Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[N:9]=1>C1(C)C=CC=CC=1>[N:7]([C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16]([F:19])([F:17])[F:18])[N:9]=1)=[C:2]=[O:3]
Reactant: COc1cc(C(F)(F)F)nc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)nc(N=C=O)n1
Reaction time: 4 h
Yield: 57.9 %

Procedure:
38.3 g of oxalyl chloride (0.3 mol) were added dropwise to a suspension of 2-amino-4-methoxy-6-trifluoromethylpyrimidine (78 mmol) in 100 ml of toluene. The refluxing mixture was stirred for 4 hours, after which the homogeneous solution obtained was subjected to fractional distillation. The title compound (9.9 g; 58% of theory) was obtained as an oil of boiling point 44°-50° C. (0.5 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22].O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:22])=[C:2]([Br:1])[CH:7]=1
Reactant: O=c1[nH]c2ccccc2c(=O)n1-c1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)c(Br)c1
Temperature: 70 °C
Yield: 93.3 %

Procedure:
A suspension of 3-(2-bromo-4-nitrophenyl)-1,3-dihydroquinazoline-2,4-dione (0.18 g, 0.5 mmol) and tin(II) chloride dihydrate (0.45 g, 2.0 mmol) in ethyl acetate (5 mL) was heated at 70° C. for 4 hr. The reaction mixture was then cooled, mixed with Celite, made basic with 4N NaOH (3 mL), filtered through Celite, and concentrated in vacuo to give the desired compound (0.155 g, 94%). ES-MS (M+H)+=332, 334 (Br).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH2:2][CH3:3].[C:15](Cl)(=[O:17])[CH3:16]>>[CH2:1]([C:4]1[CH:9]=[C:8]([C:15](=[O:17])[CH3:16])[CH:7]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: CC(=O)Cl
Reactant: CCCc1cccc(C(C)(C)C)c1O
Product: CCCc1cc(C(C)=O)cc(C(C)(C)C)c1O

Procedure:
Intermediate 2-n-propyl-6-t-butylphenol is reacted with acetyl chloride, using the conditions outlined in Example 3 above, to give 2n-propyl-4-acetyl-6-t-butylphenol. This compound is then converted to 2-n-propyl-4-(6'-heptynoyl)-6-t-butylphenol according to the following procedure:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.C1COCC1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:23]([CH3:24])[CH3:22])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 63 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (500 mg, 1.7 mmol) in methanol (14 mL) and THF (28 mL) was added dimethylamine hydrochloride (277 mg, 3.4 mmol), acetic acid (22 mg, 0.4 mmol) and NaCNBH3 (158 mg, 2.7 mmol). The mixture was stirred at 63° C. overnight. Then the resulting mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (15 mL). The mixture was washed with brine and the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 367 mg (32%) of [2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]dimethyl-amine as a trifluoroacetate salt.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]O)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:37][C:38]3[NH:42][C:41]4[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=4[N:39]=3)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][O:4]1)[CH3:2]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCC1(CCOc2ccnc(CO)c2C)OCC2(CO1)OCCO2
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a THF (10 ml) solution of the (4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methanol (560 mg, 1.65 mmol) obtained in the step (4g), triethylamine (0.48 ml, 3.44 mmol) was added at room temperature and thereafter, methanesulfonyl chloride (0.19 ml, 2.45 mmol) was added while cooling in an ice salt bath and stirred under the same conditions for 30 minutes. After the ice salt bath was removed, 2-mercaptobenzimidazole (248 mg, 1.65 mmol) was added and stirred at room temperature for 22 hours. After the reaction mixture was concentrated, NH silica gel was added to the residue and dried. The crude substance was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0, 1/1-0/1 gradient) and a desired fraction(s) was concentrated. The obtained foamy product was dissolved in chloroform and diethyl ether was added thereto. The resulting solid was collected by filtration to obtain the title compound (410 mg, yield: 52.7%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]#[N:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].Cl.C(N(CC)CC)C.[N-:41]=[N+:42]=[N-:43].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:43][N:42]=[N:41][N:31]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCCc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45.4 %

Procedure:
A suspension of the product of Example 206 (200 mg, 0.46 mmol), triethylamine hydrochloride (630 mg, 4.6 mmol) and NaN3 (299 mg, 4.6 mmol) in toluene (20 mL) was heated to toluene reflux for 60 h. Preparative HPLC afforded the title compound 100 mg (45%). LC-MS: 479.0 (WM+, m/z), 1.82 (Rt, min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=Cc1c[nH]c2c(F)cccc12
Product: Cn1cc(C=O)c2cccc(F)c21
Yield: 43 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the ethyl indole-2-carboxylate, the title compound (0.23 g, 43%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([CH2:4][O:5][C:6]2[CH:32]=[CH:31][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C@@H:21]([NH2:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl [(1S)-2-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (41.4 g) in ethyl acetate (200 mL) was added 4M hydrogen chloride/ethyl acetate (200 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr and concentrated. The obtained residue was recrystallized from hexane/ethanol to give the title compound (17.5 g) as white crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12]1.Cl>O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH:13]([CH3:14])[CH2:12][C:11]([OH:16])=[O:15]
Reactant: CC1CC(=O)O1
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)Oc1cccc(F)c1
Temperature: 23 °C

