Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[N:8]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH2:26]([N:29]1[C@H:33]([CH2:34][CH2:35][CH3:36])[CH2:32]OS1(=O)=O)[CH2:27][CH3:28].Cl>O1CCCC1.C1CCCCC1.CCCCCC>[CH:17]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([CH2:32][C@H:33]([NH:29][CH2:26][CH2:27][CH3:28])[CH2:34][CH2:35][CH3:36])=[CH:7]1)([CH3:19])[CH3:18]
Reactant: CCC[C@@H]1COS(=O)(=O)N1CCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c(Br)cc2ccccc21
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CCCN[C@H](CCC)Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ccccc12
Temperature: -70 °C
Yield: 72.9 %

Procedure:
Under an argon atmosphere, s-butyl lithium (a 0.99 mol/L cyclohexane/n-hexane solution, 68.7 mL) was added to a solution of 2-bromo-1-triisopropylsilylindole (11.99 g) in tetrahydrofuran (85 mL) under stirring at −70° C. and then stirred at −70° C. for 30 minutes. A solution of (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (7.05 g) in tetrahydrofuran (17 mL) was added to the resulting solution under stirring at −20° C. and then stirred for 13 hours, while the temperature was raised to room temperature. An aqueous 4 mol/L hydrochloric acid solution (34 mL) was added to the solution under water-cooling and stirring, and then vigorously stirred at room temperature for 1 hour. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to column chromatography (NH-DM1020, from Hexane to AcOEt/Hexane=1/7) and then further purified by column chromatography (NH-DM1020, from AcOEt/Hexane=1/9 to AcOEt/MeOH=9/1) to give (R)-1-(1-triisopropylsilylindole-3-yl)-2-propylaminopentane (9.94 g, 73% yield) as a red oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.[Si:34]([O:41][C@@H:42]([C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C@@H:47]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:49][O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:43][NH:44][CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:44]([CH3:45])[CH2:43][C@@H:42]([O:41][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:76])[CH3:77])[C@@H:47]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH2:49][O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:53])[CH3:52])=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Reactant: CNC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
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: CN(C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of acid 225 (220 mg, 0.474 mmol, scheme 54), amine 242 (309 mg, 0.474 mmol) and DIPEA (0.331 mL, 1.895 mmol) in DMF (5 mL) was added HATU reagent (270 mg, 0.710 mmol). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge) to afford title compound 243 (250 mg, 0.254 mmol, 54% yield) as a white solid. MS: 985.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[H-].[Na+].N#N>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: N#N
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Temperature: 140 °C
Yield: 64.6 %

