Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=2[O:17][CH3:18])[N:8]=1>ClCCl>[Cl:3][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=2[O:17][CH3:18])[N:8]=1
Reactant: COc1cc2nc(CO)ccc2c(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc2nc(CCl)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.7 mL) was added to a solution of 2-hydroxymethyl-5,6,7-trimethoxyquinoline (1.45 g) in dichloromethane (15 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture under reduced pressure, an aqueous solution of potassium carbonate was added to the residue to alkalify it. The thus-treated residue was extracted with diethyl ether. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:19]1[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20]1>>[O:19]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:20]1
Reactant: O=C(Cl)c1ccoc1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.010 mL (0.080 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH2:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH2:3]1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[CH3:9][C:4]1([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3]1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)C1(N)CCCC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(N2CCOCC2)CCCC(C)(C)C1
Temperature: 95 °C

Procedure:
To a solution of EXAMPLE 145C (3.5 g) in N,N-dimethylformamide (30 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (5.8 g) and K2CO3 (6.5 g). The reaction mixture was heated to 95° C. for 18 hours. The mixture was cooled to room temperature, diluted with water, and extracted with methylene chloride (3×50 mL). The combined organic layers were washed with saturated NaCl solution (1×25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 4:1 petroleum ether/ethyl acetate solution, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:34])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:14]=2[CH:33]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:34][S:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)(=[O:45])=[O:44])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:15]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:14]=2[CH:33]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccc(F)cc1)n2-c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccc(F)cc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-2-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:12]=1
Reactant: OCc1cccs1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc(OCc2cccs2)n1

Procedure:
To a solution containing 2-thiophenemethanol (1.5 g, 0.0135×1.0 mol) and sodium hydride (0.58 g, (ca.60% in mineral oil), 0.0135×1.1 mol) in tetrahydrofuran, 2,6-dichloropyridine (2.0 g, 0.0135 mol) was added and the resultant solution was refluxed for about 2 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The obtained organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and thereafter, concentrated and purified on a silica gel column to obtain the end product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@H:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@H:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)O)Cc2onc(-c3ccc(Cl)cc3)c21
Yield: 85 %

Procedure:
0.079 g (0.25 mmol) of methyl cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate in 10 ml of dioxane was stirred at room temperature for 1 hour with 5 ml of 1N aqueous sodium hydroxide solution. Water was added and the solution was partially evaporated. The solution was acidified with 1N hydrochloric acid and the precipitate was collected, washed with water and dried to give 0.065 g of cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 213° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a(13.7 g, 55.1 mmol) and of aniline (5.12 g, 55.1 mmol) were heated neat at 100° C. for 30 minutes, then cooled down to room temperature and recrystallized from dichloromethane/hexane to yield 7.94 g of 2-(3,4-Dimethyl-benzoyl)-3-phenylamino-acrylic acid methyl ester 2a as a yellow crystalline solid: LC-MSD, m/z for C19H19NO3 [M+H]+=310.4; HPLC retention time: 2.8 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(O)c(F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 27.4 %

Procedure:
A solution of 3-fluoro-4-hydroxyphenylboronic acid (103 mg, 0.66 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP using silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA59 (26 mg, 27% yield). ESI-MS (M+H)+ m/z calcd 288, found 288.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9].CCO.Cl>O>[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)COc1ccc(-c2cccnc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(-c2cccnc2)cc1Cl

Procedure:
250 mg (6.250 mmol) NaOH in 10 mL water was added to a solution of 0.400 g (1.371 mmol) ethyl (2-chloro-4-pyridin-3-yl-phenoxy)-acetate in 40 mL abs. EtOH and the mixture was stirred for 1 h at RT. The reaction mixture was acidified with aqueous HCl (1 M) to pH 7.5, the precipitate was filtered off and washed with water.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 58 mg (56%) of the title compound as an off white solid.
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]([O:21][CH3:22])[C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][NH:12]2)=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[F:23][CH:24]([F:27])[CH2:25]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:23][CH:24]([F:27])[CH2:25][N:18]1[CH2:17][CH2:16][CH:15]([C:6]2[CH:7]=[C:8]3[C:13](=[N:14][C:5]=2[CH:4]([O:3][CH3:2])[O:21][CH3:22])[NH:12][CH2:11][CH2:10][CH2:9]3)[CH2:20][CH2:19]1
Reactant: FC(F)CI
Reactant: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1nc2c(cc1C1CCN(CC(F)F)CC1)CCCN2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(dimethoxymethyl)-6-(piperidin-4-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (Intermediate 342, 0.78 g, 2.14 mmol), 1,1-difluoro-2-iodoethane (0.63 g, 3.22 mmol) and K2CO3 (0.89 g, 6.43 mmol) in DMF (20 ml) was stirred at 70° C. After 16 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by reverse phase chromatography (Reprosil C18/250×30 mm/5 um, 35 ml/min, 0.1% TFA in H2O/acetonitrile 95:5 to 40:60 in 25 min, then to 5:95 in 1 min). The product-containing fractions were treated with NaHCO3 and then concentrated to remove acetonitrile. The watery residue was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4 and evaporated to give the title compound as a yellow solid. (UPLC-MS 3) tR 0.41; ESI-MS 356.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[CH:10]1([C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C[O-].[Na+]>C(O)CCC>[Cl:24][C:22]1[CH:23]=[C:18]2[C:19](=[CH:20][CH:21]=1)[N:25]([S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=1)(=[O:27])=[O:28])[CH:2]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[C:16]2([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[OH:17]
Reactant: CCCCOC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)C2CCCCC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2C1(O)C1CCCCC1

