Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chlorobenzoyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (90%, white crystals). HPLC-MS m/z=366.1 (M+1), Rt: 5.19 min.
Reaction SMILES: [CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([C:6]([CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[NH:17][C:16]4=[O:25])[CH2:11][CH2:10]3)=[O:7])=[CH:4][C:3]=2[O:2]1.[BH4-].[Na+]>>[CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([CH:6]([OH:7])[CH2:8][N:9]3[CH2:10][CH2:11][CH:12]([N:15]4[CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[NH:17][C:16]4=[O:25])[CH2:13][CH2:14]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Product: O=C1Nc2ccccc2CN1C1CCN(CC(O)c2ccc3c(c2)OCO3)CC1
Yield: 67.8 %

Procedure:
In this example, the procedure of Example 3 is repeated except that 2.2 g of 1-(3,4-methylenedioxybenzoylmethyl)-4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine and 410 mg of sodium borohydride are used to obtain 1.69 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 1.50 g of the desired product.
Reaction SMILES: [K+].[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([O-:23])(=[O:22])=O)[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3].S(Cl)(Cl)=O.[CH3:31][N:32]([CH2:34][CH2:35][NH2:36])[CH3:33]>CN(C=O)C>[CH2:2]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[C:16]([S:20]([NH:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:5]1=[O:26])[CH3:3]
Reactant: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)[O-])c3)nc2n(CC)c1=O
Reactant: CN(C)CCN
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCn1c(=O)c2[nH]c(-c3cccc(S(=O)(=O)NCCN(C)C)c3)nc2n(CC)c1=O
Temperature: 0 °C
Yield: 18 %

Procedure:
A mixture of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid monopotassium salt (4.6 g, 0.01 moles) and DMF (250 ml) is prepared and cooled to 0° C. To this solution is added thionyl chloride (7.14 g, 0.06 mole) and the mixture allowed to come to ambient temperature with vigorous stirring. To this slurry is added unsym dimethylethylenediamine (17.6 g, 0.2 moles). The resulting solution is concentrated on a rotary evaporator, the residue taken up in water, filtered, recrystallized twice from ethanol and dried at 48° to yield 0.78 grams of 3-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)-N-[2-(dimethylamino)ethyl]benzenesulfonamide, mp, 250°-251° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH3:11])[N:6]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2.C([Li])CCC.C([O:39][B:40](OC(C)C)[O:41]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC>[CH3:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([B:40]([OH:41])[OH:39])=[CH:10][CH:9]=2)[CH2:5][N:6]1[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1c2ccc(Br)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1c2ccc(B(O)O)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -72 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
In 75 ml of anhydrous tetrahydrofuran was dissolved 15.0 g of (+)-5-bromo-1-methyl-2-trityliso-indoline, and the solution was cooled to -72° C. under a nitrogen atmosphere, after which 22.3 ml of a 1.63 M solution of n-butyllithium in n-hexane was added dropwise thereto over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added dropwise 7.45 g of triisopropoxyborane at -72° C. over a period of 20 minutes, and the resulting mixtuere was stirred at the same temperature for 30 minutes. The reaction mixture was added to 75 ml of ice water and the pH was adjusted to 6.8 with lN hydrochloric acid, after which the organic layer was separated. The organic layer obtained was washed with water, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Cyclohexane was added to the resulting residue and the crystals were collected by filtration to obtain 11.2 g ofcolorless (+)-1-methyl-2-tritylisoindoline-5-boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:37]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:35][C:36]([C:38]4[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=4)=[O:37])[CH2:26][CH2:27]3)=[C:15]2[CH:14]=[N:13]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(CC(=O)c5ccc(OC(F)(F)F)cc5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL round-bottomed flask fitted with a N2 inlet was placed a stir bar, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (43 mg, 0.1 mmol), K2CO3 (138 mg, 1 mmol) and DMF (1 mL). 2-Bromo-1-(4-trifluoromethoxy-phenyl)-ethanone (30 mg, 0.1 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The resulting suspension was filtered and concentrated under vacuum. The crude was purified by preparative HPLC to give Compound A94. 1H NMR (CDCl3, 400 MHz) δ 2.43 (m, 2H), 2.59 (m, 2H), 3.14 (s, 3H), 3.68 (m, 2H), 3.78 (m, 2H), 4.78 (s, 2H), 5.81 (m, 1H), 7.35 (d, 2H), 7.96 (m, 3H), 8.01 (m, 2H), 8.42 (s, 1H), 8.65 (s, 1H). Exact mass calculated for C26H23F4N5O5S 593.14, found 594.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:32])[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(c1cccnc1)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 60 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and nicotinoyl chloride hydrochloride as the starting materials in 60% yield. LCMS for C23H18ClN6O (M+H)+: m/z=429.0. 1H NMR (300 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.15 (s, 1H), 8.40 (s, 1H), 8.14 (s, 2H), 7.89 (s, 1H), 7.62 (s, 1H), 7.23 (m, 4H), 7.10 (m, 4H), 4.85 (m, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9](Cl)=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:4]34[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2][CH2:3]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(Cl)C12CCN(CC1)CC2
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CCN(CC1)CC2

