Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](S(C(F)(F)F)(=O)=O)=[CH:21][CH:20]1[CH3:32])=[O:18])([CH3:15])([CH3:14])[CH3:13].C[Sn](C)C.C[Sn](C)C.[Cl-].[Li+]>O1CCOCC1.[F-].[K+].C(OCC)(=O)C.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>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=3[N:6]=2)=[CH:21][CH:20]1[CH3:32])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cccc2sc(Cl)nc12
Reactant: CC1C=C(S(=O)(=O)C(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cccc2sc(C3=CC(C)N(C(=O)OC(C)(C)C)CC3)nc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Scheme IIA, Step A: To a mixture of 2-chloro-4-methylbenzothiazole (1.052 g, 5.73 mmol) in 1,4-dioxane (60 mL) was added 1-(t-butyloxycarbonyl)-2-methyl-4-trifluoromethanesulfonyl-1,2,5,6-tetrahydropyridine (2.077 g, 6.01 mmol), hexamethylditin (1.876 g, 5.73 mmol), tetrakis(triphenylphosphine)palladium (0.331 g, 0.286 mmol) and lithium chloride (0.729 g, 17.2 mmol). The mixture was heated at reflux for 20 hours, then cooled to 20° C. and diluted with saturated potassium fluoride and ethyl acetate. The mixture was stirred for 2 hours, then partitioned, and the organics were washed with brine dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel (hexanes/50% ethyl acetate in hexanes gradient elution) to give the intermediate title compound as a yellow amorphous solid (1.3 g, 66%). FDMS m/e=345 (M++1).
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[S:3][N:2]1[NH:14][C:15]([N:17]1[CH:21]=[CH:20]N=C1)=[S:16])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]1(CCN)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:22]1([CH2:20][CH2:21][NH:17][C:15]([NH:14][N:2]2[CH2:1][C:5]3[C:6]4[C:11]([CH:12]=[CH:13][C:4]=3[S:3]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[S:16])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: S=C(NN1Cc2c(ccc3ccccc23)S1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1)NN1Cc2c(ccc3ccccc23)S1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 1-[(2-naptho[1,2]thiazolyl)thiocarbamoyl]imidazole (1.6 g, 5 mmol) and 2-phenylethylamine (0.62 g, 5.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.5 g (82%) of the titled product:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3cn[nH]c3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CN(c2ccc(-c3cn[nH]c3)cc2O)S(=O)(=O)N1
Reaction time: 18 h

Procedure:
A mixture of 5-[2-benzyloxy-4-(1H-pyrazol-4-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg) and Pd(OH)2 (5 mg) in 3 mL of EtOH/EtOAc (1:1) is hydrogenated at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated. The residue is purified by preparative HPLC to give the title compound: (M−1)−=293; HPLC retention time=0.88 min (method A).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]=[C:21]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH2:25][O:24][C:23]4[CH:33]=[CH:34][CH:35]=[CH:36][C:22]3=4)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].[Cl:39]CCl.Cl>C(O)C>[ClH:39].[CH:29]1[C:28]2[C:21](=[CH:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:7]4[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=4)[CH2:17][CH2:16]3)[C:22]3[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=3[O:24][CH2:25][O:26][C:27]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1cccnc1N1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1N1CCN(CCC=C2c3ccccc3OCOc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A mixture of the above ester (0.99 g, 2 mmol) and 20% sodium hydroxide (1.5 ml) in ethanol (13 ml) was stirred at room temperature for 4 h. The mixture was poured into dichloromethane (100 ml), acidified with 2 N hydrochloric acid and washed with water (10 ml). The organic solution was dried (MgSO4) and activated charcoal was added. The mixture was stirred for 10 minutes, filtered and the solvent was removed in vacuo. The residue was triturated with acetone and the solid product was overlaid with ethyl acetate, stirred for 15 minutes, filtered off and washed with ethyl acetate. After drying, the title compound (0.80 g, 74%) was obtained.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[Br:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:17][C:18]1[CH:19]=[C:20]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[CH:21]=[N:22][CH:23]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3cncc(Br)c3)ccc2n1)C1CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1.7 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) were added 5-bromopyridine-3-ol (1.7 g, 10 mmol) and potassium carbonate (1.7 g, 13 mmol), and the mixture was stirred at 140° C. for 8 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and precipitated from ethyl acetate/diisopropyl ether to give the title compound (1.6 g, 85%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.C(N(CC)CC)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:7]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])c(O)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 57.3 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzoic acid (10.00 g) in dry N,N-dimethylformamide (150 ml), 1-ethyl-3- (3-dimethylaminopropyl ) carbodiimide hydrochloride (12.56 g) , 1-hydroxybenzotriazole (8.86 g) , triethylamine (7.18 g) , and morpholine (5.71 g) were added successively. A mixture was stirred at room temperature for 23 hours, and the solvent was evaporated in a bath at 80° C. under reduced pressure to a solution volume of approximately 100 ml. Ethyl acetate (400 ml) was added to the residue, and the mixture was washed with 1N HCl aqueous solution (100 ml), water (200 ml), saturated sodium carbonate aqueous solution (50 ml), and water (150 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain the compound ([3]-(32)-587) (7.89 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C)cc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 78.9 %