Procedure:
To a solution of 2-methoxy-5-nitro-phenol (10 g), (2-chloro-ethyl)-dimethyl-amine hydrochloride (9.37 g) in dimethylformamide (150 mL) was added NaH (2.98 g) slowly under N2 and at room temperature. The mixture was then stirred at 140° C. heating with an oil bath for 5 hours. The reaction was concentrated to dryness, dissolved in 2 M HCl (200 mL) and washed with ethyl acetate (2×100 mL). The aqueous layer was basified with K2CO3, extracted with dichloromethane (3×200 mL) and ethyl acetate (2×100 mL), dried over Na2SO4, filtered, concentrated to give [2-(2-Methoxy-5-nitro-phenoxy)-ethyl]-dimethylamine (9.17 g, 65% yield). LCMS (m/z) M+H: 241.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[C:3]=1[CH3:19].[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[NH:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:20][C:21]1([CH3:36])[C:25]2=[N:26][CH:27]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:29]=[C:24]2[N:23]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[C:3]=2[CH3:19])[CH2:22]1
Reactant: Cc1c(-c2cncc(F)c2)nc2ncccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(F)c2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(5-fluoropyridin-3-yl)-3-methyl-1,8-naphthyridine (15 mg, 0.055 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (12.79 mg, 0.055 mmol), sodium tert-butoxide (10.53 mg, 0.110 mmol) and XPhos precatalyst (4.03 mg, 5.48 μmol) in toluene (4 mL) at 110° C. for 2 h. Purification by reverse phase HPLC gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-(5-fluoro-3-pyridinyl)-3-methyl-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.17 (1H, dd, J=4.1, 2.0 Hz), 8.78 (1H, t, J=1.7 Hz), 8.61 (1H, d, J=2.7 Hz), 8.18 (1H, dd, J=8.4, 2.0 Hz), 7.91 (1H, ddd, J=9.0, 2.9, 1.8 Hz), 7.68 (1H, d, J=2.3 Hz), 7.50 (1H, dd, J=8.4, 4.3 Hz), 5.84 (1H, d, J=2.3 Hz), 3.84-3.94 (2H, m), 3.73-3.80 (4H, m), 3.01 (4H, td, J=4.9, 2.3 Hz), 2.41 (3H, s), 1.63 (3H, s), 1.58 (3H, s). Mass Spectrum (ESI) m/e=471.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[OH:26][C@@H:20]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
Ethyl 2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to −40° C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine (219 mg, 7.5 mmol) and catechol borane (750 μL, 7.04 mmol) were added and the mixture stirred at −40° C. After 2 hrs at −40° C. the reaction was quenched by the addition of 15% Na2CO3 (12 mL) and the mixture was allowed to warm to room temperature. The mixture was washed with 15% Na2CO3 (8×12 mL) and saturated NH4Cl (24 mL), organic layer was dried with sodium sulfate and concentrated in vacuo. Chromatography using silica gel using EtOAc in hexanes produced the desired (S)-ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (976 mg, 1.8 mmol) in 74% yield. 1H-NMR: 400 MHz, (CDCl3): δ 8.08-8.06 (m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80 (m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J=2.4 Hz, 1H); 2.50 (s, 3H); 1.21 (t, J=7.0 Hz, 3H).
Reaction SMILES: O=C1CC2C(=CC(NC(C3CCCC3)=O)=CC=2)N1.ClC1C=C(Cl)C=C(C=O)C=1O.[Cl:30][C:31]1[C:32]([OH:57])=[C:33]([CH:53]=[C:54]([Cl:56])[CH:55]=1)[CH:34]=[C:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45]([CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:46])=[CH:41][CH:42]=2)[NH:37][C:36]1=[O:52]>>[Cl:30][C:31]1[C:32]([OH:57])=[C:33]([CH:53]=[C:54]([Cl:56])[CH:55]=1)[CH2:34][CH:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45]([CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:46])=[CH:41][CH:42]=2)[NH:37][C:36]1=[O:52]
Reactant: O=C1Nc2cc(NC(=O)C3CCCC3)ccc2C1=Cc1cc(Cl)cc(Cl)c1O
Agent: O=C1Cc2ccc(NC(=O)C3CCCC3)cc2N1
Agent: O=Cc1cc(Cl)cc(Cl)c1O
Product: O=C(Nc1ccc2c(c1)NC(=O)C2Cc1cc(Cl)cc(Cl)c1O)C1CCCC1
Yield: 40 %

Procedure:
Cyclopentanecarboxylic acid (2-oxo-2,3-dihydro-1H-indol-6-yl)-amide was condensed with 3,5-dichlorosalicylaldehyde using method B to give a mixture of isomers of cyclopentanecarboxylic acid [3-(3,5-dichloro-2-hydroxy-benzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide as an orange solid which was reduced using method D to give 10 mg (40%) of cyclopentanecarboxylic acid [3-(3,5-dichloro-2-hydroxybenzyl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amide as an off-white crystalline solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].O.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[CH:22][C:18]=1[C:19](Cl)=[O:20].CO.ClCCl>CC(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH2:3][CH:4]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7])[C:19](=[O:20])[C:18]1[CH:22]=[C:23]([C@H:26]2[CH:30]=[N:29][N:28]=[N:27]2)[CH:24]=[CH:25][C:17]=1[O:16][CH3:15]
Reactant: C=CCC(CNC)c1ccccc1
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: C=CCC(CN(C)C(=O)c1cc([C@H]2C=NN=N2)ccc1OC)c1ccccc1
Reaction time: 10 h

