Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:11][N:12]([CH2:14][C:15]1[C:19]([F:20])=[C:18]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH:16]=1)C.C(Cl)(=O)OC(Cl)C.C(N(CC)CC)C>O1CCCC1>[F:20][C:19]1[C:15]([CH2:14][NH:12][CH3:11])=[CH:16][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:18]=1[C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN(C)Cc2cn(S(=O)(=O)c3cccnc3)c(-c3cccnc3F)c2F)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1F
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 1-(2,4-dimethoxyphenyl)-N-{[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (5.68 g) in tetrahydrofuran (25 mL) was added a solution of 1-chloroethyl chlorocarbonate (1.58 g) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 15 min. Triethylamine (4.63 mL) was added and the obtained mixture was stirred at 65° C. for 16 hr. The obtained solid was filtrated and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (25 mL) was added to the residue, and the mixture was refluxed for 1.5 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated solid was filtrated. To the obtained solid were successively added ethyl acetate, 1 mol/L aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was stirred at room temperature for 10 min. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 3.10 g, 77%).
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[CH3:12][C:13]1[CH:14]=[N+:15]([O-])[C:16]2[C:17](=[O:28])[C:18]3[C:23]([C:24](=[O:27])[C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:14]1[C:13]([CH3:12])=[CH:26][C:25]2[C:24](=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[N:15]=1)[CH3:31]
Reactant: CCO
Reactant: Cc1cc2c([n+]([O-])c1)C(=O)c1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCOc1nc2c(cc1C)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
5 portions of 0.08 g (0.42 mmol of tosyl chloride were added to an agitated solution of 100 mg. (0.42 mmol) of 3-methyl-1-azaanthracen-9,10-dione 1-oxide in absolute ethanol at 75°-78° C. for 1 hour. Then the mixture was agitated at room temperature overnight and a yellow solid (58 mg, 0.22 mmol) corresponding to the compound (I-b) (yield 52%) was filtered. The starting product was recovered from the water by means of silica gel column chromatography eluting with ethyl acetate: ethanol (9:1): m.p. 186°-188° C. (the sublime compound around 170° C.).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.COC(C)(C)C>[CH2:30]([NH:37][C:25]([CH2:24][CH:23]([OH:28])[CH2:22][CH:21]([OH:27])[CH2:20][CH2:19][CH:14]1[CH:13]2[C:12](=[CH:11][CH:10]([CH3:29])[CH2:9][CH:8]2[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]1[CH3:18])=[O:26])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(O)CC(=O)NCc3ccccc3)C21
Temperature: 25 °C