Procedure:
Ethyl ester 88 (123 mg, 0.30 mmol) was saponified with 1 N NaOH in THF and EtOH to give 90 mg (79%) of the title compound (89) as a white solid. mp 224-225° C. 1H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.61 (d, J=8.8 Hz, 2H), 7.10-7.16 (m, 2H), 7.20-7.30 (m, 5H), 7.38 (t, J=7.4 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.68 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H). LCMS (ESI): m/z 381 (M+H)+, m/z 379 (M−H)−. Anal. Calc for C26H20O3.0.33H2O: C, 80.81; H, 5.39. Found: C, 80.73; H, 5.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:23][CH2:24][CH2:25][CH3:26])/[C:18]([O:20]CC)=[O:19].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:23][CH2:24][CH2:25][CH3:26])/[C:18]([OH:20])=[O:19]
Reactant: CCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)OCC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: CCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)O

Procedure:
Compound 99b was prepared from 98b (0.148 g, 0.415 mmol) as described above for 29a to give 0.154 g (0.469 mmol, 113%) of the product as a white solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[SH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]=[C:8]1[C:9]2[C:14]3[C:13](=[C:2]([S:21][C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])[CH:3]=[CH:4][C:5]=3[C:6](=[O:20])[N:7]1[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)c1ccccc1S
Reactant: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN1C(=O)c2cccc3c(Sc4ccccc4C(=O)O)ccc(c23)C1=O
Yield: 64 %

Procedure:
A mixture of 6-chloro-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid (10.0 g, 34.5 mmoles, described in Example 2); 2-mercaptobenzoic acid (5.85 g, 37.9 mmoles) and anhydrous potassium carbonate (9.54 g, 37.9 mmoles) in dimethylformamide (300 ml) was heated at reflux for 3 hr. The product in the form of its sodium salt was precipitated from the reaction mixture. The precipitate was collected by filtration and dissolved in water. The solution of the sodium salt was rendered acidic with 2 N hydrochloric acid. The resulting precipitate was collected, dried and crystallized from dimethylformamide and water to give 9.0 g of the title compound; mp 339°-341° C.; UV (MeOH) 231, 254, 336 and 346, ε=31,450, 15,810, 8,760 and 9,210, respectively; IR (CHCl3) 2900, 1725, 1710, 1675 cm-1 ; NMR (CDCl3) δ 4.7 (s, 2H), 6.5-8.6 (m, 9H), 13.0 (broad, 1H); Anal. Calc'd: C, 61.91%; H, 3.22%; N, 3.44%; Found: C, 61.51%; H, 3.21%; N, 3.73%.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[N:30]1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:32]=[CH:33][N:29]([CH3:28])[N:30]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cn1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 2.1 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a white powder. HPLC (Condition 4) tR=5.16 min, UPLC-MS (Condition 3) tR0.98 min, m/z=464 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.90 (m, 2H) 2.85-3.00 (m, 1H) 3.06-3.26 (m, 3H) 3.59 (s, 3H) 4.19 (br. s, 1H) 4.87 (d, J=2.74 Hz, 1H) 6.39 (s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.50 (dd, J=1.76, 0.98 Hz, 1H) 7.84 (d, J=8.60 Hz, 2H) 8.01 (d, J=2.74 Hz, 1H) 8.78 (dd, J=2.54, 0.98 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[N:3]1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:17]1[N:18]=[N:19][C:20]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K2CO3 (127 g, 919 mmol) in water (480 mL). After [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N2 for 20 min and stirred at 80° C. for 16 h. The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3×800 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1%). MS (m/z): 195.1 (M+H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[C:9]([Cl:19])[CH:8]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1>[Cl:19][C:9]1[CH:8]=[C:7]([B:20]([OH:25])[OH:21])[CH:12]=[CH:11][C:10]=1[S:13]([CH:16]1[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccc(Br)cc1Cl)C1CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
n-Butyllithium (1.6 M solution in hexane, 9.2 mL) was added dropwise to a solution of 4-bromo-2-chloro-1-(cyclopropylsulfonyl)benzene obtained in Reference Example 5-30 (1.45 g) and triisopropyl borate (5.54 g) in tetrahydrofuran (15 mL) under cooling at an external temperature of −78° C. in a nitrogen atmosphere, after which the mixture was stirred at the same temperature for three hours. 1 M hydrochloric acid (10 mL) was added and the reaction solution, still basic, was extracted with chloroform. The aqueous layer was made acidic with 1 M hydrochloric acid (10 mL), followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of 3-chloro-4-(cyclopropylsulfonyl)phenylboronic acid (1.02 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([CH2:19][CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>ClC(Cl)C.ClCCl>[CH2:19]([CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[NH:41][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=2)[CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)O)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1

