Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCCCO3)c2n1
Temperature: 60 °C

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (21 mmol) is taken up as a suspension in dry ethyl acetate (50 mL). Following the addition of 4-toluenesulfonic acid monohydrate (25 mg), the mixture is heated to 60° C. and 3,4-dihydro-2H-pyran (2.5 mL) is added in drops. The reaction mixture is maintained at 60° C. for 18 hours and is then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography. Following concentration of fractions, 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine is obtained. 6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.1 mmol) is coupled to 4-acetamidophenylboronic acid (0.83 g, 4.6 mmol) with tetrakis(triphenylphosphine) palladium (0) (2.5 mol %), 2 M aqueous sodium carbonate solution, and ethylene glycol dimethyl ether (DME) and under microwave irradiation (175 C, 10 min). Following an aqueous workup and flash chromatography, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is obtained. N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide (1.2 mmol) is taken up in dioxane (5 mL), treated with 4 M hydrogen chloride in dioxane (5 mL), and allowed to stir at room temperature for 3 days. The slurry is concentrated and purified by reverse phase preparative high performance liquid chromatography, employing a Phenomenex Prodigy 250 mm×21.2 mm 5 μm column and a 5% acetonitrile/95% water/0.1% trifluoroacetic acid to 100% acetonitrile gradient over 40 minutes. After concentration, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is provided.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].F[C:25]1[C:30]([F:31])=[C:29]([I:32])[CH:28]=[CH:27][N:26]=1.CS(C)=O>C(OCC)(=O)C>[F:31][C:30]1[C:25]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)=[N:26][CH:27]=[CH:28][C:29]=1[I:32]
Reactant: Fc1nccc(I)c1F
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3nccc(I)c3F)ccc2=O)cc1
Temperature: 85 °C

Procedure:
To a 20 mL microwave vial (Biotage) was added 0.70 g (3.03 mmol) 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one, 1.26 g (9.08 mmol) potassium carbonate, 1.10 g (4.54 mmol) 2,3-difluoro-4-iodopyridine and 15 mL DMSO. A yellow suspension formed and the vial was sealed and heated at 85° C. for 48 h on a heat block. The suspension was cooled, diluted with ethyl acetate, and washed twice with 10 mL brine. The organic layer was dried over sodium sulfate, filtered, and evaporated onto silica gel. Purification by flash chromatography (silica gel 0-100% hexanes/EtOAc gradient, followed by 10% MeOH in EtOAc) afforded 3′-fluoro-4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one as a yellow solid. LCMS (M+H)+ 453.3.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:13]3[C:18]([C:19](=[O:20])[C:3]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3.C(=O)([O-])[O-].[Li+].[Li+].Cl.[CH2:28]([N:30]([CH2:34]C)[CH2:31][CH2:32][SH:33])C.CN(C)C=O>O>[CH3:28][N:30]([CH2:31][CH2:32][S:33][C:2]1[C:11]2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:13]3[C:18]([C:19](=[O:20])[C:3]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:34]
Reactant: O=C1c2ccccc2-c2nc3ccc(O)cc3c(Cl)c21
Reactant: CCN(CC)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSc1c2c(nc3ccc(O)cc13)-c1ccccc1C2=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
A mixture of 400 mg (1.4 mmol) of 10-chloro-8-hydroxy-11H-indeno[1,2-b]quinolin-11-one, 629 mg (8.5 mmol) of lithium carbonate, 963 mg (5.7 mmol) of 2-diethylaminoethanethiol hydrochloride and 8 ml of N,N-dimethylformamide was stirred for 5 hours with heating at 90° C. After completion of the reaction, the reaction mixture was added to water, and precipitated crystals were collected by filteration. The crystals were recrystallized from ethanol, giving 310 mg of the title compound (yield: 57.7%). The property values are shown in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[Cl:13]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(Br)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1Cl
Temperature: 25 °C

