Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([CH:18]=[CH2:19])[C:4]=1[CH3:20])#[N:2].C(N(CC)CC)C.[CH3:28][N:29]([CH3:35])[C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:32]2[CH2:33][CH2:34][C@H:30]([N:29]([CH3:35])[CH3:28])[CH2:31]2)=[C:5]([CH:18]=[CH2:19])[C:4]=1[CH3:20])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: C=Cc1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=Cc1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 70.3 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-vinyl-1,3-benzoxazole-2-carboxamide (I-185) (130 mg, 0.48 mmol) was dissolved in dimethyl sulfoxide (8 ml), then at room temperature, triethylamine (100 μl, 0.48 mmol) was added. The solution was gradually heated from room temperature up to 150° C. under nitrogen atmosphere, a solution of (3S)-3-(dimethylamino)pyrrolidine (79 μl, 0.62 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. The solution was stirred at the same temperature for 1.25 hours, and the cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=93:7) to obtain a roughly-purified product (124 mg). This was washed with diisopropyl ether to obtain the entitled compound (87 mg, 50%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[F:16])[N:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:11]=[CH:10]3)=[C:4]([F:25])[CH:3]=1.[C:26](=[NH:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[C:33]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:39][C:2]2[CH:24]=[CH:23][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][C:15]=3[F:16])[N:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:11]=[CH:10]4)=[C:4]([F:25])[CH:3]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)ccc1Oc1cc2cnn(C3CCCCO3)c2cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Fc1cc(N=C(c2ccccc2)c2ccccc2)ccc1Oc1cc2cnn(C3CCCCO3)c2cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The mixture of 5-(4-bromo-2-fluorophenoxy)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.97 g, 2.37 mmol), benzophenone imine (0.64 g, 3.56 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.10 g, 0.075 mol), Cs2CO3 (1.16 g, 3.56 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol) in 1,4-dioxane (20 mL) is purged with nitrogen, heated to 100° C. and stirred overnight. The reaction mixture is cooled to RT, extracted with EtOAc, washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered and concentrated (1.45 g). MS (m/z): 510 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[C:18]([Br:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:9])([CH3:6])[CH3:5].Cl>C1COCC1.[OH-].[Na+].CO>[Br:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:10]([C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[O:9])[CH:19]=1
Reactant: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1OCCOc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1cc(Br)c2ccccc2c1OCCOc1ccc(F)cc1)C(=O)O

Procedure:
61 mg 2-({4-bromo-1-[2-(4-fluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester in 0.5 ml THF, 0.36 ml of 2 M sodium hydroxide and 1.7 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After purification of the residue by RP-HPLC 27 mg of 2-({4-bromo-1-[2-(4-fluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid were obtained.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:6]=1)C.[OH-].[K+]>C(O)C>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]3[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:4]([OH:35])=[O:3])[N:16]4[N:17]=3)=[CH:22][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1

Procedure:
3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid ethyl ester (1.28 g, 2.71 mmol) was dissolved in ethanol (20 ml) and potassium hydroxide (0.45 g, 8.12 mmol) was added. The reaction was heated to reflux for 3 hrs. Upon cooling the solvent was removed in vacuo and aqueous sodium hydrogencarbonate added to the residue. The basic aqueous layer was washed with dichloromethane, then neutralised with 2M HCl and the resulting precipitate collected by filtration, washed with water and toluene, then dried under vacuum to give the desired product. Yield: 0.64 g, 53%. LCMS RT: 2.45 min, MI: 444, Method: 2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].CCN(C(C)C)C(C)C.[CH3:22][S-:23].[Na+]>C1COCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:23][CH3:22]
Reactant: C[S-]
Reactant: COc1cc([N+](=O)[O-])ccc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1SC
Yield: 68.4 %