Procedure:
Ethyl 3-(3-carboxy-4-methoxyphenyl)-2-ethylpropanoate (5.00 g, 17.8 mmol) was dissolved in 80 ml of dehydrated dichloroethane, which was cooled to −10° C. to −15° C. Triethylamine (6.21 ml, 44.5 mmol) was added under stirring. Next, ethyl chlorocarbonate (1.86 ml, 19.5 mmol), dissolved in 10 ml of dehydrated dichloromethane was added dropwise. After stirring for 10 minutes at −10° C., 4-(trifluoromethyl)benzylamine (2.51 ml, 17.8 mmol), dissolved in 10 ml of dehydrated dichloromethane was added dropwise.
Reaction SMILES: [CH:1]([CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:12]1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.[NH2:18][CH2:19][CH2:20][O:21]CCO>>[CH2:1]([CH:11]1[CH2:16][C:15](=[O:17])[N:18]([CH2:19][CH2:20][OH:21])[C:12]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCOCCO
Reactant: CCCCCCCCC=CC1CC(=O)OC1=O
Product: CCCCCCCCC1CC(=O)N(CCO)C1=O

Procedure:
Preparation of n-C10 (N-CH2CH2OCH2CH2OH)--In a similar preparation, n-decenyl succinic anhydride (10.5 g; 0.1 mole) is reacted with 2-(2-aminoethoxy) ethanol (23.8 g; 0.1 mole) to provide the title compound. GC analysis indicates the reaction to be about 85% complete after 120 minutes in a 150° C. heating bath.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C@H:18]([CH3:19])[CH2:17][N:16]([C@H:20]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[C@@H:15]([CH3:41])[CH2:14]1)[CH:11]=[CH2:12].C(N(CC)CC)C>ClCCl>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C@H:20]([N:16]2[CH2:17][C@@H:18]([CH3:19])[N:13]([CH2:10][CH:11]=[CH2:12])[CH2:14][C@@H:15]2[CH3:41])[C:28]2[CH:29]=[CH:30][C:31]([C:32](=[O:33])[N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[CH:39][CH:40]=2)[CH:22]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OC(=O)c3ccccc3)c2)C[C@H]1C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
Benzoyl chloride (0.33, 2.3 mmol) was added dropwise to a solution of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (0.92 g, 2.1 mmol) (Example 6) and triethylamine (0.60 mL, 4.2 mmol) in 20 mL dichloromethane. The reaction mixture was stirred for 1 hour and then was washed twice with 20 mL of water, dried over sodium sulfate, and concentrated to dryness. The residue was purified by chromatography on silica gel with dichloromethane:ethanol to give 0.92 g (74%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(diethylcarbamoyl)benzyl)phenyl benzoate. NMR (300 MHz, CDCl3): δ 0.9 (d, 3H); 1.2 (d, br t, 9H); 1.9 (t, J=11 Hz, 1H); 2.1 (dd, 1H); 2.5 (br m, 1H); 2.6 (m, 2H); 2.8 (m, 2H); 3.2-3.6 (br m, 5H); 5.2 (2d, 2H); 5.3 (s, 1H); 5.8 (m, 1H); 7-7.2 (2d, s, 3H); 7.3 (m, 3H); 7.5 (m, 4H); 7.6 (t, 1H), 8.2 (d, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C:14]2[N:23]3[N:24]=[C:25]([NH2:27])[N:26]=[C:22]3[C:21]3[CH:20]=[CH:19][C:18]([F:28])=[CH:17][C:16]=3[N:15]=2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:14]([CH2:13][C:12]3[CH:29]=[CH:30][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)=[N:15][C:16]3[CH:17]=[C:18]([F:28])[CH:19]=[CH:20][C:21]=32)[N:24]=1
Reactant: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: COc1cc(Cc2nc3cc(F)ccc3c3nc(N)nn23)ccc1O
Temperature: 70 °C
Yield: 98.2 %

