Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1SC=CC=1.Br[C:8]1[S:12][C:11]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.CCN(CC)CC.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>C1COCC1.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.[Cu]I>[F:15][C:14]([F:17])([F:16])[C:13]([C:11]1[S:12][C:8]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:9][CH:10]=1)=[O:18]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccc(Br)s1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Brc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C(=O)C(F)(F)F)s1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-thiophene Example 3, C2 (1.0 eq), Pd(PPh3)2Cl2 (0.025 eq), CuI (0.05 eq) and Et3N (28.7 eq) in THF (0.25 M) was degassed with a stream of Ar for 30 min. Trimethylsilylacetylene (1.5 eq) was added and the mixture was stirred O/N at RT. Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica using 0-5% EtOAc/Petroleum ether to yield the desired compound as a yellow oil. 1H NMR (300 MHz, CDCl3, 300K) δ 7.83-7.78 (1H, m), 7.25 (1H, bs), 0.28 (9H, s).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][N:7]([CH3:37])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([CH:30]([CH2:35]O)[C:31]([O:33][CH3:34])=[O:32])[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:11]=1)=[O:9].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:37][N:7]([CH3:6])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:21]=[C:20]3[O:22][C:23]4[C:28]([CH:29]([C:30](=[CH2:35])[C:31]([O:33][CH3:34])=[O:32])[C:19]3=[CH:18][CH:17]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=1)=[O:9]
Reactant: COC(=O)C(CO)C1c2ccccc2Oc2nc(-c3ccc(C(=O)N(C)C)cc3)ccc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C(=O)OC)C1c2ccccc2Oc2nc(-c3ccc(C(=O)N(C)C)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Methanesulfonyl chloride (0.072 mL, 0.925 mmol) was added to a mixture of the product from Step 2 (80 mg, 0.185 mmol), TEA (0.258 mL, 1.85 mmol) and DMAP (24.9 mg, 0.203 mmol) in DCM (2 mL) at 0° C. After 1 h at this temperature, the mixture was concentrated in vacuo. The residue was suspended in benzene (4 mL), treated with DBU (0.139 mL, 0.925 mmol) and stirred at room temperature for 1 h. Saturated NaHCO3 (5 mL) and ethyl acetate (100 mL) were added. The mixture was washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 50-100% ethyl acetate in hexanes) to provide methyl 2-(2-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)acrylate (45 mg, 59%). MS (ES+) m/z: 415 (M+H); HPLC retention time: 1.73 min (Analytical HPLC Method F).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:44]=[CH:43][C:42]4[CH2:41][CH2:40][CH2:39][NH:38][C:37]=4[N:36]=3)[CH2:31][CH2:30]2)[N:25]=[C:24]([O:45][CH3:46])[N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:44]=[CH:43][C:42]4[CH2:41][CH2:40][CH2:39][NH:38][C:37]=4[N:36]=3)[CH2:31][CH2:30]2)[N:25]=[C:24]([O:45][CH3:46])[N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)O)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1

Procedure:
200 mg (0.317 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{2-methoxy-5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl)-pyrimidin-4-ylamino}-propionate in 10 ml of dichloromethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silica gel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. 170 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:21][C:20](=O)[NH:19][C:18]1=O>C1COCC1>[CH3:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1
Reactant: Cc1ccc2[nH]cc(C3CC(=O)NC3=O)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(C3CCNC3)c2c1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (7.9 g, 200 mmol) in dry THF (380 mL) was stirred for 20 min. at RT under nitrogen atmosphere. 3-(5-Methyl-1H-indol-3-yl) pyrrolidine-2,5-dione (9.5 g, 41 mmol) was added portionwise and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, quenched with aqueous sodium sulfate, and filtered. The solid was rinsed with THF and the THF layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (25% MeOH/DCM/ammonia) to afford the title compound. Yield: 4.2 g, 49.2%.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[C:5]3=[N:4][CH:3]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: NS(=O)(=O)c1ccc(CNc2nccn3c(Br)cnc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(CNc2nccn3c(-c4ccc(O)cc4)cnc23)cc1
Temperature: 130 °C

Procedure:
To a 5 mL microwave tube is added 4-[(3-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide (0.14 g, 0.379 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.084 g, 0.417 mmol), Na2CO3 (0.1 g, 0.95 mmol), Pd(OAc)2 (approx. 7 mg, 0.028 mmol), and (oxidi-2,1-phenylene)bis(diphenylphosphine) (20 mg, 0.038 mmol). The mixture is suspended in DMF (3 mL) and water (1 mL) and the vessel is sealed under a nitrogen atmosphere. The reaction vessel is heated to 130° C. in the CEM microwave for 20 min then allowed to cool and filtered through Celite and washed with EtOAc. The filtrate is evaporated and the residue taken up in DMSO and purified by prep HPLC. The product, 4-{[3-(4-Hydroxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide, is obtained as a white solid (32 mg, 19%) (LC-MS m/z 396 [M+H]+).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](Cl)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3]
Reactant: C1CNCCN1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 42.8 %