Procedure:
To a solution of 0.13 g (0.32 mmol) of mevinolin in 15 ml of THF are added 0.5 ml (5 mmol) benzylamine. The stirred reaction mixture is heated at reflux for 7 hours. After cooling to room temperature the reaction is diluted with 20 ml of methyl-t-butyl ether and washed successively with 0.1 N HCl and brine. The organic phase is then dried over sodium sulfate and the solvent evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to afford the desired product as an oil.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([OH:40])=[O:39]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:35]([O-:42])(=[O:41])/[CH:36]=[CH:37]\[C:38]([O-:40])=[O:39]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
A suitable reactor is charged with acetone (56 mL). The acetone solution is sequentially charged with carvedilol (15.0 grams) and water (8 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution is added 1 M of aqueous Maleic acid (1 Equiv. 36.9 mL.) The reaction mixture is stirred at between 17° C. and 35° C. The solid precipitate is formed over 10 hours to 24 hours. Later, the mixture is filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 3 volume or 45.0 mL. The cake is dried under vacuum to a constant weight. The final weight is 14.08 grams.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[S:22]1[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:25]=2[CH:24]=[CH:23]1.CCN(C(C)C)C(C)C.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1>O1CCCC1.ClCCl.CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[S:22][CH:23]=[CH:24][C:25]3=4)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: c1cc2c(s1)CCCCN2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1CCCCc2sccc21
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A solution of 4-cyclohexyl-benzoic acid (0.479 g) in tetrahydrofuran (10 ml) was treated with N,N-dimethylformamide (20 μl) followed by dropwise addition of oxalyl chloride (0.260 ml). When the gas evolution stopped the solution was warmed to reflux for 5 minutes, then cooled and concentrated in vacuo to an oil. The oil was diluted with tetrahydrofuran (5 ml) and again concentrated in vacuo. This cycle was repeated one more time and then the oil was dissolved in dichloromethane (15 ml). A solution of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.300 g) and Hunig's base (1.1 equiv.) in dichloromethane (25 ml) was cooled to 0° and treated dropwise with the previously prepared solution of 4-cyclohexylbenzoyl chloride. The reaction was stirred overnight as the temperature was allowed to return to room temperature. The solution was washed sequentially with 0.1N hydrochloric acid, 50% saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residual oil was flash chromatographed on silica gel using 15% ethyl acetate in hexanes as the eluant to provide the title compound (0.54 g) as an orange tinged solid.
Reaction SMILES: [F:1][CH:2]([F:19])[C@H:3]1[CH2:8][C@H:7]([C:9]2[O:13][NH:12][C:11](=[O:14])[CH:10]=2)[CH2:6][CH2:5][N:4]1C(OC)=O.Br>>[F:19][CH:2]([F:1])[C@H:3]1[CH2:8][C@H:7]([C:9]2[O:13][NH:12][C:11](=[O:14])[CH:10]=2)[CH2:6][CH2:5][NH:4]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](C(F)F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
Trans-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (122 mg, 0.44 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 8.21 mL, 46.87 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using a gradient of 0-10% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 19 mL/min. 5-(Trans-2-(difluoromethyl)piperidin-4-yl)isoxazol-3(2H)-one (86 mg, 89%) was isolated. 1H NMR (400 MHz, cd3od) δ 1.80-2.00 (m, 3H), 2.03-2.12 (m, 1H), 2.76-2.86 (m, 1H), 2.93-3.13 (m, 2H), 3.22-3.28 (m, 1H), 5.78 (s, 1H), 5.81 (dt, 1H). MS m/z 219 (M+H)+
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].C[O:12][CH:13](OC)[CH2:14][CH2:15][CH2:16][CH:17]=O>CCOC(C)=O.CCCCCC>[N+:1]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH:13]=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCCC=C(c1ccccc1)[N+](=O)[O-]
Yield: 41.1 %

Procedure:
Prepared according to the general procedure B from 1-(nitromethyl)benzene 112d (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (E/Z=6.7/1) (1.44 g, 41% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:17][NH2:18])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(C)(C)C>Cl>[NH2:18][CH2:17][C@@H:8]([CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CCCCC[C@@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCC[C@@H](C)C[C@H](CN)CC(=O)O

Procedure:
Compound 161 (1.20 g, 4.44 mmol) was heated to 50° C. in 3N HCl (30 mL) for 4 hours. The solvent was evaporated, and the oil washed with toluene, and evaporated. The crude material was passed through an ion exchange column (Dowex 50WX8-100, strongly acidic) eluting with water, then 0.5N NH4OH. Isolate (3S,5R)-3-aminomethyl-5-methyl-decanoic acid as a white solid (0.725 g, 75%): mp=174-175° C.; 1H NMR (400 MHz, CDCl3) δ 2.83 (dd, J=12.69, 4.88 Hz, 1H), 2.70 (dd, J=13.1, 7.45 Hz, 1H), 2.08 (d, J=6.59 Hz, 2H), 1.98 (m, 1H), 1.28-1.20 (m, 1H), 1.19-1.09 (m, 2H), 0.99-0.91 (m, 2H), 0.66 (m, 6H); MS (APCl) m/z 215 (M+, 10%), 174 (M+−41, 100%); [α]D=−5.7 (c1.025 in H2O).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.C(=O)(O)[O-].[Na+:27].[Na]>O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O-:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:20][CH2:21][CH3:22])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.[Na+:27]
Reactant: CCCc1c2c(c(O)c3c(=O)cc(C(=O)O)oc13)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)[O-])oc13)CCCC2