Procedure:
To a solution of 35.72 g (0.893 mol) sodium hydroxide in 357 ml water was added 100 g (0.893 mol) 3-fluorophenol. The reaction was heated to reflux and to the gently refluxing solution was added 72.8 ml (0.893 mol) beta-butyrolactone dropwise over 1.5 hours. The reaction was cooled to 23° C. and the pH brought to 2 with concentrated hydrochloric acid. The reaction was extracted with 300 ml diethyl ether and the ether layer was separated, washed with brine and then extracted with 3×200 ml saturated sodium bicarbonate. The combined bicarbonate layers were washed with 200 ml diethyl ether, acidified with 50 ml concentrated hydrochloric acid and extracted with 300 ml diethyl ether. The latter ether extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the product as a red oil, 31.6 g (17.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.C(O[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=O)CCC(C)=O>>[C:20]([O:22][CH:23]([O:22][C:20](=[O:21])[CH2:19][C:23]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[NH:9][C:24]=1[CH3:25])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:21])[CH3:19]
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CCC(=O)OCC(=O)OCc1ccccc1
Product: COc1ccc2[nH]c(C)c(CC(=O)OC(OC(C)=O)c3ccccc3)c2c1

Procedure:
condensing 4-methoxyphenylhydrazine or its salts with benzyl levulinoyloxyacetate according to Fischer to form (5-methoxy-2-methyl-3-indoleacetoxy)-benzyl acetate, subsequently acylating the alkali salt thereof with p-chlorobenzoyl chloride to form [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indole-acetoxy]-benzyl acetate and then catalytically dehydrogenating the benzyl group (see reaction scheme A),
Reaction SMILES: [Cl:1][C:2]1[C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4]OS(C)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:4][C:3]1[C:2]([Cl:1])=[C:13]([N:14]([CH3:16])[CH3:15])[CH:12]=[CH:11][CH:10]=1)=[N+:18]=[N-:19]
Reactant: CN(C)c1cccc(COS(C)(=O)=O)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1cccc(CN=[N+]=[N-])c1Cl
Temperature: 60 °C

Procedure:
Methanesulfonic acid 2-chloro-3-dimethylamino-benzyl ester was placed in a round bottomed flask with DMF (8 mL). Sodium azide (0.35 g, 5.38 mmol) was added and the reaction was heated to 60° C. for 3 h. The reaction was cooled to rt, and the solvent was removed in vacuo. The residual crude material was purified by column chromatography using hexanes/ethyl acetate (1:1) as eluent to afford (3-azidomethyl-2-chloro-phenyl)-dimethyl-amine
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C([O-])(O)=O.[Na+]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:25])=[O:19])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCCO)CC1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=C1CCCN1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)O)CC1

Procedure:
A solution of 95 (1.14 mmol) in acetone (5 ml) was cooled to -15° and treated with Jones reagent until the color remained amber/brown. The reaction mixture was diluted with saturated NaHCO3 solution to pH 9 and this was extracted with EtOAc. The aqueous phase was acidified to pH 3 with KHSO4 solution and extracted with several portions of EtOAc. The combined organic extracts were dried (MgSO4) and the, solvent removed to give 96. Rf 0.3 (silica gel, 9/1/1 CH2Cl2 /MeOH/HOAc).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:31]([O:30][C:28]([NH:2][CH:3]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:29])[CH3:32]
Reactant: COC(=O)C(N)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(C(=O)OC)C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of methyl 2-amino-3,3-diphenylpropanoate hydrochloride (Example 1a, 28.0 g, 96 mmol), chloroform (250 ml), and 1.0M sodium carbonate (250 ml) was added ethyl chloroformate (9.20 ml, 96 mmol). After the solution had been stirred for 18 h the organic phase was separated, washed with 10% citric acid, water, saturated brine and dried (MgSO4). After removal of the solvent in vacuo the residue was recrystallised from hot methanol to give methyl 2-ethoxycarbonylamino-3,3-diphenylpropanoate, m.p.=107°-109° C. 1H NMR (250 MHz, CDCl3) δ7.18-7.33 (10H, m), 5.12 (1H, br t, J=8.5 Hz), 4.95 (1H, br d, J=8.5 Hz), 4.40 (1H, d, J=8.0 Hz), 4.06 (2H, q, J=7.0 Hz), 3.50 (3H, s), 1.17 (3H, t, J=7.0 Hz). m/z (CI+) 328(MH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](=O)[C:11](=[O:16])[C:12]=2[O:13]CC)=[C:4]([OH:18])[C:3]=1[S:19]([CH3:22])(=[O:21])=[O:20].[S:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:16])[C:10]=2[NH:28][CH:25]2[CH2:26][CH2:27][S:23][CH2:24]2)=[C:4]([OH:18])[C:3]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(C)(=O)=O)c2O)c(=O)c1=O
Reactant: NC1CCSC1
Solvent: CCO
Product: CS(=O)(=O)c1c(Cl)ccc(Nc2c(NC3CCSC3)c(=O)c2=O)c1O

