Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[F:8][C:9]1[C:14]([B:15]([C:27]2[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=2[F:37])[C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=2[F:26])=[C:13]([F:38])[C:12]([F:39])=[C:11]([F:40])[C:10]=1[F:41].[CH2:42]([N:60]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH3:61])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C1(C)C=CC=CC=1>[F:33][C:32]1[C:27]([B:15]([C:14]2[C:9]([F:8])=[C:10]([F:41])[C:11]([F:40])=[C:12]([F:39])[C:13]=2[F:38])[C:16]2[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=2[F:22])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=1[F:34].[F:33][C:32]1[C:27]([B:15]([C:14]2[C:9]([F:8])=[C:10]([F:41])[C:11]([F:40])=[C:12]([F:39])[C:13]=2[F:38])[C:16]2[C:17]([F:26])=[C:18]([F:25])[C:19]([F:24])=[C:20]([F:23])[C:21]=2[F:22])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=1[F:34].[CH2:62]([NH+:60]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH3:61])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79].[Cl:1][C:2]1[N:3]=[CH:4][N-:5][C:6]=1[Cl:7]
Reactant: CCCCCCCCCCCCCCCCCCN(C)CCCCCCCCCCCCCCCCCC
Reactant: Clc1nc[nH]c1Cl
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC[NH+](C)CCCCCCCCCCCCCCCCCC
Product: Clc1nc[n-]c1Cl

Procedure:
4,5-dichloroimidazole (0.2675 g, 1.953 mmol), tris(pentafluorophenyl)borane (2.0000 g, 3.9063 mmol) and dioctadecylmethylamine (1.0469 g, 1.9531 mmol) were placed in a 50 mL flask, taken up in 21 mL of toluene and refluxed under argon for hours. The volatiles were then stripped under vacuum. Yield, 2.937 g, 88.62 percent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)#[CH:2].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>ClCCl.CN(C)C1C=CN=CC=1>[C:17]([Si:21]([O:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([C:1]#[CH:2])[CH:4]=1)([CH3:24])[CH3:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#Cc1csc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1csc(CO[Si](C)(C)C(C)(C)C)c1
Yield: 94 %

Procedure:
To a solution of (4-ethynyl-2-thienyl)methanol (0.88 g, 6.4 mmol) that was obtained in Example 9 (9c) in dichloromethane (20 ml) were added successively triethylamine (1.3 ml, 9.6 mmol), t-butyldimethylchlorosilane (1.2 g, 7.6 mmol), and 4-dimethylaminopyridine (78 mg, 0.64 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, water (50 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:1 to 1:9) as the eluent to afford the title compound (1.5 g) in a yield of 94% as a brown oily product.
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)(=O)[CH3:7].Cl.[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])CCCl)([CH3:21])[CH3:20].[H-].[Na+]>C(O)C>[CH:19]([N:22]([CH:26]([CH3:28])[CH3:27])[CH2:7][CH2:6][NH:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(=O)Nc1nc(C)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1

Procedure:
To 600 ml of dry dimethylformamide is added 2-acetamido-4,6-dimethylpyrimidine (34.8 g., 0.21 mole) and 2-diisopropylaminoethyl chloride hydrochloride (48 g., 0.24 mole). The mixture is stirred under nitrogen and sodium hydride (50% in mineral oil) (24.7 g., 0.515 mole) is added in portions over one hour while the temperature is maintained below 45° C. The mixture is then heated at 75°-78° C. for 1/2 hour and then at 90°-95° C. for 31/2 hours. On cooling, ethanol, 25 ml, is added and the solvents removed under reduced pressure. The residue is suspended in 75 ml of 1-propanol and 400 ml of 5N sodium hydroxide and refluxed with stirring for 18 hours. On cooling the mixture is extracted with methylene chloride. The organic extracts are then extracted with dilute hydrochloric acid. The acid extracts are extracted with hexane and then made alkaline with a molar excess of sodium hydroxide. The crude product is extracted from the basic solution with diethyl ether. The ethereal extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under vacuum. The residue is distilled and the product diamine (37.2 g., 0.149 mole) collected at 130°-134° C./0.4 mm; melting point 79.5°-82° C.
Reaction SMILES: C(O[CH:4]1[CH2:8][CH:7]2[C:9](=[O:13])[CH2:10][CH2:11]C[CH:6]2[O:5]1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:35]C(/N=N/C(OCC)=O)=O.C1(P([N:59]=[N+:60]=[N-:61])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:59]([C@@H:8]1[C@@H:7]2[C@@H:6]([O:35][CH2:11][CH2:10][C@@H:9]2[OH:13])[O:5][CH2:4]1)=[N+:60]=[N-:61]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCOC1CC2C(=O)CCCC2O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H]1CO[C@@H]2OCC[C@H](O)[C@@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 180 %

