Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:35])=[CH:8][C:9](=[O:34])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:35])=[CH:8][C:9](=[O:34])[N:10]2[CH2:13][CH2:14][CH2:15][C:16]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCNCC1
Reaction time: 14 h

Procedure:
To 2 mL of a chloroform solution containing 0.45 g of 1-tert-butyl 4-ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate, 1 mL of trifluoroacetic acid was added, and the mixture was stirred for 14 hours. The solvent was removed under reduced pressure, and water and diethyl ether were added thereto. The aqueous layer was separated, ethyl acetate was added thereto, and the resultant solution was adjusted to pH 12.5 with a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.29 g of a yellow oily substance, ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:24])[CH:10]2[NH:14][C:15](=[O:23])[CH2:16][C:17]2[S:18][C:19](=[O:22])[S:20][CH:21]=2)[C:7]=1[C:25]([OH:27])=[O:26])(=O)C.C(=O)(O)[O-].[Na+].[C:33]([NH:36][CH:37]1[S:41][C:40](=[S:42])[N:39]=[N:38]1)(=[O:35])[CH3:34].[S-]C#N.[K+]>O>[C:33]([NH:36][C:37]1[S:41][C:40]([S:42][CH2:5][C:6]2[CH2:13][S:12][CH:11]3[N:8]([C:9](=[O:24])[CH:10]3[NH:14][C:15](=[O:23])[CH2:16][C:17]3[S:18][C:19](=[O:22])[S:20][CH:21]=3)[C:7]=2[C:25]([OH:27])=[O:26])=[N:39][N:38]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NC1N=NC(=S)S1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Agent: N#C[S-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 60 °C
Yield: 17.7 %

Procedure:
A mixture of 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo-[4.2.0]-oct-2-ene (12.9 g.) in water (50 cc.), sodium bicarbonate (5.52 g.) and 5-acetylamino-2-thioxo-1,3,4-thiadiazoline (6.3 g.) and potassium thiocyanate (58 g.) is heated to 60° C. for 10 hours. The mixture is allowed to cool and diluted with 1 liter of water. A slight amount of insoluble matter is filtered off on "Supercel" and the filtrate is washed with ethyl acetate (250 cc.), which is discarded. It is brought to pH 2 by adding 4 N hydrochloric acid in the presence of ethyl acetate (250 cc.). A solid (6.3 g.) is filtered off and taken up in boiling methanol (200 cc.). An insoluble material is filtered off and the filtrate is concentrated to dryness under reduced pressure (20 mm.Hg). The solid residue obtained is washed with methanol (5 cc.) to give 3-[(5-acetylamino-1,3,4-thiadiazol-2-yl)-thiomethyl]-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2.9 g.).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:23]1[CH2:26][N:25]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CN(C=O)C>[C:28]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]2[CH2:26][CH:23]([N:11]3[C:7]([CH2:6][C:5]4[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:10]3)[CH2:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: IC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)n[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-[5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (3.7 g, 14.6 mmol) in DMF (40 mL) was added NaH (0.584 g, 14.6 mmol) and the solution was stirred for 10 minutes under nitrogen. 3-Iodo-N-benzhydryl-azetidine (5.61 g, 16.1 mmol) was then added and the reaction mixture was heated to 110° C. for 2 hours under nitrogen. The solvent was removed in-vacuo and the residue was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and stripped to yield a crude mix of regioisomers. The residue was purified by flash chromatography (5:95 MeOH/CH2Cl2) to yield a clean mix of regioisomers that were separated by SF chromatography to yield the title compound as a lyophilized solid (2.35 g, 34%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.62 (d, 2 H), 7.69 (d, 2 H), 7.42 (d, 4 H), 7.24-7.31 (m, 4 H), 7.14-7.24 (m, 2 H), 7.02-7.09 (m, 2 H), 6.97 (s, 2 H), 6.36-6.39 (m, 1 H), 4.74-4.87 (m, 1 H), 4.57 (s, 1 H), 3.94 (s, 2 H), 3.51-3.62 (m, 4 H); m/z (APCI+) for C32H27N4F 475.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[S:48](Cl)(=[O:50])=[O:49].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:41]=[CH:40][C:39]=1[S:48]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:19][CH:18]=1)(=[O:50])=[O:49]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2-chloro-4-trifluoromethyl benzenesulfonyl chloride (0.084 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 6 days. PS-isocyanate resin (Argonaut Technologies, Foster City, Calif.; 0.050 g) and PS-trisamine resin (Argonaut Technologies; 0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off and was washed with methylene chloride. The filtrate was concentrated to give the title compound of Step A. MS 639.4 (M+1)+
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13]C(=O)C)[C:9]([CH:17]([CH3:19])[CH3:18])=[CH:8][C:7]=1[CH:20]([CH3:22])[CH3:21])(=O)C.[OH-].[K+]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[C:9]([CH:17]([CH3:18])[CH3:19])=[CH:8][C:7]=1[CH:20]([CH3:22])[CH3:21]
Reactant: CC(=O)OCc1cc(COC(C)=O)c(C(C)C)cc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(C(C)C)c(CO)cc1CO