Procedure:
Combine N-methyl-(2-phenylpent-4-enyl)amine (1.00 g, 5.7 mmol), acetone (50 mL), water (20 mL), and sodium bicarbonate (0.3 g, 2.85 mmol). Add portionwise, a solution of 2-methoxy-5-(4H-triazol-4-yl)benzoyl chloride (1.4 g, 6.3 mmol) in acetone (50 mL). After 10 hours, dilute the reaction mixture with a saturated aqueous sodium bicarbonate solution and evaporate in vacuo to remove most of the acetone. Extract five times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give (S)-N-methyl-N-(2-phenylpent-4-enyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide: Rf=0.25 (silica gel, 5% methanol/dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: CC(C)CC(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CC(C)C)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and isovaleric acid (25.5 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isovaleramide. NMR; δH [2H6]—DMSO 9.84,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.48,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.16-2.15,(5H, m), 2.06,(1H, m), 1.04,(1H, m), 0.91,(6H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.25 min, MH+365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCCl.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(4-Methoxyphenyl-6-methoxybenzo[b]thiophene (10 g, (37 mmol) of was dissolved in 700 mL of 1,2-dichloroethane and the mixture cooled to 0° C. To the reaction solution was added, slowly, a mixture of 4-methoxybenzoyl chloride (6.31 g, 37 m mol) and aluminum chloride (5.07 g 38 mmol). The reaction was allowed to proceed at 0° C. for two hours and was terminated by pouring into ice-water. The organic layer was separated and aqueous layer extracted with chloroform. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, and filtered. The volatiles were removed by evaporation yielding a yellow oil, which was dissolved in 500 mL of methanol and 15 mL of 5N sodium hydroxide and refluxed until the methanol had evaporated (thirty minutes). The resulting oil was dissolved in diethylether, washed with brine, and evaporated. This yielded 14.6 g of a yellow oil which was purified by chromatography. This yielded 13.9 g of the title compound as a yellow oil. EA calculated for C24H20O4S: C, 71.25; H, 4.98; O, 15.82; S, 7.93. Found: C, 71.25; H, 4.90; O, 15.78; S, 7.65. MS(EI): m/e=404 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[CH:18]=1
Reactant: CC(C)Oc1cc(F)ccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C
Temperature: 110 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4-fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) were dissolved in dioxane (3.0 ml). The reaction was heated at 110° C. under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:6]([O:8]C)=O.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[F:18][C:19]1[CH:20]=[C:21]([CH2:22][C:6]([C:5]2[CH:10]=[C:11]([O:16][CH3:17])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:8])[CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Reactant: Fc1cccc(CBr)c1
Product: COc1cc(C(O)(Cc2cccc(F)c2)Cc2cccc(F)c2)cc(OC)c1C(C)C
Yield: 70 %

Procedure:
This material was prepared in 70% yield from the methyl 3,5-dimethoxy-4-i-propylbenzoate and 3-fluorobenzyl bromide using the same method as described in example 1(b). 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 1.85 (s, 1H), 3.07 (d, J=13.3 Hz, 2H), 3.29 (d, J=13.3 Hz, 2H), 3.56 (qint, J=7.1 Hz, 1H), 3.72 (s, 6H), 6.42 (s, 2H), 6.7-7.2 (m, 8H).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1)C1C=CC=CC=1.C1CC=CCC=1>C(O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C@H:12]2[C:24]1[N:28]([CH3:29])[N:27]=[N:26][N:25]=1
Reactant: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1nnnc1[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2N
Yield: 79.1 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-1-phenyl-6-(1-methyl-1H-tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Description 33a; 57 mg, 0.12 mmol) was dissolved in ethanol (5 mL) and treated with 1,4-cyclohexadiene (5 mL), followed by 10% palladium on activated charcoal (50 mg). The suspension formed was heated at reflux for 72 hours, then cooled and filtered. The filtrate was concentrated, and the residue taken up in ethyl acetate (2 mL) and treated with ethereal hydrogen chloride (2 mL, 1M). The solid formed was removed by filtration, washed with diethyl ether and dried to give the crude title compound as a solid (27 mg). MS (ES+) 285 (M+H).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])[CH:10]=[CH:11][CH:12]=1)([O:5][CH3:6])=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(OC)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COP(=O)(OC)c1cccc(/C=C/C(=O)O)c1