Procedure:
The product of step (a) (1.4 g) was suspended in water (20 ml) and sodium bicarbonate (356 mg) was added over 10 minutes. When homogeneity had been achieved the mixture was freeze-dried to yield a yellow solid which was shown to be a pure sample of the desired sodium salt (1.4 g; 93%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1S.Cl.C(O)CO>O>[S:21]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:20]=[C:19]1[C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8]
Reactant: Nc1ccccc1S
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: O=S(=O)(Nc1cccc2cc(-c3nc4ccccc4s3)[nH]c12)c1cccs1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), 2-aminothiophenol (0.10 mL), concentrated hydrochloric acid (0.5 mL) and ethylene glycol (6 mL) was stirred at 100° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.14 g, yield 38%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 201-202° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([C:11]2[O:12][C:13](=[O:17])[N:14]([CH3:16])[N:15]=2)[CH:5]=1)[CH3:2].C(OC1C=CN=C(C2OC(=O)N(C)N=2)C=1)C.C1C=C([Cl:40])C=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:40][C:8]1[N:7]=[C:6]([C:11]2[O:12][C:13](=[O:17])[N:14]([CH3:16])[N:15]=2)[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc[n+]([O-])c(-c2nn(C)c(=O)o2)c1
Agent: CCOc1ccnc(-c2nn(C)c(=O)o2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cc(Cl)nc(-c2nn(C)c(=O)o2)c1
Temperature: 0 °C
Yield: 75 %

Procedure:
Step-4: 4-Ethoxy-2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine1-oxide: A solution of 5-(4-ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (200 mg, 0.90 mmol) and mCPBA (156 mg, 0.90 mmol) in DCM (5 mL) was stirred at RT for 48 h. Ice water (10 mL) was added to the above reaction mixture, basified with aqueous saturated sodium bicarbonate solution (5 mL) and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 160 mg (75%) of title compound as a white solid. 1HNMR (400 MHz, DMSO) δ 8.29 (d, J=5.5 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.13 (dd, J=5.5 & 2.5 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.42 (s, 3H), 1.32 (t, J=7.0 Hz, 3H); GC-MS (m/z) 237 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Cc1cc(OCc2ncccn2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2ncccn2)ccc1N
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine (0.18 g, 0.7 mmol) in ethanol (4.0 mL) and water (1.0 mL), iron (0.40 g, 7.2 mmol) and ammonium chloride (0.020 g, 0.37 mmol) were added. The mixture was refluxed for 1.5 h. Cooled to ambient temperature, the reaction mixture was filtered over Celite to remove unneeded materials and the filtrate was concentrated to afford 2-methyl-4-(2-pyrimidinylmethoxy)aniline (0.15 g, crude material) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1>[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Product: Clc1ccn(-c2cccnc2)n1