Procedure:
40.2 g (131 mmol) of the compound from Example 2 are stirred at 50° C. for 3 h with 16.1 g (0.3 mol) of potassium hydroxide in 200 ml of methanol. After distilling off the solvent, the residue is taken up in ether, washed with water, dried using sodium sulphate and recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [OH:1][C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][CH:23]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:24])[CH2:4][CH2:3]1.[BH4-].[Na+]>>[OH:1][C:2]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[CH:19]([OH:20])[C:18]3[CH:21]=[CH:22][CH:23]=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:24])[CH2:6][CH2:7]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1c2cccc3cccc(c23)C(O)N1CCN1CCC(O)(c2ccccc2)CC1

Procedure:
The product from part (a) is reacted with sodium borohydride as taught in either example 1 or 38 to yield the titled compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>>[O:23]=[C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH2:12][CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[NH:22]1
Reactant: CCOC(=O)C1CCC(Cc2nc3ccccc3c(=O)[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CCC(Cc2nc3ccccc3c(=O)[nH]2)CC1
Temperature: 65 °C

Procedure:
The cis/trans mixture of 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid ethyl ester (Compound BBA) (1 g) was dissolved in a minimal amount of TBF (10 mL) and mixed with concentrated aqueous LiOH (5 mL). The resulting reaction mixture was stirred vigorously and heated at 65° C. for 3 h. After cooling and concentration, the reaction mixture was acidified to pH 4 with dilute HCl and concentrated to dryness: mass spectrum m/z 287 [(M+H)+; calcd for C16H18N3O3: 286].
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH:33]=O)([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (WO 0130768) (1.09 g, 3.19 mmol) and (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Seki et. al. Chem. Pharm. Bull. 1996, 44, 2061) (0.59 g, 3.19 mmol) in dichloromethane (80 mL) was added sodium triacetoxyborohydride (1.01 g, 4.79 mmol). The resultant cloudy mixture was maintained at ambient temperature for 4 hours, at which time it was quenched with brine (75 mL) and stirred vigorously for 10 minutes. The aqueous layer was extracted with dichloromethane (50 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (1.62 g, 99%) as a yellow solid which was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH:5]=[C:4]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:4]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:3]=1
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
tert-Butyl 3-[2-methyl-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.96 g, 2.5 mmol) was dissolved in trifluoroacetic acid (8 ml), and the mixture was stirred at 0° C. for 2 hrs. The solvent was evaporated, and the residue was recrystallized from diisopropyl ether-ethanol to give the titled compound (0.74 g, 90%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]Cl)=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:14][NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][N:15]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH3:14])=[C:6]([Cl:8])[N:7]=1
Reactant: CCOC(=O)c1ccc(NC)cc1
Reactant: N#Cc1nc(CCl)c(Cl)nc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)Cc2nc(C#N)c(N)nc2Cl)cc1
Yield: 34.7 %

