmol) and DMAP (0.05 mmol). The mixture was stirred at 60° C. for 3H an then evaporated to dryness in vacuo. The crude product was purified on silica gel (gradient, from heptane:ethyl acetate (10:1) to heptane:ethyl acetate (3:1)) to give {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5]O.P(Br)(Br)[Br:17]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5][Br:17]
Reactant: BrP(Br)Br
Reactant: COc1c(C)c(C)c(OC)c(CO)c1C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(CBr)c1C
Yield: 119.9 %

Procedure:
A solution of 16.5 g (78.5 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzylalcohol in 90 ml of tetrahydrofuran was cooled to 0° C., to which 14.2 g (52.5 mmol) of phosphorus tribromide was added with stirring. After stirring at the same temperature for 30 minutes, the reaction mixture was diluted with water and extracted with isopropyl ether. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried, from which the solvent was evaporated off. The residue was crystallized from methanol, to give 17.2 g (80.0%) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide. m.p. 71°-72° C.
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Br:13]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:13][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: OCC1COc2ccccc2O1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: BrCC1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-1,4-benzodioxane (17.9 g, 107 mmol) is taken up in acetonitrile (200 mL) and treated with dibromotriphenylphosphorane (50 g, 119 mmol). The mixture is stirred for 30 minutes and evaporated. The residue is taken up in a 1:1 mixture of ether/hexane, and triphenylphosphine oxide is removed by filtration. The solvent is removed by evaporation to give 2-bromomethyl-1,4-benzodioxane as a brownish solid. This material is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[F:11].[Li+].CC([N-]C(C)C)C.CN([CH:23]=[O:24])C>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[C:7]=1[CH:23]=[O:24]
Reactant: CCOc1ccc(F)c(Cl)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(Cl)c1C=O
Reaction time: 0.12 h

Procedure:
To a cold (−78° C.) solution of 2-Chloro-4-ethoxy-1-fluorobenzene (5.0 g, 28.6 mmol) in THF (100 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene; 40 mL, 72 mmol). After 7 minutes, DMF (7 mL, 85.8 mmol) was added dropwise while keeping the temperature below −60° C. After 40 minutes, the reaction mixture was quenched with sat. aq. ammonium chloride. The organic layer was separated and the aq. layer was washed with ethyl acetate (2×50 mL). The combined organic layer was washed with water (30 mL) followed by brine. The organic layer was dried (Na2SO4) and concentrated to give a 1:1 mixture of the target compound and a regioisomeric aldehyde. The mixture was purified by column chromatography (5/95, ethyl acetate/hexanes) to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=1.46 (t, 3H, J=7.2 Hz), 4.11 (q, 2H, J=7.2 Hz), 6.84-6.86 (m, 1H), 7.25-7.28 (m, 1H), 10.48 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[O:2][CH3:3].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[C:16]([N:33]([CH:43]3[CH2:45][CH2:44]3)CC3C=CC(OC)=CC=3)[C:17]3[N:18]([C:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[O:24])=[CH:21][N:22]=3)[N:19]=2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:43]1([NH:33][C:16]2[C:17]3[N:18]([C:20]([C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[CH:21][N:22]=3)[N:19]=[C:14]([NH:13][C@H:10]3[CH2:11][CH2:12][C@H:7]([NH:6][C:1](=[O:4])[O:2][CH3:3])[CH2:8][CH2:9]3)[CH:15]=2)[CH2:44][CH2:45]1
Reactant: COC(=O)Cl
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl carbonochloridate (7.81 mg, 0.083 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (30 mg, 0.055 mmol) and DIEA (0.00617 mL, 0.035 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 2 hrs, concentrated and treated with TFA (0.127 mL, 1.653 mmol) at 65° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)). The title compound, methyl (trans-4-((8-(cyclopropylamino)-3-((3-fluoro-4-pyridinyl)carbamoyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)carbamate, was isolated as a white solid (15 mg, 56.4%). 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=1.63 (M+H=483.24). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, s), 8.74 (1H, d, J=2.27 Hz), 8.51 (1H, t, J=6.17 Hz), 8.44 (1H, d, J=5.54 Hz), 8.01 (1H, s), 7.61 (1H, s), 7.18 (1H, d, J=8.06 Hz), 6.94 (1H, d, J=8.31 Hz), 5.98 (1H, s), 3.79 (1H, br. s.), 3.42-3.64 (4H, m), 3.30 (1H, br. s.), 2.02 (2H, d, J=9.57 Hz), 1.79 (2H, br. s.), 1.17-1.45 (4H, m), 0.70-0.82 (2H, m), 0.54-0.68 (2H, m).