Procedure:
A mixture of 0.3 g (1.01 mmole) 1-(1,1-dimethylethyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 0.3 g (3.48 mmoles) piperazine in 1 mL pyridine was heated under reflux for 18 hours. After cooling the mixture was concentrated under reduced pressure. The residue was poured in 10 mL of 10% acetic acid. After filtration of little insoluble the solution was taken to pH 6.5, saturated with brine and extracted three times with dichloromethane. After evaporation the resulting solid obtained was purified in water to give 0.15 g of 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-piperazinyl-4-oxo-3-quinolinecarboxylic acid purified as in method 1.
Reaction SMILES: C([N:8]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[N:9]1)C1C=CC=CC=1.C(O)(=O)C.C([O-])=O.[NH4+].C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:23][CH:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:12]2[NH:8][N:9]=[CH:10][CH:11]=2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CC(C)Oc1ccc(Nc2ccnn2Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Nc2ccn[nH]2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a suspension of 1-benzyl-N-[4-(1-methylethoxy)phenyl]-1H-pyrazol-5-amine (0.80 g) and palladium hydroxide (10 wt %, 0.80 g) in ethanol (4.5 mL)-acetic acid (0.5 mL) was added ammonium formate (0.49 g) at 80° C. After stirring at 80° C. for 2 hr, the mixture was allowed to cool, ethyl acetate was added, and the insoluble material was filtered off. Saturated aqueous sodium hydrogen carbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.37 g, 66%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([CH:22]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([CH:22]=1)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
Sodium hydride (210 mg) was suspended in DMF (10 mL), and the suspension was cooled to 0° C. and thereto were added benzyl alcohol (568 mg) and a solution of 5-chloro-N,N-dimethyl-2-nitrobenzamide (1.00 g) in DMF (2 mL). The mixture was stirred at 50° C. for 0.5 hour and then concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→2:3) to give 5-benzyloxy-N,N-dimethyl-2-nitrobenzamide (1.18 g)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][N:4]([C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:5][CH2:6]2)[NH:13][CH:14]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(Nc1c[nH]c2nccc(N3CCNCC3)c12)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2ccnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 2 h
Yield: 46.7 %

Procedure:
Crude N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri din-3-yl)nicotinamide (0.025 g, 0.058 mmol, see Example 50), 2-(tert-butoxycarbonylamino)acetic acid (0.0111 g, 0.0637 mmol), HOBT-H2O (0.0124 g, 0.0811 mmol) and EDCI (0.0144 g, 0.075 mmol) were placed in DCM (3 mL). DIEA (d 0.742; 0.0504 mL, 0.290 mmol) was then added. The reaction was stirred for 2 hours and quenched with saturated Na2CO3. The mixture was then extracted with DCM. The organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (500:20-500:30) to give tert-butyl 2-(4-(3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (0.013 g, 46.8% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH:4]1[CH2:10][CH3:11])[CH3:2]
Reactant: CCC1CC(=O)CCN1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1CC(O)CCN1CC

Procedure:
In a manner similar to Preparation 5, react 1,2-diethyl-4-piperidone with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](I)=[CH:10][C:5]2=[CH:4][CH:3]=1.[Cu][C:13]#[N:14]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:13]#[N:14])=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc(I)sc2n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc2ccc(Cl)nc2s1
Temperature: 130 °C

Procedure:
A mixture of 6-Chloro-2-iodothieno[2,3-b]pyridine (80 mg, 0.27 mmol) and Copper (I) Cyanide (36 mg, 0.41 mmol) in DMF (3 mL) was heated to 130° C. for 16 hrs. LC showed formation of the title product. The crude reaction was adsorbed onto silica gel, and purified by flash chromatography to obtain the title product. LC-MS (IE, m/z): 195 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][N:16]2[CH:24]=1.C[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=CC=CC=2)[C:27]=1C1N=C2C=C(C(O)=O)C=CN2C=1>>[O:30]1[CH2:26][CH2:27][CH:28]([NH:29][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:22])[CH2:31][CH2:36]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)NC3CCOCC3)ccc2n1
Yield: 76 %

Procedure:
As described for Example 17, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid (64 mg, 0.2 mmol), instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid, was converted to the title compound (61 mg, 76%) which was obtained as an off white solid. MS: m/e=403.5 [M+H]+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[S:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(Br)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
4.2 g (12.5 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (10.4 mmol, 1.0 eq) of 5-bromothiophene-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.1 g of methyl 3-(5-bromothiophen-2-yl)acrylate are obtained. Yield=82%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[N:6][CH:7]=1.P(Br)(Br)[Br:12].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]([Br:12])[CH3:9])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1cncc(Br)c1
Reaction time: 4 h
Yield: 43.4 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-ethanol (1.5 g, 7.4 mmol) is dissolved in DCM (70 mL) and phosphorus tribromide (0.73 mL, 7.4 mmol) is added. The mixture is stirred for 4 hrs and saturated NaHCO3 aqueous solution is used to adjust the pH to about 7. The mixture is then extracted with DCM (3×50 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 850 mg of 3-bromo-5-(1-bromo-ethyl)-pyridine.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:26])([F:25])[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:14])[N:6]=1.Cl>C1COCC1.CO.O>[F:25][C:4]([F:3])([F:26])[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])[N:6]=1
Reactant: COC(=O)CCNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reaction time: 0.5 h