Procedure:
2-Iodo-5-nitroanisole (5.58 g, 20.0 mmol), Pd2(dba)3 (0.025 eq, 457 mg), Xantphos (0.05 eq, 578 mg), Hunigs Base (1 eq, 3.48 ml) and sodium methanethiolate (1 eq, 1.40 g) were dissolved in THF. The mixture was heated to reflux overnight. Upon cooling the mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (4:1 Hexanes/Ethyl Acetate) to give 2-methoxy-1-methylsulfanyl-4-nitro-benzene (2.72 g, 68.3%) as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:14])[C:11](=[O:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:9][CH:10]([CH3:14])[C:11](=[O:13])[CH:12]=[CH:17][N:18]([CH3:20])[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(C)OC(=O)c1ccccc1
Product: CC(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Reaction time: 8 h

Procedure:
A mixture of 3-benzoyloxybutan-2-one (15.5 g) and dimethylformamide dimethylacetal (14.4 g) was heated on a steam bath for 2 hours 30 minutes. The solvent was removed from the mixture under reduced pressure. Petroleum ether (b.p. 60°-80° C.) was added to the residue, with shaking and the ether layer separated from an insoluble red oil. Further petroleum ether was added to the oil with shaking and excess ether was removed under reduced pressure to give a red-brown oil which partially crystallised on standing overnight. Petroleum ether was added and the solid was collected by filtration and washed with petroleum ether to give a yellow crystalline solid of 4-benzoyloxy-1-dimethylamino-1-penten-3-one. Yield 5.6 g. The solid was used directly without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:21]=[N:22][C:23]([N:27]([CH3:29])[CH3:28])=[CH:24][C:25]=1[CH3:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:21]=[N:22][C:23]([N:27]([CH3:29])[CH3:28])=[CH:24][C:25]=3[CH3:26])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2cnc(N(C)C)cc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCO)c12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
A mixture of the resulting thiourea (3.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.28 g, 6.66 mmol), and triethylamine (0.93 mL) in tetrahydrofuran (30 mL) was stirred at 50° C. for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (2.20 g, 5.26 mmol, 34% in 2 steps).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[F:23])=[O:6].[OH-].[NH4+:26]>C1COCC1>[F:23][C:9]1[CH:10]=[C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C

Procedure:
A solution of N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester (150 mg, 0.45 mmol) and ammonium hydroxide (2.0 mL) in THF (1.0 ml) in a sealed tube was heated at 55° C. for 6 h. After cooling to room temperature the mixture was evaporated and the title compound (60 mg, 42%) was purified by trituration from diethylether. MS: m/e=321.2 (M++H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12](S(C)(=O)=O)=[CH:11][C:10]=3Cl)[N:7]=[CH:6][C:5]=2[C:20]([OH:22])=O)[CH2:3][CH2:2]1.[NH2:23][C:24]([NH2:26])=[NH:25]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:10]=3[CH:4]=[CH:5][CH:6]=[N:7]4)[N:7]=[CH:6][C:5]=2[C:20]([NH:25][C:24]([NH2:26])=[NH:23])=[O:22])[CH2:2][CH2:3]1
Reactant: N=C(N)N
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C(=O)O)c2C2CC2)c(Cl)c1
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-(2-chloro-4-methanesulfonylphenyl)-1H-pyrazole-4-carboxylic acid with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@H:10]([CH3:25])[CH2:9]1)C1C=CC=CC=1.Cl>CCO.[Pd]>[CH3:25][C@H:10]1[C@H:11]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CCOC(=O)c1cccc([C@@H]2CCN(Cc3ccccc3)C[C@H]2C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc([C@@H]2CCNC[C@H]2C)c1
Yield: 109 %

Procedure:
Ethyl 3-[(3S,4R)-1-benzyl-3-methylpiperidin-4-yl]benzoate (9 g, 26.7 mmol) was dissolved in EtOH: 1M HCl (1:1, 160 mL) and was hydrogenated at 50 psi in the presence of a catalytic amount of palladium on carbon (1 g) for 36 hr. Palladium was filtered through a celite plug and the filtrate was evaporated to dryness to give 7.2 g of ethyl 3-[(3S,4R)-3-methylpiperidin-4-yl]benzoate as an HCl salt.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1coc(N)n1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1coc(NC(C)=O)n1
Temperature: 25 °C

