Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1([C:16](=[O:17])NC(=O)[NH:13]1)[CH2:8][CH2:7][CH2:6]2.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(=O)([O-])[O-:31].[NH4+].[NH4+]>O>[NH2:13][C:9]1([C:16]([OH:17])=[O:31])[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)CCCC21NC(=O)NC1=O
Agent: [Ba+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1)CCCC2(N)C(=O)O
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a suspension of 2.95 g (0.012 mol) of the product of Step A in 100 mL of water was added 15.1 g (0.0479 mol) of barium hydroxide octahydrate. The reaction was heated at reflux for 3 days. To the reaction mixture was carefully added 6.4 g (0.067 mol) of ammonium carbonate. Refluxing was continued for another 2 hours. The solid was filtered off while hot and the pH of the filtrate adjusted to 6. The filtrate was then concentrated to give 1.86 g of a tan solid: mp>250° C. 1H NMR (D2O) d 7.20 (d, 1H), 6.85 (d and s, 2H), 3.835 (s, 3H), 2.85 (t, 2H), 1.70-2.40 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[NH:4][C:5]([C:23](F)([F:25])[F:24])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:25][CH:23]([F:24])[C:5]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:28])([F:1])[F:27])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1CC(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1CC(C)C
Yield: 50.3 %

Procedure:
A mixture of 10.0 g (0.0240 mole) of diethyl 2,6-bis(trifluoromethyl)-l,4-dihydro-4-isobutyl-3,5-pyridinedicarboxylate, 3.65 g (0.0240 mole) of DBU and 150 ml of THF is held at reflux for 18 hours and concentrated. The residue is dissolved in ether and washed with diluted hydrochloric acid, dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 0.1 torr to give 4.80 g (50%) of the desired product as an oil, nD25 1.4436.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of 75B (96 mg, 0.4 mmol) in 3 mL THF was added BH3 (2M in THF, 0.5 mL, 1 mmol). The solution was stirred at rt for 16 h. EtOAc (20 mL) was added, and the organic phase washed with 1M H3PO4, sat. NaHCO3 and brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 75C (86 mg, 96%). MS (ESI) m/z 211.2(M−H2O)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:16][CH2:17][C:18]([N:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]3[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[C:23]=1[Cl:50])[CH3:21])=[O:19].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:50][C:23]1[C:24]([CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]3[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[CH2:17][NH:16][C:13](=[O:15])[CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:10][CH:9]=1
Reactant: CNC(=O)c1ccc(CCC(=O)O)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cc1

Procedure:
Compound 31 was prepared from 3-(4-(methylcarbamoyl)phenyl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)-N-methylacetamide in a as described for compound 1. MS (APCI) 700 (M+), 1H NMR (CDCl3) 2.42-2.52 (m, 2H), 2.61 (s, 3H), 2.85-2.95 (m, 5H), 3.15 (s, 3H), 3.32-3.45 (m, 1H), 3.62-3.68 (m, 1H), 5.41 (s, 2H), 5.61 (s, 2H), 6.41-6.51 (m, 1H), 6.55-6.62 (m, 1H), 6.71 (s, 1H), 7.15-7.31 (m, 4H), 7.31-7.45 (m, 2H), 7.55-7.62 (m, 1H), 7.62-7.71 (m, 2H), 7.71-7.81 (m, 1H), 7.91-7.95 (m, 1H), 8.65-8.72 (m, 1H).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:53])C(O)=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52]([N:54]1[CH2:55][CH2:56][O:57][CH2:58][CH2:59]1)=[O:53])[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A mixture of 500 mg (0.90 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 10 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature and under an atmosphere of nitrogen for 30 minutes, and then the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and then the solvent was removed by distillation under reduced pressure. The same operation was repeated in total three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and then the residue was suspended in 10 ml of anhydrous tetrahydrofuran. 