Procedure:
To a solution of 5-(4-benzyloxy-3-methoxy-benzyl)-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.04 g, 0.09 mmol) in MeOH (5 mL), prepared as described in example 34, were added 1,4-cyclohexadiene (0.1 mL, 1.40 mmol) and 10% Pd/C (0.02 g, 50% w/w). The reaction was heated at 70° C. for 1 h, then filtered through Celite® washing with MeOH and THF and evaporated, to afford the title compound (0.03 g, 97% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][CH3:22])=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)(OC)=[O:8]>C1COCC1>[CH3:22][O:21][C:15]1[C:14]2[C:19](=[CH:20][C:11]([CH2:7][OH:8])=[CH:12][CH:13]=2)[N:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc2c(OC)ccnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccnc2cc(CO)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2 mL of 1 M LAH (2 mmol) in 25 mL THF is cooled in an ice bath. 450 mg (2.07 mmol) of the title B compound, 7-carbomethoxy-4-methoxyquinoline suspended in 15 mL THF is added and allowed to stir at RT for 18 h. The mixture is quenched with saturated aqueous Na2SO4, filtered, and the filtrate dried over anhydrous MgSO4, filtered, and solvent removed to give (4-methoxyquinolin-7-yl)-methanol: 1H-NMR (CDCl3) δ 4.04 (3H, s), 4.89 (2H, s), 6.72 (1H, d, J=5.3), 7.51 (1H, d, J=8.5), 8.04 (1H, s), 8.16 (1H, d, J=8.5), 8.72 (1H, d, J=5.3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH:13]=O.[Br:15][C:16](Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][C:16]([Br:17])=[CH:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1onc(-c2ccccc2)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1onc(-c2ccccc2)c1C=C(Br)Br
Yield: 82.8 %

Procedure:
To a stirred solution of 5-methyl-3-phenyl-isoxazole-4-carbaldehyde (5.20 g, 27.8 mmol) was added tetrabromomethane (12.9 g, 38.9 mmol) and then triphenylphosphine (14.57 g, 55.5 mmol) and the resulting mixture stirred under argon for 2 h at 0° C. The solution was concentrated to approximately 90 mL and the resulting precipitate filtered, washed with dichloromethane and discarded. This was repeated until the majority of the triphenylphospine oxide and bromide was removed. Purification by chromatography (silica, heptane:ethyl acetate 9:1 to 2:3) afforded the title compound (7.9 g, 83%) which was obtained as a colorless oil. MS: m/e=344.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[N:7][CH:6]=1
Reactant: Oc1ccc(Br)nc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(O)cn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
The mixture of 6-bromopyridin-3-ol (5.22 g, 30.0 mmol), ethyl acrylate (4.51 g, 45.0 mmol), palladium acetate (175 mg, 0.78 mmol), tri-o-tolylphosphine (438 mg, 1.44 mmol), and triethylamine (4.55 g, 45.0 mmol) in N,N-dimethylformamide was placed in a sealed tube, and the mixture was stirred at 140° C. for 24 h. The mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×4), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 2.3 g (40%) of the title compound as a yellow oil. ((E), (Z) mixture)