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through a three step, no isolation reaction sequence as disclosed in Scheme 6. In step a2, 3-hydrazinopyridine dihydrochloride is reacted with methyl acrylate in the presence of a base such as sodium methoxide or sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one, followed by chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphoryl chloride in a two-step process to yield 3-chloro-dihydropryazole (5a). In step b2, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with manganese (IV) oxide to yield the product (5b). Subsequent treatment of (5b) with an acid such as hydrochloric acid may provide the salt of the product (5b). The first step may be conducted in a polar protic solvent such as methanol or ethanol, at a temperature from about 40° C. to about 80° C. The second step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 90° C. The third step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 110° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=[C:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:29]1[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]1[CH2:38][CH3:39])=[N:6][C:7]=2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:29]1[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[C:30]1[CH2:38][CH3:39])=[N:6][C:7]=2[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A suspension of tert-butyl 3-((9-methyl-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methylene)azetidine-1-carboxylate (1.1 g, 2.1 mmol) and Pd/C (10 wt %, 0.4 g) in ethanol (25 mL) was stirred under a hydrogen atmosphere (balloon) at room temperature for 24 hours. The reaction mixture was then filtered through celite and concentrated. The crude product was purified by flash chromatography (0-5% MeOH in DCM) to give the title compound (0.64 g, 58%). LCMS m/z: 547.2 (MH+)
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:25]=[CH:24][C:16]([CH2:17][C:18]4[NH:22][C:21](=[S:23])[O:20][N:19]=4)=[CH:15][CH:14]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:26][CH2:27][CH2:28][C:4]2=[N:3]1.[BH4-].[Na+].Cl>C(O)C>[O:29]=[S:2]1(=[O:1])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:25]=[CH:24][C:16]([CH2:17][C:18]4[NH:22][C:21](=[S:23])[O:20][N:19]=4)=[CH:15][CH:14]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:26][CH2:27][CH2:28][CH:4]2[NH:3]1
Reactant: O=S1(=O)N=C2CCCN2c2ccc(Oc3ccc(Cc4noc(=S)[nH]4)cc3)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3ccc(Cc4noc(=S)[nH]4)cc3)cc21

Procedure:
The product obtained in Step B (290 mg, 0.68 mmol) in ethanol (12 ml) in the presence of NaBH4 (77 mg, 2.03 mmol) is stirred at ambient temperature for 1 hour. 10 ml of 1N HCl are added and extraction (CH2Cl2) is carried out. The title product is purified by chromatography on a silica column (CH2Cl2/MeOH 99/1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[Cl:25])(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Temperature: 50 °C
Yield: 87 %

Procedure:
To the slurry of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (prepared as described in Example 5) was added 144 ml of methanol at 25° C. To this slurry was sparged 6.0 g (1.3 equivalents) of anhydrous HCl and the slurry was heated to 50° C. for between 4 hours and 5 hours. The solution was sampled and analyzed by GC to determine reaction completion. The reaction time is dependent on the equivalents of anhydrous HCl employed in the reaction. Using larger excesses of HCl, such as above 1.3 equivalents of HCl, results in shorter reaction times. However, increased volumes of base are subsequently required in the neutralization/work-up to neutralize the excess acid. The reaction mixture was cooled to 25° C. and 127.1 g of a 10% potassium carbonate solution was slowly added until a pH of 7.95 was reached. The organic and aqueous phases were separated and the organic (top) phase was transferred to a 1-L reactor. A total of 140 ml of a saturated sodium chloride solution was added and the mixture was stirred for several minutes. The organic and aqueous phases were separated and the organic (top) phase was transferred to a 1-L reactor equipped with a mechanical stirrer, distillation head, temperature probe, and vacuum capability. The organic phase was concentrated via a vacuum distillation to about a 30% by weight solution. To the solution at 70° C. was added 662.8 g of heptane over 45 minutes. After adding about half of the heptane; a product began to precipitate from solution. The minimum temperature during the heptane addition was 65° C. Upon completion of the heptane addition, the slurry was cooled to about 5° C. The product was collected by filtration and washed with 195 ml of heptane. The product was dried in a vacuum oven at 55° C. overnight to give 87%-90% yield (based on AcAP-Me) of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:17]=O)=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(N1CCC[C@H](NCC2C=C3C(CCC4N3N=NN=4)=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:17][C:4]2[C:3]([O:2][CH3:1])=[CH:16][C:7]3[CH2:8][CH2:9][CH2:10][N:11]4[N:15]=[N:14][N:13]=[C:12]4[C:6]=3[CH:5]=2)[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1cc2c(cc1C=O)-c1nnnn1CCC2
Agent: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-c1nnnn1CCC2

Procedure:
This compound was prepared from Compound 10 and Compound 5 in the same manner of Compound 7.