275 mg (0.92 mmoles) of 2(R)-benzyl-3-(morpholinocarbonyl)propionic acid were added to the suspension, and then 0.15 ml (0.99 mmoles) of diethyl cyanophosphate and 0.42 ml (3.01 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 8 hours, after which the solvent was removed by distillation under reduced pressure and the residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent) and then recrystallization of the product from ethyl acetate, to give 500 mg (yield 78%) of the title compound as white crystals, melting at 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:15][C:12]1[CH:11]=[N:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A suspension of (2-(4-chlorophenylamino)pyrimidin-5-yl)methanol (0.15 g, 0.636 mmol) and Et3N (0.177 ml, 1.273 mmol) in DCM (6.4 mL) was cooled to 0° C. and methanesulfonyl chloride (0.099 mL, 1.273 mmol) was added. The reaction was stirred for 1.5 h while warming to room temperature. The mixture was diluted with DCM and quenched with sat. NaHCO3. The organic layer was isolated and dried over Na2SO4, then concentrated to give crude 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a yellow solid (0.1 g, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (2H, s), 7.58 (2H, d, J=8.78 Hz), 7.31 (2H, d, J=8.78 Hz), 7.25 (1H, br. s.), 4.53 (2H, s).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1>CN(C=O)C.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([S:2][CH3:1])[CH:10]=1
Reactant: C[S-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Sodium thiomethoxide (1.6 g, 23 mmol) was added to a solution of 3,5-dibromopyridine (5 g, 21 mmol) in DMF (25 mL). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and washed several times with brine. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude material was chromatographed on silica (10% ethyl acetate/hexanes) to give the title compound (3.8 g, 89% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[N:4]([NH2:15])[CH:3]=1.[CH3:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=2)[N:4]([NH:15][C:23]([C:22]2[C:17]([CH3:16])=[N:18][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:20][CH:21]=2)=[O:24])[CH:3]=1
Reactant: Cc1cn(N)c2ccc(C(F)(F)F)cc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2cc(C(F)(F)F)ccc21
Yield: 28.5 %

Procedure:
A mixture of 3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 1.04 mmol), 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (224 g, 1.04 mmol), HATU (475 mg, 1.25 mmol), DIPEA (404 mg 3.13 mmol) is stirred in DMF at 150° C. for 1 h. The reaction is quenched with water, extracted with extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-methyl-5-trifluoromethyl-indol-1-yl)-amide (122 mg, 28%). MS: 412 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.22 (s, 1H), 8.79 (d, 1H), 8.66 (d, 1H), 8.06 (t, 1H), 7.91 (s, 1H), 7.60 (dd, 1H), 7.51 (s, 2H), 7.29 (s, 3H), 2.88 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][OH:26])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:36][CH3:37])=[N-]>O1CCCC1.CCOCC>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:28])[C@@H:15]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[N:25][O:26][CH2:36][CH3:37])[CH:20]=3)[C@H:12]2[S:11][CH2:10][C:9]=1[CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3cc[nH]c(=NO)c3)[C@H]2SC1
Reactant: CC=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCON=c1cc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@H]23)cc[nH]1

Procedure:
A solution of t-butyl-3-acetoxymethyl-7β-(2-hydroxyiminopyrid-4-ylacetamido)-ceph-3-em-4-carboxylate (syn-isomer) (1.15g) in tetrahydrofuran (20 ml) was treated with an excess of diazoethane at 20° for 40 minutes. The mixture was diluted with ether, washed with water and extracted with 2N-hydrochloric acid. The aqueous extract was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Evaporation of the dried organic extract offered the title ester as a foam (0.84 g, 69%), [Ε]D + 47° (c 0.84, DMSO), λmax. (EtOH) 259 nm (ε 15,450), νmax. (Nujol) 3300 (NH), 1788 (β-lactam), 1740 (OAc), 1724 (CO2R), 1678 and 1540 cm.-1 (CONH), τ (d6 -DMSO) values include 0.12 (d, J 8Hz; NH), 1.26 and 2.42 (multiplets; aromatic protons), 5.69 (q, J 7Hz, OCH2CH3 ), 7.93 (s; OCOCH3), 8.50 (s; (CH3)3) and 8.69 (t, J 7Hz; OCH2CH3).
