Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][O:30][CH3:31])C1C=CC=CC=1.C1CCCCC1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH2:29][O:30][CH3:31]
Reactant: CCCOc1ncnc(COCc2ccccc2)c1-c1ccc(OC)cc1OCOC
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCCCC1
Product: CCCOc1ncnc(CO)c1-c1ccc(OC)cc1OCOC

Procedure:
A solution of 6-benzyloxymethyl-5-(2-methoxymethoxy-4-methoxyphenyl)-4-propoxy-pyrimidine (3.41 g, 8.04 mmol), cyclohexane (35 ml), Pd(OH)2 (3.4 g) and ammonium formate (3.4 g) in ethanol (100 ml) was kept at reflux for 3 d. After cooling the mixture was filtered through celite and concentrated to an oil. (2.42 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][O:19][CH3:20])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][O:19][CH3:20])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: CO
Product: COCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP12), chlorination of 1-iodo-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (720 mg; 1.274 mmol) and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (254 mg; 42%). LC-MS: tR=1.09 min.; [M+H]+=474.42 g/mol.
Reaction SMILES: [CH2:1]([N:3]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)[CH3:2].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([CH3:18])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)ccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1ccc(C)c2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.6 %

Procedure:
To a solution of ethyl 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxylate (2.12 g) in tetrahydrofuran (15 ml)-methanol (15 ml) was added an aqueous solution (5 ml) of 85% potassium hydroxide (1.0 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxylic acid (2.0 g, yield quantitative) as a colorless amorphous solid. To a mixture of the obtained solid (2.0 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.0 g) and N,N-dimethylformamide (20 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.3 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, and washed successively with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-3:1) to give the title compound (2.0 g, yield quantitative) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]1=[O:17])[CH:2]=[CH2:3].[C:18]([O:22][C:23](=[O:32])[NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1I)([CH3:21])([CH3:20])[CH3:19].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]=[CH:2][CH2:3][C:30]2[CH:29]=[N:28][CH:27]=[CH:26][C:25]=2[NH:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:32])[C:5](=[O:17])[CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Reactant: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccncc1CC=CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-Allyl-4-(tert-butyloxycarbonyl)-piperazin-2-one (0.49 g, 2.0 mmol) is treated with (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (0.64 g, 2.0 mmol), Pd(OAc)2 (14 mg, 0.06 mmol), P(o-tol)3 (37 mg, 0.12 mmol), and Et3N (0.56 mmol) in a seal tube. The mixture is stirred at 100° C. overnight, then diluted with CH2Cl2 and washed H2O (2×). The CH2Cl2 layer is concentrated and the residue is chromatographed (5% MeOH/CH2Cl2) to give a mixture of two isomers (0.40 g, 0.92 mmol). The mixture is separated into its constituent isomers upon further chromatography (EtOAc) to give 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.21 mmol, higher Rf value) and 4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-allyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester_(0.24 g, 0.56 mmol, lower Rf value). For the former: MS m/z 433 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.38 (d, 1H), 8.28 (s, 1H), 7.93 (d, 1H), 7.48 (d, 1H), 6.67 (s, 1H), 5.10 (m, 1H), 4.15 (s, 2H), 3.70 (t, 2H), 3,46 (t, 2H), 3.39 (d, 2H), 1.48 (s, 9H), 1.45 (s, 9H). For the latter: MS m/z 433 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.39 (s, 1H), 8.37 (d, 1H), 7.98 (d, 1H), 6.77 (s, 1H), 6.52 (d, 1H), 6.07 (m, 1H), 4.23 (d, 2H), 4.12 (s, 2H), 3,69 (t, 2H), 3.40 (t, 2H), 1.52 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:24][CH2:25][CH3:26])[N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:24][CH2:25][CH3:26])[N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCn1nc(C(=O)c2cccc(OC)c2)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCn1nc(C(=O)c2cccc(O)c2)c2cccc(C(F)(F)F)c21