Procedure:
1-Azabicyclo[2.2.2]octane-4-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-4-carboxamide.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]2[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=2[N:23]=1>CN(C=O)C.CCOC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:21][C:22]2[N:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:24]=3[N:23]=2)[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A suspension of 1-isopropyl-1,3-dihydro-benzoimidazol-2-one (0.79 g, 4.5 mmol) and Cs2CO3 (4.40 g, 13.5 mmol) in DMF (50 mL) was stirred for 30 minutes then 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (1.34 g, 4.5 mmol) was added and the mixture stirred for 5 h at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was evaporated to dryness and the residue taken up in EtOAc (100 mL), washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, hexanes:EtOAc 3:1 to 1:1) to give 1.71 g (95%) of 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNc1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
195 mg (0.56 mmol) of tert-butyl {3-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 56A) are dissolved in 6 ml of dichloromethane, and 656 mg (5.6 mmol) of trifluoroacetic acid are slowly injected. The mixture is stirred at RT for 16 h and then all the volatile constituents are removed in vacuo. 185 mg (96% of theory) of the product are obtained.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:39]
Reactant: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude methyl 2-(4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate from above step E was treated with 50% TFA/H2O (3 mL) and stirred at room temperature for 1 h. Solvent was removed to yield thick oil, Methyl 2-(4-((7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate which was used in the next step directly without further purification. HPLC-MS tR=1.72 min (UV254 nm); mass calculated for formula C25H20BrN5O2 501.1, observed LCMS m/z 502.0 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1F)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)#[N:18]
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)OC(C)(C)C)ccc32)c(C#N)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
tert-Butyl 1H-indole-5carboxylate (0.800 g, 3.68 mmol), methyl 2-(3-cyano-4-fluorophenyl)acetate (0.593 g, 3.07 mmol), and potassium carbonate (0.509 g, 3.68 mmol) were combined in 15 mL of DMSO and the reaction mixture was stirred at 95° C. for 24 hours. Reaction was diluted with ethyl acetate washed twice with water, dried over magnesium sulfate and concentrated. Silica gel chromatography eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylate (0.380 g, 0.973 mmol, 32%). MS (APCI)=390.9 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([OH:27])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.O>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH:8]([CH3:10])[CH3:9])[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Temperature: 50 °C

Procedure:
K2CO3 (6.14 g, 44.4 mmol) and 2-iodopropane (1.28 mL, 12.76 mmol) were added successively to a stirred solution of 4-benzyloxy-2-hydroxybenzaldehyde (2.33 g, 10.21 mmol) in dry DMF (12.8 mL) at 25° C. under N2. The reaction was heated at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was azeotroped from toluene to afford 4-(benzyloxy)-2-isopropoxybenzaldehyde. LCMS calc.=293.1; found=292.9 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([NH:20][NH2:21])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CN([CH:25]=[O:26])C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]2[O:19][C:25](=[O:26])[NH:21][N:20]=2)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(I)cc2F)cc1=O
Product: Cn1cc(-c2n[nH]c(=O)o2)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid hydrazide was dissolved in DMF (20 mL) and treated with the 1,1′-carbonydiimidazole (2.90 g, 17.92 mmol). The mixture was stirred at room temperature for 24 hours. The solid was precipitate out. This material was isolated by filtration, washed well with water and hexanes, then dried to afford 4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one as an off white solid (5.0 g, 71%). (APCI+) calcd for C14H10FIN4O3 428.16 (M+1), found 428.9. Anal. Calcd for C14H10FIN4O3: C, 39.27; H, 2.35; N, 13.09. Found: C, 39.55; H, 2.88; N, 13.12.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:14]1[N:31]([CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]2)[C:17]2[C:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=3)=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[N:15]=1)[O:11][CH2:12][CH3:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2[C:17]3[N:31]([CH2:32][C@H:33]4[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]4)[C:14]([CH:10]([O:11][CH2:12][CH3:13])[CH2:9][OH:8])=[N:15][C:16]=3[CH:21]=[C:20]([C:22]#[N:23])[N:19]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CCOC(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(CO)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
2-(2-((tert-butyldimethylsilyl)oxy)-1-ethoxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was dissolved in THF (3.9 mL) and cooled to 0° C. before adding TBAF (1M in THF, 1.5 mL). After stirring at 0° C. for 25 minutes, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM/0-10% MeOH) to afford 4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C24H28ClN5O2 [M+H]+ 454. found 454.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=O)=[C:2]1[CH:12]=O.C([NH:17][CH:18](P(OC)(OC)=O)[C:19]([O:21][CH3:22])=[O:20])(=O)C.N12CCCN=C1CCCCC2>C(Cl)Cl>[CH:10]1[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]=2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[N:17]=1
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Reactant: O=Cc1sc2ccccc2c1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cc2sc3ccccc3c2cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
1-Benzothiophene-2,3-dicarbaldehyde (C180) (1.91 g, 10.0 mmol) is dissolved in CH2Cl2 (100 ml) and chilled in an ice bath. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (C152) (2.63 g, 11.0 mmol) is dissolved in CH2Cl2 (50 ml) and added to 1,8-diazabicyclo[5.4.0]undec-7-ene (1.65 ml, 11.0 mmol), stirring for 5 minutes. This solution is added dropwise to the chilled thiophene solution. The reaction mixture is stirred in the ice bath for 1 h and then over night at rt. The reaction is concentrated in vacuo and the crude material is chromatographed over 500 g slurry-packed silica eluting with 50% ethyl acetate/hexane to afford methyl benzothieno[3,2-c]pyridine-3-carboxylate (C 181) as a white solid (73% yield). MS for C13H9NO2S, (EI) m/z: 243 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.O>[Br:19][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[NH2:11]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(N)c(Br)c1