Procedure:
A mixture of 1 g (6.41 mmol) ethyl 2-aminooxazole-4-carboxylate and 9.1 ml (96.3 mmol) acetic acid anhydride are stirred at r.t. over night. The solvent is removed in vacuo. Toluene is added and evaporated. This procedure is repeated three times.
Reaction SMILES: [C:1]([O:5][C:6](=O)[CH2:7][NH:8][CH2:9][CH:10](OC)OC)([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24]([NH:26][C@H:27]([C:34]([OH:36])=[O:35])COC(C)(C)C)=O)C1C=CC=CC=1>>[C:1]([O:5][CH2:6][C@@H:7]1[NH:8][CH2:9][CH2:10][N:26]([CH2:27][C:34]([OH:36])=[O:35])[C:24]1=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CNCC(=O)OC(C)(C)C)OC
Product: CC(C)(C)OC[C@@H]1NCCN(CC(=O)O)C1=O

Procedure:
In substantially the same manner as in Reference Example 2, the title compound was synthesized from N(2,2-dimethoxyethyl) glycine tert-butyl ester and N-benzyloxycarbonyl-O-tert-butyl-L-serine. M.p. 178°-180° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1[CH:36]=[C:37]([C:41](=[O:43])[CH3:42])[CH:38]=[CH:39][CH:40]=1>CS(C)=O>[C:29]([N:27]1[CH2:26][CH2:25][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=[C:7]([NH:34][C:35]3[CH:36]=[C:37]([C:41](=[O:43])[CH3:42])[CH:38]=[CH:39][CH:40]=3)[C:8]=2[CH2:28]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CC(=O)c1cccc(N)c1
Solvent: CS(C)=O
Product: CC(=O)c1cccc(Nc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CN(C(C)=O)CC3)c1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) dispensed in a library plate. 1-(3-aminophenyl)ethanone (9.5 mg, 0.07 mmol) was added and it was left to shake overnight at 80° C. before filtered and purified by preparative HPLC to yield 1-(3-(6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)phenyl)ethanone (17.5 mg, 49%).
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:7].[CH:8]1[CH2:14][CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[CH:9]12[CH:8]=[CH:14][CH:13]([CH:12]3[CH:10]1[CH2:11]3)[CH:4]1[CH:3]2[C:2](=[O:7])[O:1][C:5]1=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: C1=CC=CCC=C1
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Temperature: 144 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
Furan-2,5-dione (5.32 g, 54.26 mmol) was partially dissolved in xylene (100 mL). Cyclohepta-1,3,5-triene (5 g, 54.26 mmol) was added. The reaction was stirred at 144° C. for 5 h. The mixture was allowed to cool to 25° C. and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in hexanes) afforded the desired products, rac-(1R,2R,6S,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (7.46 g, 39.22 mmol, 72%) and rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (0.88 g, 4.63 mmol, 8%), as white solids. 1H NMR (400 MHz, CDCl3) δ: exo: 0.27-0.42 (2H, m), 1.11-1.15 (2H, m), 3.25 (2H, t, J=1.6 Hz), 3.46-3.50 (2H, m), 5.89 (2H, dd, J1=4.8 Hz, J2=3.2 Hz); endo: 0.14-0.26 (2H, m), 1.12-1.16 (2H, m), 3.09 (2H, s), 3.40-3.44 (2H, m), 5.94 (2H, dd, J1=4.8 Hz, J2=3.2 Hz). LC-MS (ESI) calcd for C11H10O3 190.20, found exo 191.0; endo 191.3 [M+H+].
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[C:23]1[CH:55]=[N:54][C:26]2[NH:27][C:28]([C:33]3[C:34](=[O:53])[N:35]([CH2:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)[CH:36]4[CH:41]([C:42]=3[OH:43])[CH:40]3[CH2:44][CH:37]4[CH2:38][CH2:39]3)=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1.[Cl-].[NH4+]>CS(C)=O.ClCCl.[Cu](I)I.C(OCC)(=O)C>[F:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][N:35]2[C:34](=[O:53])[C:33]([C:28]3[NH:27][C:26]4[N:54]=[CH:55][C:23]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:24][C:25]=4[S:30](=[O:32])(=[O:31])[N:29]=3)=[C:42]([OH:43])[C@H:41]3[C@@H:36]2[C@H:37]2[CH2:44][C@@H:40]3[CH2:39][CH2:38]2)=[CH:47][CH:48]=1
Reactant: CS(N)(=O)=O
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)C2C3CCC(C3)C2N1Cc1ccc(F)cc1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cnc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 17.5 %