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[C:13](N(C)C)=O)[CH:8]=[S:9].BrC[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH2:13][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:8]=[S:9]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=S)ccc1C(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(C=S)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (4.92 g) in water (5 ml) is diluted with ethanol (80 ml), and the mixture is subjected to deaeration, and then put under nitrogen atmosphere. To the mixture is added 3-methoxy-4-dimethylaminocarbonylthiobenzaldehyde (20 g), and the mixture is refluxed for 14 hours. After cooling, to the mixture is added dropwise ethyl bromoacetate (9.74 ml), and the mixture is stirred at room temperature for three hours. To the mixture are added ethanol, 1.5N hydrochloric acid and water, and the mixture is extracted with chloroform. The extract is dried over sodium sulfate and concentrated, and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=9:1→5.6:1→4:1) to give 3-methoxy-4-ethoxycarbonylmethylthiobenzaldehyde (11.8 g) as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([O:4][C:5]([NH:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:17][CH2:16]1)[C:9]([OH:11])=O)=[O:6])[CH3:3].Cl.[CH2:33]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:31][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:9]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:33][CH3:34])[CH2:36][CH2:37]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:19][CH2:20]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O
Reactant: CCC1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1CCN(C(=O)[C@H](CCCC2CCN(C(=O)OCc3ccccc3)CC2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
1.7 g (4.4 mmol) of O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HBTU) are added portionwise, at 0° C. under nitrogen, to a solution of 1.73 g (4.0 mmol) of (S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]-piperidine-4-pentanoic acid, 0.66 g (4.4 mmol) of 4-ethylpiperidine hydrochloride and 1.8 ml (10.4 mmol) of N,N-diisopropylethylamine (DIEA) in dichloromethane. The reaction mixture is allowed to warm slowly to room temperature and the reaction is continued for 18 hours. The reaction mixture is then taken up in 200 ml of ethyl acetate and is washed with 100 ml of 1N hydrochloric acid solution and then with 100 ml of saturated sodium hydrogen carbonate solution and with 100 ml of saturated sodium chloride solution. The resulting product is dried over sodium sulphate and is filtered and then concentrated. The residue obtained is purified by chromatography on a column of silica gel, eluting under pressure with a 4/6 ethyl acetate/cyclohexane mixture. 2 g of phenylmethyl (S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate are obtained in the form of a viscous oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[CH:8]=[CH2:9].Cl.[NH:12]1[C:20]2[C:15](=[C:16]([C:21]3([OH:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:23]1[CH2:24][CH2:25][CH2:26][C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[CH:14]=[CH:13][NH:12]3)([OH:27])[CH2:22]1)[CH:8]=[CH2:9]
Reactant: C=CCBr
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCN1CCCC(O)(c2cccc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
22.9 g of sodium carbonate and 7.6 ml of allyl bromide were added to a mixture of 18 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride in 350 ml of dimethylformamide and the mixture was stirred under an inert atmosphere at room temperature for 2 hours. Then, one liter of water and 500 ml of ethyl acetate were added thereto and the decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 17 g of residue were chromatographed over silica gel and eluted with a 6-3-1 cyclohexanechloroform-triethylamine mixture to obtain 14 g of 1-(2-propenyl)-3-(1H-indol-4-yl)-3-piperidinol with an Rf=0.15.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:19])=O>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:19])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
A solution of 1-(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole (1.0 g, 4.70 mmol), in thionyl chloride (5 ml), was stirred at 70° C. for 16 hrs. The solvent was evaporated in vacuo and the resulting solid suspended in CH2Cl2, collected by filtration and dried in vacuo. The material was sufficiently pure to be used without furthur purification.