Procedure:
Compound 4 (4.04 g, 0.02 mole) and ethyl 4-methylaminobenzoate hydrochloride (3) (4.10 g, 0.02 mole) were dissolved in 200 ml of tetrahydrofuran. The solution was chilled in an ice bath, and to the solution was added slowly a potassium carbonate solution (3.0 g, 0.022 mole in 200 ml water) with stirring. After 24 hours of continuous stirring at room temperature, a yellow precipitate was collected and washed with water. Recrystallization of the product from methanol gave 2.4 g (70% yield) of yellow solid 5. This solid had a melting point of 206°-207° C. The IR spectrum (KBr) showed absorptions corresponding to --NH2 at 3389.9, 3194, and 3264 cm-1, --C≡N at 2240 cm-1, and --C(=O)O-- at 1713 cm-1. The nmr spectrum (DMSO-d6) revealed signals at 7.75 δ (2H,b,NH2), 7.70 δ (2H,d,arom), 6.67 δ (2H,d,arom), 4.35 δ (2H, s,CH2N--), 4.21 δ (2H,q,OCH2CH3), 3.20 δ (3H,s,NCH3), and 1.32 δ (3H,t,CH2CH3). The FAB mass spectrum showed a molecular ion peak at m/z 345. This peak confirmed that the molecular weight of this compound was 345. Elemental analysis confirmed the presence of C, H, N and Cl in the compound.
Reaction SMILES: [N+:1]([C:4]1[C:8]([C:9]2[CH:14]=[C:13]([O:15][C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=2[OH:20])=[CH:7][N:6]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:5]=1)([O-:3])=[O:2].[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45](F)=[CH:44][C:43]=1[F:50])(=[O:41])=[O:40])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:27]([O:31][C:32](=[O:51])[N:33]([S:39]([C:42]1[CH:47]=[C:46]([Cl:48])[C:45]([O:20][C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:14][C:9]=2[C:8]2[C:4]([N+:1]([O-:3])=[O:2])=[N:5][N:6]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:7]=2)=[CH:44][C:43]=1[F:50])(=[O:40])=[O:41])[C:34]1[N:35]=[CH:36][S:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(OC(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethoxy)phenol (Preparation 24, 2.00 g, 5.36 mmol) and tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 4, 2.20 g, 5.36 mmol) in dimethylsulfoxide (30 mL) was added potassium carbonate (1.5 g, 11 mmol). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was then diluted with water and extracted with ethyl acetate (×3). The combined organic phase was washed with water (×2) then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ether and the solid collected by filtration and dried in vacuo to afford the title compound with a 5% de-boc impurity (3.70 g). The compound was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5]2.[H-].[Na+].Cl[CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=1)[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5]2
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CC(C)c1cc2cc(Cl)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(C(C)C)cc3cc(Cl)ccc32)o1
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-2-isopropylindole (136 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 32 mg) under cooling with ice, and the mixture was stirred for 30 minutes. Then ethyl 5-(chloromethyl)furan-2-carboxylate (0.107 mL) was added, and the mixture was stirred at 60° C. for 20 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (133 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-:11].[K+].[K+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10](=[O:11])[O:9][C:3]=2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(F)cc1O
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(F)cc2o1
Temperature: 25 °C
Yield: 96 %

Procedure:
To 5.0 g (39.3 mmol) 2-amino-5-fluorophenol in 150 ml of CH2Cl2 at 0° C. was added 13.4 (98 mmol) of potassium carbonate and 23 g (47 mmol) of 20 wt % phosgene in toluene. After warming to room temperature, the reaction was stirred an additional hour before pouring into 200 ml ice/water. The layers were separated and the aqueous phase was extracted with EtOAc (1×100 ml) before the organics were combined and dried over Na2SO4. The solvent was removed in vacuo to give 5.76 g (96% yield) of the desired product as determined by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:24]([CH3:27])=[N:25][N:26]=4)[C:18]=3[CH:17]=[C:16]2[C:28]2[O:29][CH:30]=[N:31][N:32]=2)[CH:13]=1)[CH2:5][N:6]1[CH2:9][CH:8](O)[CH2:7]1.N1CCC1>C1COCC1>[N:6]1([CH2:5][C:4]2[CH:11]=[C:12]([CH:13]=[C:2]([Cl:1])[CH:3]=2)[CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:24]([CH3:27])=[N:25][N:26]=4)[C:18]=3[CH:17]=[C:16]2[C:28]2[O:29][CH:30]=[N:31][N:32]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CN4CC(O)C4)c3)n12
Agent: C1CNC1
Solvent: C1CCOC1
Product: Cc1nnc2ccc3c(cc(-c4nnco4)n3Cc3cc(Cl)cc(CN4CCC4)c3)n12
Reaction time: 0.33 h

