Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[CH2:28]([O:35][CH2:36][C:37]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:42][CH2:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH2:28]([O:35][CH2:36][C:37]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:42][CH2:41][C:40]([C:2]2[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]3[N:25]=[CH:26][CH:27]=[C:4]3[N:3]=2)=[CH:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1(COCc2ccccc2)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(COCc2ccccc2)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
A mixture of 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (2.99 g, 6.97 mmol), ethyl 1-(benzyloxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (8.36 mmol), PdCl2(dppf)CH2Cl2 (683 mg, 0.836 mmol), and K3PO4 (5.32 g, 25.1 mmol) in dioxane/H2O (40/2 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-20% EtOAc/Hexanes, Rf=0.45 in 20% EtOAc) to afford ethyl 1-(benzyloxymethyl)-4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohex-3-enecarboxylate as a pale yellow oil (3.06 g). HPLC-MS TR=3.17 min (UV 254 nm, 5 min method); mass calculated for formula C35H54N4O5Si2 666.4, observed LCMS m/z 667.3 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH:46]([CH3:49])[CH2:47]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:47][CH:46]([CH3:49])[CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(CCl)CBr
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC1CS/C(=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)N(c2ccccc2C(C)C)C1
Temperature: 80 °C

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (100 mg, 0.191 mmol) and potassium carbonate (105 mg, 0.763 mmol) in butanone (4 ml) was added 1-bromo-3-chloro-2-methylpropane (39.0 mg, 0.229 mmol). The reaction was heated to 80° C. overnight. The reaction mixture was then diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided the title compound as a light yellow solid as a mixture of rotational diastereoisomers: mp 186-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=3.6 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.06 (s, 1H), 7.84-7.77 (m, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.38 (d, J=9.0 Hz, 3H), 7.32 (td, J=7.5, 1.4 Hz, 1H), 7.26 (s, 1H), 7.17 (t, J=7.1 Hz, 1H), 3.69-3.26 (m, 1H), 3.55-3.37 (m, 1H), 3.18-2.98 (m, 2H), 2.93-2.80 (m, 1H), 2.47 (d, J=35.9 Hz, 1H), 1.31-1.12 (m, 9H); ESIMS m/z 580 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([N:8]1[CH2:9][CH2:10][C:11]2[N:3]([CH2:1][CH3:2])[C:4]([CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:5][C:6]=2[CH2:7]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(Cn2ccnc2-c2ncccn2)nc2cnccc21
Solvent: CC(C)=O
Product: CCn1c(Cn2ccnc2-c2ncccn2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 1-ethyl-2-(2-pyrimidin-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (100 mg, prepared as described in Example 2) and benzyl bromide (42 mg) in 5 mL of acetone in a sealed tube is refluxed overnight and then allowed to cool. The solvent is decanted and 10 mL of MeOH is added to the residue. The resultant solution is transferred to a 25 mL flask, excess NaBH4 is added to the solution. The reaction mixture is then stirred at room temperature for about one hour, treated with 5 mL of 1 N HCl solution and evaporated. The residue is made basic with 1N NaOH solution and extracted with CH2Cl2. The organic extract is dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (10% MeOH in CH2Cl2 as eluent) gives 5-benzyl-1-ethyl-2-(2-pyrimidin-2-yl-imidazol-1-ylmethyl)-4,5,6,7-tetrahydro-1H -imidazo[4,5-c]pyridine (50 mg). 1H NMR (CDCl3): 8.85 (d, 1H), 7.20-7.40 (m, 8H), 7.10 (s, H), 6.05(s, 2H), 3.80 (q, 2H), 3.70 (s, 2H), 3,55(s, 2H), 2.78(t, 2H), 2.58 (t, 2H), 0.96 (t, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[O:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[O:24][N:23]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:16])([F:17])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
A mixture of 2-butyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.050 g, 0.19 mmol), 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.054 g, 0.21 mmol), Cs2CO3 (0.067 g, 0.21 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). Drying (MgSO4) and filtration was followed by concentration. The resulting material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.070 g, 76%) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.88 (s, 2H), 2.92 (t, J=7.5 Hz, 2H), 1.74-1.66 (m, 2H), 1.44-1.35 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); MS m/z 493 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.CN(C)C=O>[N:40]1([C:31](=[O:33])[CH2:30][C:24]2([CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][CH:16]([N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[O:10])[CH2:17][CH2:18]3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)nc1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)N4CCOCC4)CCCCC3)CC2)nc1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a solution of [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3A-3) (300 mg) in dichloromethane (4 mL) was added N,N-dimethylformamide (1 drop) dropwise and then oxalyl chloride (0.087 mL) under ice cooling. The solution was stirred under ice cooling for 2 hours. A 2 mL aliquot of the reaction solution was taken and it was added to a solution of morpholine (288 mg) in dichloromethane (4 mL) dropwise under ice cooling. The solution was stirred under ice cooling for 1.5 hours. NH silica gel was then added to the reaction solution and it was concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[P:31]([O:43][CH2:44][CH2:45][N:46]([CH3:76])[CH2:47][CH2:48][C@@H:49]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](=[O:68])(=[O:67])[NH2:66])=[CH:61][C:60]=1[S:69]([C:72]([F:75])([F:74])[F:73])(=[O:71])=[O:70])[CH2:50][S:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[P:31]([O:43][CH2:44][CH2:45][N:46]([CH2:47][CH2:48][C@@H:49]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](=[O:68])(=[O:67])[NH:66][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[CH:61][C:60]=1[S:69]([C:72]([F:74])([F:75])[F:73])(=[O:71])=[O:70])[CH2:50][S:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:76])([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:32]
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Product: CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 61.5 %