Procedure:
Methane sulfonamide (0.348 g, 3.66 mmol), potassium phosphate (0.078 g, 0.366 mmol), L-proline (0.021 g, 0.183 mmol) and copper iodide (0.035 g, 0.183 mmol) were combined and suspended in dimethylsulfoxide (0.5 mL). The flask was degassed and backfilled with argon. The mixture was heated, while stirring, at 110° C. for 5 min. 5-(7-Bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 62, 0.1 g, 0.183 mmol) was dissolved in dimethylsulfoxide (0.5 mL) and transferred to the reaction mixture. The mixture was stirred at 110° C. for 16 h. Upon cooling, the mixture was poured into ethyl acetate (150 mL) and saturated aqueous ammonium chloride solution (100 mL). The mixture was shaken and everything was passed through a plug of Celite. The organic layer was separated from the filtrate, washed with saturated aqueous ammonium chloride solution (50 mL), saturated aqueous brine solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to a brown waxy solid. Flash column chromatography (Merck silica gel 60, 40-63 μm; 0 to 50% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.018 g, 0.032 mmol, 17.5%), as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.04-1.52 (6H, m), 2.37-2.41 (1H, m), 2.53-2.56 (1H, m), 3.05 (3H, s), 3.25-3.34 (2H, m), 4.25 (1H, d, J=15.1 Hz), 4.93 (1H, d, J=15.0 Hz), 7.11 (2H, t, J=9.1 Hz), 7.27 (2H, dd, J1=8.7 Hz, J2=5.4 Hz), 7.81 (1H, s), 8.36 (1H, s), 10.01 (1H, bs). LC-MS (ESI) calcd for C24H24FN5O6S2 561.12, found 562.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:43][CH3:44])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:32]>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>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:43][CH3:44])[CH2:31][CH3:32])=[CH:35][CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Reactant: CCN(CC)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)cc3)c2)cc1
Yield: 102.3 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1 g of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (2 mmol) with 580 mg of 4-diethylaminophenylboronic acid (3 mmol) in the presence of tetrakis(triphenylphosphine)palladium. 1.15 g of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate (yield=100%) are obtained in the form of a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11](Br)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:10][C:9]=3[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c(Br)nc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: C1CCNCC1
Product: O=c1c2[nH]c(N3CCCCC3)nc2n(CC2CC2)c(=O)n1CC1CC1

Procedure:
The title compound was prepared from 1,3-di-cyclo-propylmethyl-8-bromo xanthine (1.2 g, 0.0037 mol) and piperidine (0.79 g, 0.009 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 215-216° C.). MS(ES+) m/z 228 ([M+1]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:19]([CH:17]([C:14]2[CH:15]=[N:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH3:18])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1ccc(C(C)N)cn1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1ccc(C(C)n2c(C)cc(O)cc2=O)cn1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A stirred mixture of 4-Hydroxy-6-methyl-2-pyrone (1.394 g, 11.1 mmol) and 1-(6-Methyl-pyridin-3-yl)-ethylamine (1.806 g, 13.3 mmol) in water (18 ml) was boiled under reflux for 65 h. The mixture was cooled to ambient temperature and the supernatant liquid was decanted off to leave a dark semi-solid residue. This was triturated with ethyl acetate to give 4-Hydroxy-6-methyl-1-[1-(6-methyl-pyridin-3-yl)-ethyl]-1H-pyridin-2-one as a grey solid (475 mg) which was used in the next step without further purification. LC-MS m/z 245 [M+H]+ Rt=1.21 min.