Procedure:
Ethyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 187, 2.87 g, 12.4 mmol) was dissolved in dry DMF (30 ml), N-chlorosuccinimide (1.66 g, 12.4 mmol) was added and resulting mixture was stirred at room temperature over night, more N-chlorosuccinimide (0.83 g, 6.2 mmol) was added and the reaction temperature was increased to 35° C., stirred for 4 hours. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (50 ml), extracted with diethyl ether (2×50 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and purified by column chromatography(hexanes/ethyl acetate, gradient) to give the desired product as a white crystal. (1.2 g).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([C:46]2[CH:51]=[CH:50][C:49]([O:52]C)=[CH:48][CH:47]=2)[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][C:12]([O:44]C)=[CH:13][CH:14]=2)[S:9][CH2:8]1)[CH3:6].O>ClCCl>[CH2:5]([C:7]1([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:40])([F:39])[F:41])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][C:12]([OH:44])=[CH:13][CH:14]=2)[S:9][CH2:8]1)[CH3:6]
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(OC)cc2SCC1(CC)c1ccc(OC)cc1)CCCCCCC(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(CC)c1ccc(O)cc1)CCCCCCC(F)(F)C(F)(F)F
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M, 8.82 ml, 8.82 mmol) was added dropwise to a solution of ethyl 10-[(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (1.05 g, 1.47 mmol) in dichloromethane (15 ml) at −78° C. under argon atmosphere. The reaction mixture was warmed with stirring up to 10° C. over 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was dissolved in ethanol (5 ml) and mixed with concentrated sulfuric acid (1 drop), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (550 mg, Yield 55%).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH:8](I)[CH2:7][CH2:6][C:5]2[C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:4]1=2)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([CH:8]1[C:9](=[O:10])[N:3]([CH2:1][CH3:2])[C:4]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[C:5]=2[CH2:6][CH2:7]1)=[N+:22]=[N-:23]
Reactant: CCN1C(=O)C(I)CCc2c1ccc([N+](=O)[O-])c2OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(N=[N+]=[N-])CCc2c1ccc([N+](=O)[O-])c2OC

Procedure:
Combined (+/−)-1-ethyl-3-iodo-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.3 g), Sodium azide (2.17 g) and N,N-Dimethylformamide (20 mL) in flask under nitrogen and stirred overnight. Partitioned between EtOAc/water. The organic layers were further washed with water, brine, dried (MgSO4), filtered and concentrated. Stripped onto Celite and purified by ISCO chromatography (120 g SiO2, hexane to EtOAc gradient). (+/−)-3-Azido-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one isolated as a clear oil (402 mgs). 1H-NMR (CDCl3, 400 MHz): 7.86 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 4.33-4.25 (m, 1H), 3.98 (s, 3H), 3.78-3.71 (broad m, 2H), 3.35-3.23 (broad m, 1H), 2.65-2.35 (broad m, 3H), 1.25-1.21 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH3:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:29][C:25]1[C:24]([CH3:30])=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), prepared as described in Example 3, step f, 1-(bromomethyl)-3-chloro-2-methylbenzene (237 mg, 1.08 mmol) and Na2CO3 (153 mg, 1.44 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (100 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (239 mg, 80%); LC/MS: MS (ES+) m/e 415 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 2.44 (s, 3H), 3.42 (t, J=4.8 Hz, 4H), 3.69 (t, J=4.8 Hz, 4H), 3.92 (s, 3H), 5.45 (s, 2H), 6.37 (d, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 7.36 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[C@@H:30]4[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][CH:16]=2)=[O:20])[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Yield: 77.3 %