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A solution of (3-methoxyphenyl)[1-propyl-7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.24 g, 0.66 mmol) in 10 mL of CH2Cl2 containing 0.2 mL cyclohexene was cooled to −78° C. under an argon atmosphere. Boron tribromide (0.25 mL, 2.65 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched by the careful addition of methanol. The reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The solvents were removed in vacuo and the residue purified by flash chromatography to give 0.077 g of the title compound (mp 118° C.) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]=O)=[CH:5][CH:4]=1)#[N:2].O.[CH3:15]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH:12]=[CH2:15]
Reactant: N#Cc1ccc(CCCC=O)cc1
Reactant: COC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of 6.5 g of methyl-triphenylphosphonium bromide in 50 ml of t-butyl methyl ether was treated with 2.1 g of potassium t-butylate at -5° C. and the mixture was then stirred at room temperature for 40 minutes. Subsequently, the mixture was treated at 0° C. with a solution of 2.6 g of 4-(p-cyanophenyl)butyraldehyde in 30 ml of t-butyl methyl ether and the resulting mixture was stirred for 1 hour at room temperature. Thereafter, the reaction mixture was treated with water and extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated. The crystalline residue was dissolved in hot ethyl acetate, the solution was treated with petroleum ether and the precipitated triphenylphosphine was filtered off. The oil obtained after concentrating the filtrate was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 5:95), whereby 1.92 g of p-(4-pentenyl)benzonitrile were isolated as a light yellowish liquid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:42]([CH2:41][CH3:2])[CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:44]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 44.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-N′-methyl-1,2-ethanediamine (130 mg, 1.0 mmol) for N-methylethanamine to afford 30.0 mg of the title compound (44.5%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1.[CH3:26][C:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29](C(OC(C)(C)C)=O)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:26][C:27]1[NH:28][N:29]=[CH:30][C:31]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
tert-Butyl (1R,3S,4S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.03 g) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.49 g), sodium carbonate (768 mg), 1,2-dimethoxyethane (8.0 mL) and water (4.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (197 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (690 mg) as a pale-yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.C(OC(=O)C)C.O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
5 g (22.7 mmol) of 4-iodophenol are added to a suspension of 75% sodium hydride (872 mg; 27.25 mmol) in 20 ml of dimethylformamide. The mixture is stirred for 30 minutes at room temperature and 2.59 ml (34.1 mmol) of methoxymethyl chloride are then added. The solution is stirred for 2 h and the medium is then poured into an ethylacetate/water mixture. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. 5.74 g (96%) of a colourless oil are obtained.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][CH:70]=[CH:71][C:72]=2[CH3:73])[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][CH:70]=[CH:71][C:72]=4[CH3:73])[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccncc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccncc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.104 g, 0.39 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-3-yl)quinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.079 g, 0.82 mmol) in toluene (3.3 mL) at 120° C. for 19 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(4-methylpyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (1H, d, J=5.1 Hz), 8.48 (1H, br. s), 7.78 (1H, d, J=5.7 Hz), 7.65 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.51 (1H, ddd, J=13.3, 9.2, 2.5 Hz), 7.41 (1H, d, J=5.1 Hz), 6.34 (1H, s), 3.74 (1H, br. s), 3.65 (4H, app t, J=4.3 Hz), br. s.), 3.19 (2H, br. s), 2.96 (4H, app t, J=5.0 Hz), 2.2 (2H, br. s), 2.15 (3H, s), 1.87 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1.[Br-].[CH3:26][C:27]1[N:32]=[C:31]([Zn+])[CH:30]=[CH:29][CH:28]=1.C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]=4)=[CH:3][C:4]=3[O:23][CH3:24])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Cc1cccc([Zn+])n1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3OC)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3OC)c(C)nc12
Temperature: 65 °C
Yield: 31 %