Procedure:
The title compound is prepared from 3-(4-chloro-2-hydroxy-3-methanesulfonyl-phenylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione analogously to 6-chloro-2-hydroxy-N,N-dimethyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesulfonamide (Example 3) by replacing (R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamine p-toluenesulfonate salt with tetrahydrothiophen-3-ylamine. The reaction is carried out in EtOH. The title compound is obtained. MH+ 403.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[C:9]([OH:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]3[CH:13]([CH3:17])[C:14](=[O:16])[O:18][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C(=O)O)c1ccc(C2CCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1C(=O)Oc2cc(C3CCCCC3)ccc21

Procedure:
5g of 2-(4-cyclohexyl-2-hydroxyphenyl)- propionic acid are heated at reflux in a water separator for 2 hours in the presence of 50 mg of p-toluenesulphonic acid in 200 cc of toluene. The solution is concentrated by evaporation and the residue is chromatographed on 500 g of silica gel. Elution with methylene chloride yields pure 6-cyclohexyl-2,3-dihydro-3-methylbenzofuran-2-one having an M.P. of 87-89° after crystallization from petroleum ether.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:16])([CH3:15])[C:13]#[CH:14]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:13]([C:12]([CH3:16])([CH3:15])[CH3:11])=[CH:14][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)c1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), 3,3-dimethyl-1-butyne (0.556 ml, 4.51 mmol), Cp*RuCl(PPh3)2 (50 mg, 0.063 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 4 hours; yield, 0.54 g (83%). EI-MS: m/z 216 [M+1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(CCO)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
4-(2-Hydroxyethyl)benzonitrile (200 mg, 1.35 mmol) in tetrahydrofuran (4 mL) was mixed with 4-methylbenzene-1-sulfonyl chloride (389 mg, 2.04 mmol) and triethylamine (569 μL, 4.08 mmol) and stirred at room temperature for 1 day. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1→1/1 (v/v)) to give the title compound as a colorless solid (174 mg, yield 43%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1)#[CH:2].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]3[S:4][C:5]([CH3:8])=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#Cc1ccc(C)s1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(C)s3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Ethynyl-5-methylthiophene (176 mg, 1.442 mmol) and diisopropylamine (0.475 mL, 3.39 mmol) were added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (420 mg, 0.721 mmol; prepared as described in example 34) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (11.0 mg, 0.0576 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25.3 mg, 0.0361 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 19:1) yielding methyl (E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]acetate as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][C:35]3[N:36]=[CH:37][S:38][C:34]=3[CH:33]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:38]1[C:34]2[CH:33]=[C:32]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N:18]5[CH2:22][CH2:21][CH2:20][C@@H:19]5[CH3:23])[N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[CH:40]=[CH:39][C:35]=2[N:36]=[CH:37]1
Reactant: CC1(C)OB(c2ccc3ncsc3c2)OC1(C)C
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc4ncsc4c3)nn3ccnc23)n1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.15 g, 0.456 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.119 g, 0.456 mmol), Pd2(dba)3 (0.052 g, 0.09 mmol), X-phos (0.087 g, 0.18 mmol) and Na2CO3 (0.145 g, 1.368 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 15 g, 200-300 mesh, ethyl acetate:petroleum ether=1:5) to afford (S)-6-(benzo[d]thiazol-6-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (58 mg, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.71 (s, 1H), 9.49 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H), 8.23-8.08 (m, 3H), 7.66 (s, 1H), 7.43 (t, 1H, J=7.8 Hz), 6.74 (d, 1H, J=7.8 Hz), 6.06 (d, 1H, J=7.8 Hz), 4.26-4.23 (m, 1H), 3.59-3.55 (m, 1H), 3.44-3.40 (m, 1H), 2.08-1.98 (m, 3H), 1.69-1.66 (m, 1H), 1.09 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 428, tR=1.997 min, HPLC: 95.07% at 214 nm, 98.34% at 254 nm, tR=4.349 min.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([C:11]1[O:15][N:14]=[C:13]([CH:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:19][N:18]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH2:17]2)[N:12]=1)[CH3:10])(C)(C)C>O1CCOCC1>[ClH:1].[NH2:8][C@H:9]([C:11]1[O:15][N:14]=[C:13]([CH:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[CH2:19][N:18]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH2:17]2)[N:12]=1)[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.11 ml (0.45 mmol) of a 4N solution of hydrogen chloride in dioxane was added to a solution of 25 mg (0.05 mmol) of the compound from Example 88A in 0.2 ml of dioxane. The reaction mixture was stirred at room temperature for 20 hours. The mixture was then concentrated to dryness under reduced pressure and dried until the weight remained constant. Yield: 20 mg (93% of theory).