Procedure:
cis-4-[4-(octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid t-butyl ester (0.06 g, 0.14 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue product was purified by flash chromatography on a SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.036 g). LCMS m/z 333.20 [M+H]+ RT=6.44 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 3.8 (m, 1H), 3.2 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.0-1.1 (m 18H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=[S:30])[CH3:2]
Reactant: CNc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CNc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluoro-phenyl]oxazolidine-2-one (0.100 g, 0.356 mmol) and Lawesson reagent (0.144 g, 0.356 mmol) in dioxane (3 mL) was stirred at 65° C. for 2 h. Solvent was removed under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a product as foam. Yield 0.097 g (92%). MS (m/z): [M+H]+=298.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32](=[O:34])[CH3:33])[N:27]=[CH:26]2>ClCCl>[C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:31][CH:30]=2)[CH:26]=[N:27]1)(=[O:34])[CH3:33]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)n1ncc2cc(O)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)n1ncc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
112 μl (1.2 eq; 0.667 mmol) of trifluoromethanesulfonic anhydride and 337 μl (17.5 eq; 49.557 mmol) of pyridine, under an argon atmosphere, are added dropwise to a solution of 98 mg (1 eq; 0.556 mmol) of 1-(5-hydroxyindazol-1-yl)ethanone in 10 ml of dichloromethane on amylene, pre-cooled to 0° C. The medium is stirred and kept at 0° C. overnight under an argon atmosphere. 112 μl of trifluoromethanesulfonic anhydride and 337 μl of pyridine are added to the medium, which is stirred for 2 hours at 0° C. 112 μl of trifluoromethanesulfonic anhydride and 337 μl of pyridine are then added, and the medium is then stirred for 3 hours at 0° C. The reaction mixture is washed with 10 ml of water. The aqueous phase is treated with 2 times 10 ml of dichloromethane. The organic phase is dried over magnesium sulfate and then filtered and the solvent is evaporated off under reduced pressure in a rotary evaporator to obtain 168.9 mg of trifluoromethanesulfonic acid 1-acetyl-1H-indazol-5-yl ester are obtained.
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([C:20]3[CH2:21][CH2:22][O:23][CH2:24][CH:25]=3)[N:12]2[N:11]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][C:10]1[NH:15][C:14](=[O:16])[C:13]2=[CH:17][N:18]=[C:19]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:12]2[N:11]=1
Reactant: O=c1[nH]c(COCc2ccccc2)nn2c(C3=CCOCC3)ncc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]c(CO)nn2c(C3CCOCC3)ncc12
Yield: 143.7 %

Procedure:
To a solution of compound 6 (650 mg, 1.14 mmol) in MeOH (30 mL) was added Pd(OH)2/C (120 mg). The reaction mixture was stirred under 50 psi of hydrogen at 70° C. until LC-MS showed that the starting material was almost consumed. The suspension was filtered through celite and washed with MeOH (20 mL×2) and the filtrate was concentrated in vacuo to afford compound 7 (410 mg, 85% yield) as a white solid. LC-MS: m/z 251.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[OH-].[Na+].O.[CH2:13]([SH:16])[CH2:14][CH3:15]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([S:16][CH2:13][CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: CCCS
Reactant: Clc1cc(Br)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCSc1ncc(Br)cc1Cl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2,3-dichloropyridine (4.47 g, 19.7 mmol) and NaOH (867 mg, 21.7 mmol) in DMSO (50 mL) was treated with sufficient H2O to effect dissolution. n-PrSH (1.96 mL, 21.7 mmol) was added, then the reaction was stirred at 20° C. for 4 h. The mixture was poured onto crushed ice (200 g) and then extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extracts were washed with H2O (3×100 mL) and brine (3×100 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH) provided 5-bromo-3-chloro-2-propylsulfanylpyridine: m/z (ES+)=268.0 [M+H]+. Step 2: Reaction of this bromopyridine (2.73 g, 10.2 mmol) with (Z)-methyl 3-cyclopentyl-2-iodoacrylate (1.84 g, 6.6 mmol), according to the cross-coupling conditions described in Step 2 of Preparation 9, gave (E)-methyl 2-(5-chloro-6-propylsulfanylpyridin-3-yl)-3-cyclopentylacrylate: m/z (ES+)=340.1 [M+H]+. Step 3: Saponification of this ester (770 mg, 2.3 mmol), using a similar protocol to that described by Step 2 of Preparation 3, furnished the title compound: δH (CDCl3): 1.05 (t, 3H), 1.40-1.85 (m, 10H), 2.45-2.60 (m, 1H), 3.20 (t, 2H), 7.15 (d, 1H), 7.40 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.B.C1COCC1.Cl>C1COCC1.O1CCOCC1>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([CH2:16][NH2:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:5]2=[N:4][CH:3]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Agent: B
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)COc1c(CN)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (477 mg, 1.0 mmol, prepared according to Example 35, Step 20.2) in anhydrous THF (12 mL) were added a BH3.THF complex (1.0 M solution in THF, 4.5 mL, 4.5 mmol) followed by a 4M HCl solution in dioxane (10 drops) at RT. The reaction mixture was heated at 50° C. and stirred for 3 h, then cooled to 0° C. (ice bath), quenched by the cautious addition of a 2M HCl solution in water (10 mL) and poured into water (100 mL). The aqueous mixture was washed with Et2O (2×30 mL) then basified to pH 10 by the addition of a 2M Na2cO3 solution in water and extracted with DCM (2×30 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated to dryness to yield the crude C-[3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-yl]-methylamine intermediate.
Reaction SMILES: [CH3:1][NH2:2].O.Cl[C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=[C:7]([Cl:15])[CH:6]=1>CC#N>[Cl:15][C:7]1[CH:6]=[C:5]([NH:2][CH3:1])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CN
Solvent: CC#N
Solvent: O
Product: CNc1cc(Cl)ncc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
40% Methylamine in water (0.847 mL, 9.78 mmol) was added slowly over 5 minutes at 0° C. to a solution of methyl 4,6-dichloronicotinate (0.40 g, 1.94 mmol) in MeCN (6 mL). The solution was stirred at 0° C. for 30 minutes then at room temperature for 2 hours. The reaction mixture was concentrated in vacuo onto silica gel. Gradient chromatography, eluting with 5% EtOAc:c-Hex over 5 column volume and 5-50% over 15 column volume, gave methyl 6-chloro-4-(methylamino)nicotinate (278 mg, 1.386 mmol, 71.4% yield) as a white solid.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5].S(OC)(O[CH3:22])(=O)=O>[OH-].[Na+].O>[CH3:22][O:1][CH:2]=[C:3]([C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][CH:13]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=CO)c1cccc(C(F)(F)F)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC=C(C(=O)OC)c1cccc(C(F)(F)F)c1
Reaction time: 40 h