Procedure:
This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([NH:42]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=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>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[CH2:38][C@H:37]([NH2:42])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6) (47.3 mg, 0.133 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (41.0 mg, 0.118 mmol) and HATU (142.3 mg, 0.3742 mmol), DMF (2.0 mL) was added followed by DIPEA (115.8 mg, 0.8960 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (25.2 mg, 44%). LCMS calc. for C23H25F2N6O2S (M+H)+: m/z=487.2. found 487.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[F-].[Cs+].C[Si](C)(C)[C:38]([F:41])([F:40])[F:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23]([C:38]([F:41])([F:40])[F:39])([OH:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC1(C(F)(F)F)CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: -10 °C

Procedure:
rac-(4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13 b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3 (2H)-one (149, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.291 g, 0.662 mmol) was suspended in DME (7 mL) then CsF (0.060 g, 0.397 mmol) was added. The mixture was cooled to about −10° C. then trimethyl(trifluoromethyl)silane (0.185 g, 1.30 mmol) was added. After 15 min TBAF (1 M in THF) (0.695 mL, 0.695 mmol) was added and the mixture was allowed to warm to rt. The mixture was concentrated under reduced pressure then water (25 mL) was added to the material and the resulting solids collected by filtration. The material was purified on silica gel (12 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(3R,4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,7,13b-octahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3-ol (151, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Trifluoromethyl) (0.185 g, 55%); LC/MS, method 2, Rt=2.54 min, MS m/z 510 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.39-8.37 (m, 1H), 8.18 (s, 1H), 7.98-7.89 (m, 3H), 7.74 (s, 1H), 7.40-7.36 (m, 1H), 7.27-7.18 (m, 2H), 7.09-7.03 (m, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.97 (s, 1H), 3.59 (d, J=13.2 Hz, 1H), 3.43-3.32 (m, 1H), 3.15 (d, J=13.4 Hz, 1H), 3.08-3.03 (m, 1H), 2.23-2.17 (m, 1H), 2.13-2.07 (m, 1H), 2.04-1.86 (m, 3H), 1.83-1.67 (m, 5H), 1.46-1.36 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:24]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN(C)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 4-dimethylaminobenzylamine dihydrochloride (0.20 mmol, 45 mg) in glacial acetic acid (1 mL) was added triethylamine (0.40 mmol). The mixture was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:22]=1[CH3:37].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:22]=3[CH3:37])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2ccccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (63.5 mg, 0.24 mmol; described herein), 4-chloro-3-methyl-2-(pyridin-2-yl)quinoline (61.2 mg, 0.24 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (280 μL, 2.9 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, d, J=4.7 Hz), 8.19 (1H, d, J=8.2 Hz), 7.85-7.95 (2H, m), 7.81 (1H, dd, J=8.2, 0.8 Hz), 7.71 (1H, td, J=7.6, 1.2 Hz), 7.59 (1H, d, J=2.7 Hz), 7.47-7.55 (1H, m), 7.34-7.45 (1H, m), 6.78 (1H, s), 6.24 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.73 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.13-3.36 (4H, m), 2.87-3.01 (4H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=483.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:16]2[C:15](=[O:18])[N:4]3[N:5]=[CH:6][C:7]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:23][CH:22]=1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 55 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirring suspension of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.12 g, 4.0 mmol) and 4-(trifluoromethyl)benzyl bromide (1.24 g, 5.2 mmol) in DMF (15 mL) at RT under argon was added K2CO3 (0.83 g, 5.2 mmol). The resulting mixture was heated at 55° C. for 2 h. After 2 h, HPLC/MS analysis indicated the reaction was complete. The reaction mixture was cooled to RT and EtOAc (100 mL) was added. The resulting mixture was washed with saturated NaCl (50 mL×2). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. This crude product was washed with MeOH (10 mL×2), then dried under vacuum at room temperature for 3 h to obtain the title compound, 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.3 g, 74%) as a yellow solid. MS [M+H]+ 439; HPLC retention time=3.92 min; 1HNMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.45-7.61 (m, 8H), 5.32 (s, 2H).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:17]2[NH:21][CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[C:7]1([CH:17]2[N:21]([C:24](=[O:25])[CH2:23][Cl:22])[CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc2c(C3NCCO3)cccc2c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)N1CCOC1c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nineteen and nine tenths (19.9) ml of a benzene solution containing 5 g. of 2-α-naphthyl oxazolidine was combined with 50 ml. of benzene and 2.8 g. of chloroacetyl chloride. To this was added 2.6 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred at room temperature for 30 minutes after addition was complete, washed with water, separated and dried over magnesium sulfate. The solvent was stripped under vacuum. There was obtained a yield of 6.7 g. of an oil, the title compound, ND30 =1.6030.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1([CH3:28])[CH2:19][C:18]2[CH:20]=[CH:21][C:22]([CH3:27])=[C:23]([N:24]=[C:25]=[O:26])[C:17]=2[O:16]1>C(OCC)(=O)C>[C:1]1([C:7]2([CH2:12][NH:13][C:25]([NH:24][C:23]3[C:17]4[O:16][C:15]([CH3:14])([CH3:28])[CH2:19][C:18]=4[CH:20]=[CH:21][C:22]=3[CH3:27])=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1(c2ccccc2)CCCC1
Reactant: Cc1ccc2c(c1N=C=O)OC(C)(C)C2
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1NC(=O)NCC1(c3ccccc3)CCCC1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 60 mg amount of (1-phenycyclopentyl)methylamine was added to a solution of 70 mg of 2,2,6-trimethyl-2,3-dihydrobenzofuran-7-yl isocyanate in 2 ml of ethyl acetate, and the mixture was stirred at room temperature for 15 hrs. The solvent was removed by evaporation under reduced pressure, and the residue was subjected to recrystallization to provide 65 mg of the intended title compound.