Reaction SMILES: [CH2:1]([CH:5]([Sn])C=C(CCCC)CCCC)[CH2:2]CC.Br[C:18]1[C:19]([F:38])=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]1[C:27]([CH2:36][CH3:37])([CH2:31][C:32]([O:34][CH3:35])=[O:33])[O:28][CH2:29][CH2:30][C:23]2=1>C1C=CC=CC=1.[Pd].CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:36]([C:27]1([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]2[NH:25][C:26]3[C:22]([C:23]=2[CH2:30][CH2:29][O:28]1)=[CH:21][CH:20]=[C:19]([F:38])[C:18]=3[CH2:5][CH:1]=[CH2:2])[CH3:37]
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(Br)c(F)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=CCc1c(F)ccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Temperature: 80 °C
Reaction time: 42 h
Yield: 78 %

Procedure:
According to the procedure of Kosugi et al, Chem. Letters 301 (1977) tetrakis-(triphenylphosphine) palladium [O] (60 mg) was added to a mixture of tributylallyltin (1.75 g, 0.0053 mol) and 8-bromo-1-ethyl-7-fluoro-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-1-acetic acid, methyl ester (1.6 g, 0.0043 mol) in benzene (4.0 mL) under N2. The sealed tube was then heated to 80° C. for 15 hours, more palladium catalyst was added (30 mg), and heating continued for 42 hours at 110°-120° C. The cooled reaction mixture was diluted with Et2O, then filtered through a glass wool plug. The ether was washed twice with brine, then dried (MgSO4) to yield an oil that was purified via flash chromatography. Using 1:7 EtOAc:hexane to afford 1.12 g, (~78%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid, methyl ester as a colorless oil. The oil was dissolved in ethanol (40 mL) and 1N sodium hydroxide added (15 mL). The mixture was heated to reflux for 2 hours then cooled and concentrated. 1N HCl was added and the aqueous solution extracted with ether. The ether layers were washed (brine), dried (MgSO4) and concentrated to yield a foamy oil. This was purified by flash chromatography on SiO2 -pretreated with 2% H3PO4 -MeOH. Using 1:2 EtOAc:hexane to give 1 g (73%) of 1-ethyl-7-fluoro-1,3,4,9-tetrahydro-8-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid as a colorless oil which crystallized from toluene:petroleum ether, m.p. 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=2)O1>>[F:15][C:14]([F:16])([F:17])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.223 g, 0.5 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide [CAS-No. 486-422-08-6] (0.283 g, 1.0 mmol) according to the general procedure VI. Obtained as a light brown solid (0.125 g, 43%). MS (ISP) 523.3 [(M+H)+]; mp 176-179° C.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:21].[Na+]>C(O)(=O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[C:5]3[C:4](=[O:19])[NH:3][C:2](=[O:21])[NH:10][C:9]=3[N:8]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: Nc1nc2ncn(Cc3ccc(Cl)cc3)c2c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccc(Cl)cc2)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (6.8 g, 24.7 mmol) in acetic acid (80 mL) and water (10 mL) was added a solution of sodium nitrite (3.4 g, 24.7 mmol) in water (10 mL) dropwise at 50° C. The reaction was stirred at 50° C. for 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The precipitate was collected, washed with water and ethanol, and dried in vacuo to give 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (6.5 g, 95.3% yield) as yellow solid. LCMS retention time 0.635 min; LCMS MH+ 277.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]O>S(=O)(=O)(O)O>[C:1]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(=O)c1ccccc1

Procedure:
Precursors suitable for preparation of fullerene derivatives were prepared. First, methyl 4-benzoylbutyrate was prepared as follows. A solution of 4-benzoylbutyric acid (11.9 g, 0.0619 mol) in MeOH (250 ml) with a catalytic amount of sulfuric acid (96%, 6 drops) was refluxed for 5 hours. Solvent was removed and 50 ml water was added. The reaction product was extracted with dichloromethane to provide an organic layer. The organic layer was separated, dried over MgSO4 and passed through a plug of silica, which was rinsed with 2% acetone in dichloromethane. Solvent was removed to afford the methyl ester as light-yellowish oil (12.57 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=[O:15])=[C:11]3[CH2:23][CH2:24][CH2:25][C:10]3=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:37]1[C:42]([F:43])=[C:41]([F:44])[C:40]([F:45])=[C:39]([F:46])[C:38]=1[F:47])=O>CN(C=O)C>[F:43][C:42]1[C:37]([O:15][C:14](=[O:16])[CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:25][CH2:24][CH2:23][C:11]=23)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:38]([F:47])[C:39]([F:46])=[C:40]([F:45])[C:41]=1[F:44]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid (300 mg, 836 umol) in DMF (3 ml) was added pyridine (70 ul, 920 umol) and pentafluorophenyl trifluoroacetate (290 ul, 1.7 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/0.1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/sat. aqueous NaHCO3 solution 1/1, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as an orange oil (762 mg; quant.) which was directly used in the next reaction step without further purification.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)(C)C>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([OH:16])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5H-Dibenzo[a,d]cyclohepten-5-one (10 g) is dissolved in 80 ml of isopropyl alcohol and sodium borohydride (1.8 g) is added at once. The mixture is stirred at room temperature for two hr. 5 ml of water are added to quench the reaction and the solvent is evaporated. The residue is taken up in diethyl ether and washed with water, dried over MgSO4 and evaporated. (9.8 g 98% yield) of 5H-dibenzo-[a,d]-cyclohepten-5-ol is obtained.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[Si]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](=O)[CH:43](OCC)[O:44]CC)=[CH:37][CH:36]=1)(C(C)(C)C)(C)C.Cl.CCCCCC>O1CCOCC1>[OH:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]2[C:43](=[O:44])[N:19]3[CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[NH:16][C:17]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[C:18]3[N:21]=2)=[CH:39][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Reactant: CCOC(OCC)C(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(-c3cccs3)[nH]c(-c3ccc(O)cc3)cn1-2
Temperature: 25 °C
Yield: 22.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (276 mg, 720 μmol) and 3-[4-(tert-butyldimethylsilyloxy)phenyl]-1,1-diethoxypropan-2-one (8) (381 mg, 1.08 mmol) dissolved in 1,4-dioxane (2 mL) was added 4 M hydrochloric acid (780 μL) at 0° C. and the mixture was heated to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography in an argon flow (acidic silica gel 20 g, n-hexane/ethyl acetate=1/2→ethyl acetate→ethyl acetate/methanol=20/1). To the suspension obtained during the concentration under reduced pressure was added n-hexane. The precipitates were collected by filtration and dried in vacuo to give Compound 3f (TMD-278) (68.2 mg, 164 μmol, 22.8%) as a brown solid. Rf=0.67 (ethyl acetate/methanol=20/1); HPLC retention time 9.5 min; 1H NMR (400 MHz, CD3OD) δ 4.22 (s, 2H), 6.72-6.78 (AA′BB′, 2H), 6.90-6.97 (AA′BB′, 2H), 7.11-7.18 (AA′BB′, 2H), 7.32 (dd, 1H, J=3.8, 5.2 Hz), 7.87 (dd, 1H, J=1.1, 5.2 Hz), 7.91-7.97 (AA′BB′, 2H), 8.12 (dd, 1H, J=1.1, 3.8 Hz), 8.48 (s, 1H); IR (KBr, cm−1) 521, 581, 629, 721, 777, 841, 881, 966, 1109, 1172, 1261, 1341, 1429, 1508, 1533, 1609, 1653, 2822, 3107; HRMS (ESI+) m/z 416.1075 ([M+H]+, C23H18N3O3S+ requires 416.1063).