Procedure:
ba) 26 g of methyl 3-hydroxy-2-(α,α,α-trifluoro-m-tolyl)acrylate were dissolved in 1N sodium hydroxide solution while cooling in an ice-bath and treated with 10.6 ml of dimethyl sulfate. The mixture was stirred at about 0° for about 40 hours and an additional 40 ml of 1N sodium hydroxide solution and 3.8 ml of dimethyl sulfate were added. After the reaction was completed, the mixture was diluted with water and extracted with methylene chloride. After drying with sodium sulfate, the extract was distilled, whereby methyl 3-methoxy-2-(α,α,α-trifluoro-m-tolyl)-acrylate was obtained as a colorless oil of b.p. 75°-90°/0.2 mm.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[CH:36]([C@H:38]1[CH2:43][CH2:42][C@H:41]([C:44]#[N:45])[CH2:40][CH2:39]1)=O.C(=O)([O-])O.[Na+]>C(OCC)C>[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:36][C@H:38]3[CH2:43][CH2:42][C@H:41]([C:44]#[N:45])[CH2:40][CH2:39]3)=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Reactant: Fc1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: N#C[C@H]1CC[C@H](C=Cc2ccc(-c3ccc(F)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 12.05 g of [2-(3,4-difluorophenyl)-5-pyridyl]methyltriphenylphosphonium chloride in 70 ml of diethyl ether is treated with 2.67 g of potassium tert.-butylate in a nitrogen atmosphere. The dark yellow suspension is stirred at room temperature for a further 30 minutes. A solution of 2.74 g of -trans-4-formylcyclohexanecarbonitrile in 30 ml of diethyl ether is then added dropwise at 0° C. The reaction mixture is stirred at 0° C. for a further 1 hour, then stirred with 40 ml of 1N sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase is separated, washed neutral with water, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane/ethyl acetate 3:1 (v/v). There is obtained trans-4-[2-[2-(3,4-difluorophenyl)-5-pyridyl]vinyl]cyclohexanecarbonitrile.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][C:6]([OH:8])=O.[OH:10][PH:11]([OH:13])=[O:12].P(Cl)(Cl)Cl>O>[CH3:1][N:2]1[C:3]([P:11]([OH:13])(=[O:10])[OH:12])([P:11]([OH:13])(=[O:10])[OH:12])[CH2:4][CH2:5][C:6]1=[O:8]
Reactant: CNC(=O)CCC(=O)O
Reactant: O=[PH](O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CN1C(=O)CCC1(P(=O)(O)O)P(=O)(O)O
Reaction time: 5 h

Procedure:
28.5 gm of succinic acid monomethylamide (0.216 mol) were melted with 35.4 gm of H3PO3 (0.432 mol) at 70°C and then slowly mixed with 37.8 ml of PCl3 (0.432 mol). After an additional 5 hours at 70°C, the product was hydrolyzed with 300 ml of H2O. Filtration with activated carbon at the boiling point yielded a clear solution from which the N-methylpyrrolidone-5,5-diphosphonic acid was precipitated with ethanol and acetone. Crude yield 4.2 gm (7% of the theory).