Procedure:
The remaining mesylate solution prepared in Example 139, Step 5 was treated with the solution of azetidine (0.023 mL, 0.33 mmol, Aldrich) in THF (0.2 mL). After 20 minutes, additional azetidine (0.078 mL, 1.1 mmol, Aldrich) was added and the reaction was stirred overnight. The product was isolated by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5 mg, 10%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:25])=[N:20][C:21]=1[CH2:22][CH2:23][CH3:24]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:25][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]=2)[CH:7]=1
Reactant: CCCc1nc(N)ccc1OC
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCCc1nc(Nc2cc(Cl)nnc2C(=O)OCC)ccc1OC
Temperature: 70 °C
Yield: 40.5 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.9 g, 8.6 mmol) in acetonitrile (28.7 mL) was added 5-methoxy-6-propylpyridin-2-amine (1.43 g, 8.6 mmol) and the mixture heated at 70° C. for 72 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 10 to 60% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol, 41%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.58 (s, 1H), 8.84 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.58 (q, J=7.3 Hz, 2H), 3.88 (s, 3H), 2.87 (t, J=7.5 Hz, 2H), 1.84 (m, 2H), 1.52 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 351.0 [M+H].
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:17]([SH:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([S:21][C:2]1[C:3]([C:8]2([OH:16])[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:18][CH2:19][CH3:20]
Reactant: OC1(c2nccnc2Cl)CN2CCC1CC2
Reactant: CCCCS
Product: CCCCSc1nccnc1C1(O)CN2CCC1CC2
Temperature: 25 °C

Procedure:
A 1 g sample of 60% NaH dispersion in oil was triturated twice with hexane then suspended in 300 ml of THF. The mixture was treated with 5 ml of butanethiol and after 30 min the mixture was heated to reflux for 45 min. After cooling to ambient temperature, 1.5 g of (7), (0.0063 mol) was added and the reaction was heated to reflux for 1 h. The mixture was diluted with 100 ml of butanethiol and the reaction was heated to reflux overnight. The solvent was removed by distillation, the residue suspended in 50 ml of H2O, and the mixture extracted 3× with 25 ml of CHCl3, the extracts washed with brine, and the solvent evaporated. The brown solid residue was recrystallized from ether to give 1.25 g of 3-(3-butylthiopyrazinyl)-1- azabicyclo[2.2.2]octan-3-ol (29a). NMR ppm (CDCl3) 0.97 (3H, t), 1.19 (1H, t), 1.19 (1H, m), 1.35-1.57 (4H, m), 1.7 (2H, m), 2.21 (1H, m), 2.5-3.02 (6H, m), 3.2 (2H, m), 4.1 (1H, d), 4.5 (1H, m), 8.17 (1H, d), 8.25 (1H, d). A solution of 1.2 g of (29a) (0.0041 mol) in 100 ml of CH2Cl2 was cooled to 0° C. as 0.95 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1 h the reaction was heated to reflux for 45 min. After cooling to ambient temperature, the reaction was treated with ice and the solution was made basic with 1 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated to give a brown liquid. The liquid was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3 to give 1 g of 3-chloro-3-(3-butylthiopyrazinyl)-1-azabicyclo[2.2.2]octane (29b). NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (3H, m), 1.7 (4H, m), 2.38 (1H, m), 2.7 (2H, m), 2.98 (1H, m), 3.05-3.4 (4H, m), 3.76 (1H, d), 4.19 (1H, d), 8.18 (1H, d), 8.3 (1H, d). A mixture of 1 g of (29b) (0.0032 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi of H2. The catalyst was removed, the solvent was evaporated, the residue suspended in 5 ml of H2O, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% NH4OH-CHCl3 and then 10% ethanol-1% NH4OH-CHCl3. The hydrochloride salt (29) crystallized from ethyl acetate to give 0.44 g of a floculant white solid, mp 193°-194° C. NMR ppm (CDCl3) 0.99 (3H, t), 1.5 (2H. m), 1.7 (4H, m), 2.15 (2H, m), 2.5 (1H, m), 3.23 (3H, m), 3.4 (3H, m), 3.64 (2H, m), 4.38 (1H, q), 8.21 (1H, d), 8.31 (1H, d). Anal. C15H23N3S-HCl requires C: 57.40; H: 7.71; N: 13.37%. Found C: 57.14; H: 7.92; N: 13.12%.