Procedure:
A similar procedure to that described for INTERMEDIATE 55 utilizing (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 63 mg, 0.14 mmol) and (R)-di-tert-butyl 2-(methyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate (INTERMEDIATE 54, 105 mg, 0.14 mmol) as starting materials was followed, with subsequent purification by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc) to give the title product (98 mg, yield: 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 4-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After 1 hour, the mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 5.15 g, 82% was obtained as a colorless crystalline.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[N:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[NH:42]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[N:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:43]
Reactant: NN
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6cnccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 10-2 (0.5 g, 0.9 mMol) in anhydrous 1,4-dioxane (5 mL) was added hydrazine (0.56 mL, 17.8 mMol). The solution was heated to 100° C. in a microwave reactor for 20 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times. The crude solid was triturated with a saturated NaHCO3 solution for 20 minutes. The suspension was filtered and washed with copious amounts of water. The solid was dried azeotropically with toluene three times to yield 10-3 as a brown solid. LC/MS (M+1) calculated: 555.6; observed: 555.2
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2>>[F:35][C:24]([F:23])([F:34])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(C(F)(F)F)cc4C3)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-trifluoromethylisoindoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.12 (2H, t, J=6.0 Hz), 4.10 (4H, s), 4.21 (2H, t, J=5.9 Hz), 7.45 (1H, d, J=8.0 Hz), 7.55 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.81 (1H, s), 7.86 (1H, s), 8.26 (1H, s), 8.56 (1H, m). [M+H] Calc'd for C20H17F3N4O2, 403. Found, 403.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(C#N)CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (5 g, 25 mmol), t-butyldimethylsilyl chloride (4.46 g, 29 mmol) and imidazole (2.34 g, 34 mmol) were stirred in DMF (15 ml) at room temperature. After 30 minutes, a yellow suspension was observed. The reaction was partitioned between ether (75 ml) and water (100 ml). The ether was then washed further with water (4×50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The title compound was isolated as a pale orange waxy solid (7 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2,4,6-trifluorobenzoyl chloride (30 μL, 0.229 mmol) and mixing for 24 h, 45.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH2:5][CH2:4][CH:3]=1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CN(C)C=O>[CH2:25]([O:7][CH2:1][C:2]1[O:6][CH2:5][CH2:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCC1=CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC1=CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of 4.09 g of 4,5-dihydrofurfuryl alcohol (prepared as described in Preparation 12) in 10 ml of dimethylformamide was added dropwise to 2.62 g of a 55% w/w suspension of sodium hydride in mineral oil, itself suspended in 40 ml of dimethylformamide, whilst maintaining the temperature of the mixture at from 5° to 12° C. by ice-cooling. The mixture was then stirred at room temperature for 30 minutes, 18.32 g of hexadecyl bromide were added to the solution, and the whole was stirred at room temperature for 15 hours. The reaction mixture was then poured into 200 ml of water, and extracted twice with diethyl ether. The extract was washed with water, dried and condensed by evaporation under reduced pressure. The oily residue, 17 g, was subjected to column chromatography through 400 g of Grade II-III alumina (a product of Woelm Pharma, West Germany). The fraction eluted with a 1:20 by volume mixture of diethyl ether and hexane gave 9.512 g of the title compound as a solid, melting at 30.5°-31.5° C. (cold hexane).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH:23]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:29])=[CH:16][CH:17]=1)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: CC(C)N(Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(C(=O)N2CCNCC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-diisopropylaminomethylbenzoyl)piperazine (4.6 g) in ethyl acetate (10 ml) was added trifluoroacetic acid (20 ml), and the solution was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in water. The solution was made alkaline with sodium hydroxide solution, extracted with dichloromethane. The extract was dried and concentrated to give amorphous powders which were filtered, washed with hexane and dried to afford the title compound (3.12 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([OH:28])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([OH:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccc(O)c(=O)cc1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(O)c(=O)cc2)=C(O)c2ccccc2S1(=O)=O
Reaction time: 8 h
Yield: 53.3 %