Procedure:
tert-butyl (2E)-3-[3-(dimethoxyphosphoryl)phenyl]acrylate was dissolved in dichloromethane (6 ml). TFA (3 ml, 38.9 mmol) was added. The reaction was allowed to stir for approximately one and a half hours. The reaction was complete as indicated by LCMS. The reaction was diluted with DCM and washed with brine. The aqueous layer was extracted three times with DCM. The combined organic layer was dried over Na2SO42, filtered, and concentrated. MS: calc'd 257 (MH+), exp 257 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([CH3:12])[N:6]=[CH:5]2.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28](=[O:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[F:11])[N:7]([CH3:12])[N:6]=[CH:5]4)([OH:30])[CH3:29])=[CH:26][N:27]=2)[N:24]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Reactant: Cn1ncc2cc(Br)c(F)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: -100 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 5-bromo-6-fluoro-1-methyl-1H-indazole (intermediate L) (1.800 g, 7.86 mmol) in THF (79 mL) at −100° C. was added n-BuLi (5.40 mL, 8.64 mmol) dropwise. After stirring for 1 h at −100° C., a solution of 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethanone (intermediate M) (1.691 g, 8.64 mmol) in THF (20 mL) was added dropwise. The reaction solution was stirred for additional 2 h and quenched with NH4Cl (aq). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NH4Cl (aq), dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography (hexanes:EtOAc) to give the title compound in 34% yield. LCMS (method B): [MH]+=346, tR=2.14 min.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[CH2:12]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[CH2:12]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][C:24]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:25]=2[CH2:26][CH2:27]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Yield: 69.3 %

Procedure:
Combine 4-cyanophenylhydrazine hydrochloride (27.4 g, 162 mmol) and (4-oxo-cyclohexyl)-carbamic acid benzyl ester (Preparation 42) (40.0 g, 162 mmol) in acetic acid (800 mL). Heat the reaction to 90° C. overnight, then cool to room temperature and concentrate under reduced pressure. Triturate the residue in dichloromethane and discard the filter cake. Concentrate the filtrate under reduced pressure. Purify the resulting residue by flash chromatography (silica gel, 9:1 chloroform:acetone). Recrystillize the resulting material from benzene to provide 38.8 g (69%) of the title compound. m.p.=141-143° C.; mass spectrum (m/e): 344 [C21H19N3O2−1]−; 1H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 7.73 (s, 1H), 7.29-7.38 (m, 7H), 5.12 (s, 2H), 4.89-4.92 (m, 1H), 4.18 (m, 1H), 3.09 (dd, J=5.0, 15.5 Hz, 1H), 2.78-2.91 (m, 2H), 2.59 (dd, J=7.0, 15.5 Hz, 1H), 2.07-2.17 (m, 1H), 1.93-2.05 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)(O)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C(C)(O)COCCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(C(C)COCCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 2-(3-methoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether (498 mg. 1.74 mmole) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 μl., 5.22 mmole). The reaction is allowed to warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20° C. and then added to ether (150 ml.) and 15% sodium carbonate (100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3×50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake ceases the reaction is filtered through diatomaceous earth and the filtrate evaporated to an oil. The oil is purified via preparative layer chromatography on silica gel plates, eluted twice with 6:1 pentane:ether to yield the title compound.