Procedure:
A sodium hydroxide solution (0.2 mL, 5 M) was added to a solution of methyl 3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoate in THF/MeOH/water (4:1:1, 15 mL). The reaction was stirred for 30 min and acidified with 2 M HCl. The reaction was extracted with ethyl acetate several times, dried over sodium sulfate, and used crude. MS (ESI) m/z: Calculated for C13H10F3N3O4: 329.06. found: 330.1 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:13]([CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])[C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:3]2)[CH3:12]
Reactant: CCOc1ccc(NCc2cccc(C(=O)OC)c2)c(C=C(Br)Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(=O)OC)c1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 65.1 %

Procedure:
A suspension of methyl 3-{[2-(2,2-dibromovinyl)-4-ethoxyphenylamino]methyl}benzoate (258 mg), phenylboronic acid (134 mg), tris(dibenzylideneacetone)dipalladium (0) (25.1 mg), tris(2-methylphenyl)phosphine and potassium carbonate (381 mg) in toluene (5 mL) was stirred at 85° C. for 3.5 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (138 mg).
Reaction SMILES: [CH3:1][C:2](=[CH2:27])[CH:3]([N:8]1[C:11](=[O:12])[CH:10]([N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:9]1[S:24](Cl)=[O:25])[C:4]([O:6][CH3:7])=[O:5]>C(OCC)(=O)C>[C:17]1(=[O:18])[N:13]([CH:10]2[C:11](=[O:12])[N:8]3[CH:3]([C:4]([O:6][CH3:7])=[O:5])[C:2](=[CH2:27])[CH2:1][S:24](=[O:25])[C@H:9]23)[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl
Solvent: CCOC(C)=O
Product: C=C1CS(=O)[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N2C1C(=O)OC
Temperature: 0 °C
Yield: 27.4 %

Procedure:
Methyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoate (0.20 g.) was stirred in about 27 g. of polyphosphoric acid for 20 minutes. Ice water and ethyl acetate (25 ml.) was added to the reaction mixture. The organic layer was separated and washed successively with water, aqueous sodium bicarbonate, and brine, dried (MgSO4), and evaporated in vacuo to dryness to give methyl 7-phthalimido-3-methylenecepham-4-carboxylate 1-oxide (0.05 g.) as a white foam.
Reaction SMILES: C([CH:4]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]2[S:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[CH2:31][C:32]5[NH:36][N:35]=[N:34][N:33]=5)=[CH:19][C:17]=4[CH:18]=3)=[N:13][C:5]1=2)(=O)C.[OH-].[Na+].O.Cl>C(O)C>[N:13]1[C:5]2[CH2:4][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[S:11][C:12]=1[C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:19][C:17]=2[CH:18]=1
Reactant: CC(=O)C1CCCNc2sc(-c3cc4cc(OCc5ccccc5Cc5nnn[nH]5)ccc4o3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(Cc2nnn[nH]2)c(COc2ccc3oc(-c4nc5c(s4)NCCCC5)cc3c2)c1
Yield: 58.8 %

Procedure:
A mixture of 5-{2-[2-(8-acetyl-4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepin-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (65 mg) and 2N aqueous sodium hydroxide (0.65 ml) in ethanol (6 ml) was stirred under reflux for 4 hours. After being cooled, the resulting mixture was concentrated under reduced pressure to give residue. Water was added to the residue and adjusted to pH 3 with diluted aqueous hydrochloric acid. The appeared precipitates were collected by filtration and washed with water to give 5-{2-[2-(4,5,6,7-tetrahydro-8H-thiazolo[5,4-b]azepin-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (35 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH:3][CH3:4].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>[Pt](Cl)(Cl)(Cl)Cl.C=CCCCCCC.[Pt]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH:2]=[CH:3][CH3:4]
Reactant: C=CCOCC=CC
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: [Pt]
Solvent: C=CCCCCCC
Product: CC=CCOCCC[Si](OCC)(OCC)OCC
Temperature: 120 °C

Procedure:
About 84 g of allyl but-2-enyl ether are heated under reflux (about 120° C.) in a three-necked flask fitted with a reflux condenser, stirrer and dropping funnel. To this are added dropwise over a period of two hours a solution containing 82 g of triethoxysilane, in which 2 mg of platinum, calculated as the element, are dissolved in the form of a solution of platinum tetrachloride in 1-octene. After heating for an additional five hours under reflux, more than 99 percent of the Si-bonded hydrogen atoms have been converted. The intermediate obtained in this manner, (but-2-enyloxypropyl)triethoxysilane, is purified by distillation at 104° C. and at 7 hPa (abs.) and contains 5 percent by weight, based on the total weight of the intermediate, of (but-1enyloxypropyl)triethoxysilane.