Procedure:
In a nitrogen atmosphere, a solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (0.54 g) and 5-amino-2-hydroxy-2,4,6 -cycloheptatrien-1-one (0.33 g) in xylene (15 ml) is refluxed for 7.5 hours. The reaction mixture is then allowed to stand at room temperature overnight. The crystals that have separated out are collected by filtration and recrystallized from dimethylformamidemethanol to give 4-hydroxy-2-methyl-N-(2-hydroxy-1-oxo-2,4,6-cycloheptatrien-5-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.4 g), m.p. 258°-265° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33](=[O:60])[CH:34]([NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46])[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:31])([CH3:30])[CH3:29].[O:61]1[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=2[CH:63]=[C:62]1[C:70](O)=[O:71]>>[C:28]([O:32][C:33](=[O:60])[CH:34]([NH:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:70]([C:62]3[O:61][C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=4[CH:63]=3)=[O:71])=[CH:57][CH:58]=2)=[CH:51][CH:52]=1)=[O:46])[CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:29])([CH3:30])[CH3:31]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Yield: 40.1 %

Procedure:
BOP coupling of 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (349 mg, 0.77 mmol) with 2-Benzofuran carboxylic acid (124 mg, 0.77 mmol, 1 equiv.) was carried out according to procedures in step A of Example 6B to give 185 mg of 2-({4′-[(Benzofuran-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester in 40% yield. MS (ESI) m/z 597.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH:18]=[C:19]([CH3:21])[O:20][C:3]=12>C1COCC1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH2:18][CH:19]([CH3:21])[O:20][C:3]=12
Reactant: CCCCCC1CCc2c(c(F)c(F)c3oc(C)cc23)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1CCc2c3c(c(F)c(F)c2O1)OC(C)C3

Procedure:
2.0 g (7.51 mmol) of 4,5-difluoro-2-methyl-7-pentyl-8,9-dihydro-7H-furo-[3,2-f]chromene are hydrogenated for 18 h at elevated temperature in THF using elemental hydrogen in the presence of Pd/C (5% Pd). The reaction soln. is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). Further purification is carried out by recrystallisation from ethanol at 5° C., giving 4,5-difluoro-2-methyl-7-pentyl-1,7,8,9-tetrahydro-2H-furo[3,2-f]chromene as a colourless solid having an m.p. of 76° C. (Δ∈=−8.2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH:23]1([CH2:26]O)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCC1CC1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CC1CC1

Procedure:
Compound IIi was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and cyclopropylmethanol following the general procedure for the Mitsunobu reaction as described above.