Procedure:
To a flask containing 3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.49 mmol) and PdCl2(dppf) (0.018 g, 0.024 mmol) is added a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (3.0 mL, 1.47 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.066 g, 1.57 mmol, 31%). 1H NMR (CDCl3) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.50 (s, 3H), 2.51 (s, 3H), 2.55 (s, 3H), 3.26-3.37 (m, 1H), 3.90 (s, 3H), 6.63 (s, 1H), 6.99 (d, J=7.4 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.54 (dd, J=7.4, 7.7 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4OS (M+H)+: 421.6; found: 422.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)cc2)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]C(C)=C)=[O:6])=[N+:2]=[N-:3].[CH3:11][S:12](O)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:11][S:12]([O:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)O
Reactant: C=C(C)OC(=O)CN=[N+]=[N-]
Solvent: ClCCl
Product: CS(=O)(=O)OC(=O)CN=[N+]=[N-]
Reaction time: 3 h

Procedure:
Isopropenyl azidoacetate (1.41 g, 0.01 mole) and anhydrous methanesulfonic acid (0.96 g, 0.01 mole) in 15 ml of methylene chloride is allowed to stand at room temperature for three hours. The solvent is removed in vacuo to give azidoacetyl methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27]OS(C3C=CC(C)=CC=3)(=O)=O)[O:24][C:23]2=[O:39])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[N-:40]=[N+:41]=[N-:42].[Na+].CCOC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][N:40]=[N+:41]=[N-:42])[O:24][C:23]2=[O:39])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3cc(F)c(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)C(=O)O2)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Temperature: 60 °C
Yield: 98.3 %

Procedure:
The [[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate (29.661 g, 52 mmol) was dissolved in dry DMF (125 mL) and then treated with solid NaN3 (10.19 g, 156 mmol) at room temperature. The reaction was heated to 60° C. for three hours and then allowed to cool to room temperature overnight under N2. The reaction was found to be complete by TLC (30% EtOAc/hexane, run twice, UV short wave). The reaction mixture was concentrated in vacuo to give a cream colored solid. The crude product was dissolved in 600 mL EtOAc and then washed with both H2O (2×500 mL) and brine (500 mL). The aqueous portions were back-extracted with more EtOAc (2×400 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to yield 22.41 g (91%) of the title compound as a pale yellow solid with mp 115°-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(O)CO.COC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: COC
Solvent: c1ccncc1
Solvent: OCCO
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(NS(C)(=O)=O)c1
Yield: 91.5 %

Procedure:
To a stirred solution of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol) in anhydrous ethylene glycol, dimethyl ether (5 ml) was added portionwise, over a few hours, pyridine (0.228 ml, 2.82 mmol) and methanesulphonyl chloride (0.174 ml, 2.25 mmol), and the mixture was heated at 50° C. for 1.5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to leave 0.1119 g (92%) of the title compound as a yellow solid; mp 332-341° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.28 (3H, s), 3.06 (3H, s), 7.24 (2H, dd, J 7.9, J′1.8 Hz), 7.40 (1H, m), 7.43 (2H, d, J 9.0 Hz), 7.46 (1H, t, J 8.0 Hz), 8.13 (2H, d, J 9.0 Hz), 8.56 (1H, s); MS (ES+) m/z 429/431[MH]+. Anal. found: C, 55.89; H, 4.06; N, 12.60. C20H17CLN4O3S.0.2H2O requires: C, 55.54; H, 4.06; N, 12.95%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15].C[Si]([Br:20])(C)C>>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15]
Reactant: C[Si](C)(C)Br
Reactant: O=C1N(c2ccccc2CO)CC1(F)F
Product: O=C1N(c2ccccc2CBr)CC1(F)F
Yield: 25 %

Procedure:
60 mg (0.28 mmole) of compound 4a are treated with 4 equivalents (0.15 ml) of trimethylsilylbromide at ambient temperature for 35 min. The compound obtained is purified by silica gel plate chromatography using an ether:pentane mixture (1:6). This gives 16 mg of compound 5d corresponding to a 25% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14]I)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:29]1[CH:28]=[CH:27][C:26]([N:32]2[CH2:33][C:34](=[O:45])[N:35]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[S:36]2(=[O:38])=[O:37])=[C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:30]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1CI
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from ((1R*,2R*)-2-iodomethylcyclohexyl)-carbamic acid tert-butyl ester and 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one analogous to the method used in Example 57, step B.