Procedure:
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([NH2:12])=[O:11])[C:6]=1[N+:13]([O-])=O)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)C>[NH2:13][C:6]1[C:7]([C:10]([NH2:12])=[O:11])=[N:8][NH:9][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1[nH]nc(C(N)=O)c1N
Yield: 76.5 %

Procedure:
5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3.1 g, 17.0 mmol) and 10% palladium on carbon (600 mg) in ethanol (50 ml) were stirred under hydrogen (50 psi) at room temperature for 18 hours. The reaction mixture was filtered and the solid was washed with methanol (50 ml), dichloromethane (50 ml), ethanol (50 ml) and ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (95:5 changing to 90:10, by volume) to give 4-amino-5-butyl-1H-pyrazol-3-carboxylic acid amide (2.37 g) as an an orange solid. 1H NMR (400 MHz, DMSO-D6): δ=12.24-12.32 (1H, brs), 7.02-7.14 (1H, brs), 6.80-6.95 (1H, brs 4.28-4.46 (2H, brs), 2.39-2.50 (2H, t, partially masked by solvent), 1.45-1.56 (2H, quin), 1.22-1.35 (2H, sext), 0.83-0.90 ppm. LRMS (electrospray): m/z [M−H]+ 181, [2M−H]+ 363. Anal. Found C, 52.58; H, 7.80; N, 30.56. C8H14N4O requires C, 52.73; H, 7.74; N, 30.75%.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]1[O:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][CH:18]1[O:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Clc1ccc(OCC2CO2)c(Cc2ccccc2)c1

Procedure:
A suspension containing 21.87 g of 2-benzyl-4-chlorophenol, 27.76 g of 1-chloro-2,3-epoxypropane and 27.64 g of potassium carbonate in 200 ml of butanone is refluxed for 12 hours. The inorganic salts formed are filtered off and drained. The solvent and excess 1-chloro-2,3-epoxypropane are evaporated off under vacuum and the residue is distilled at between 160° C. and 180° C. under 0.01 mm of mercury.
Reaction SMILES: [OH-].[K+].Br[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1.O>C(O)C>[Br:13][C:14]1[CH:15]=[C:16]([S:20][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:17]=[CH:18][CH:19]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CSc1cccc(Br)c1)c1ccccc1
Reaction time: 16 h
Yield: 101 %

Procedure:
Add potassium hydroxide (4.89 g, 87.3 mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) to a solution of 3-bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% in water) at 0° C. After stirring 16 h, add water to precipitate a yellow solid. Filter to obtain the desired intermediate (24.6 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N([CH2:27][CH3:28])CC)C.C(Cl)Cl.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:32]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:21][CH2:2][CH2:3][CH2:4][CH2:27][CH3:28]
Reactant: CCN(CC)CC
Reactant: OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84 mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride (1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixture was stirred for 1 hour., then was concentrated to a crude solid. The solid was extracted into ethyl acetate, and the insoluble salts were filtered. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOH in DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumarate salt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.48 g, m.p.=109°-110° C.