Procedure:
To a solution of 11 (2.2 g, 4.80 mmol) in THF (50.0 mL) at 0° C. was added triphenyl phosphine (5.0 g, 19.2 mmol), diethylazodicarboxylate (3.3 g, 19.2 mmol), Diphenylphosphoryl azide (2.5 g, 9.6 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h after which it was concentrated under vacuum and purified on silica gel to get the desired azide (1.6 g, 70% yield). Rf=0.35 (10% ethyl acetate/hexanes). [α]23D=+16.3 (c 1.6, CHCl3). 1H NMR (400 MHz, Chloroform-d) δ 7.56-7.39 (m, 6H), 7.38-7.13 (m, 10H), 5.48 (dt, J=17.3 Hz, 10.1 Hz, 1H), 4.96 (dd, J=10.3 Hz, 1.9 Hz, 1H), 4.84 (dd, J=17.3 Hz, 1.8 Hz, 1H), 4.30 (dt, J=11.9 Hz, 2.4 Hz, 1H), 3.98 (td, J=12.1 Hz, 2.7 Hz, 1H), 3.88-3.71 (m, 1H), 3.69-3.64 (m, 1H), 3.38 (dd, J=10.1 Hz, 2.6 Hz, 1H), 3.07 (dd, J=10.0 Hz, 7.9 Hz, 1H), 1.98 (td, J=10.2 Hz, 2.2 Hz, 1H), 1.81-1.59 (m, 1H), 1.49 (s, 3H), 1.35 (s, 3H), 1.20-1.03 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 143.8, 133.6, 128.6, 127.8, 127.0, 119.6, 98.4, 87.0, 67.2, 65.4, 62.3, 59.9, 50.5, 29.7, 28.4, 18.9.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([OH:22])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])[CH3:20]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)O
Product: CC(C)OC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 122-124° C. and MS: m/e=297 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and isopropyl alcohol.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([CH:9]=O)[CH2:5][CH2:4]1.[C-:11]#[N:12].[K+].[NH4+:14].[Cl-]>O.N.O>[NH2:14][CH:9]([CH:6]1[CH2:7][CH2:8][N:3]([O:2][CH3:1])[CH2:4][CH2:5]1)[C:11]#[N:12]
Reactant: [NH4+]
Reactant: CON1CCC(C=O)CC1
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CON1CCC(C(N)C#N)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-Methoxy-piperidine-4-carbaldehyde (2.86 g, 20 mmol) was added to a mixture of KCN (1.95 g, 30 mmol) and NH4Cl (2.2 g, 41 mmol) in H2O (20 ml) and NH3.H2O (20 ml). The mixture was stirred at room temperature for 12 h and then was extracted with CH2Cl2 (5×50 ml). The combined organic layers were dried with Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel. Yield: 2.0 g of amino-(1-methoxy-piperidin-4-yl)-acetonitrile as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([OH:15])[CH:6]=1.[OH-].[Na+]>O>[N+:1]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([OH:15])[CH:6]=[N:5]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cccc2ncc(O)cc12
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of concentrated sulfic acid is added concentrated nitric acid dropwise at −30° C. Quinolin-3-ol is added to the mixture at −30° C., and then stirred at 30° C. for 2 hours. After cooled to ambient temperature, the mixture is poured into water and then neutralized with aqueous 4N sodium hydroxide solution. After extracted with ethyl acetate, the organic layer is dried, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to provide 5-nitroquinolin-3-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].Br[CH2:15][CH2:16][Si:17]([CH2:20][CH2:21]Br)([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:18][Si:17]1([CH3:19])[CH2:20][CH2:21][N:1]([CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:15][CH2:16]1
Reactant: NCCNC(=O)CN1CCCC1=O
Reactant: C[Si](C)(CCBr)CCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si]1(C)CCN(CCNC(=O)CN2CCCC2=O)CC1
Yield: 15 %

Procedure:
A mixture of 1.90 g (10.3 mmol) of N-(2-aminoethyl)-2-oxo-1-pyrrolidineacetamide, 2.76 g (10.1 mmol) of bis(2-bromoethyl)dimethylsilane, 5.20 g of Huenig base, and 20 ml of chloroform was stirred and then the solvent was removed in vacuo. The resulting mixture was heated at 100°-105° C. for 8 hours. Aqueous NaHCO3 was added to the cooled reaction mixture, and the aqueous solution was extracted with chloroform. The dried chloroform solution was concentrated in vacuo and chromatographed on silica gel column to afford 450 mg (Yield: 15.0%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=1.O[O:28][S:29]([O-:31])=O.[K+].[CH2:33](Cl)Cl>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]2[C:18]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([S:29]([CH3:33])(=[O:31])=[O:28])[N:20]=1
Reactant: O=S([O-])OO
Reactant: ClCCl
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3F)nc3c(C)nccn23)n1
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3F)nc12
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-8-methyl-3-(2-methylsulfanylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (5.26 g, ˜75% pure, 10.7 mmol) in DCM (90 mL) and MeOH (90 mL) was added a solution of Oxone® (13.1 g, 21.4 mmol) in water (45 mL). After about 16 h, the mixture was diluted with water (250 mL) and extracted with DCM (3×200 mL). The combine organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography using a step-wise gradient of DCM:EtOAc (3:1 to 3:2 to 1:1). Fractions enriched in product were crystallized from hot ACN. The resulting solid was filtered, washing with additional ACN, and dried in a vacuum oven at about 70° C. for about 2 h to give 1.19 g (28%) of the title compound. Additional product can be obtained from further purification of column fractions and filtrate: LC/MS (Table 1, Method b) Rt=1.77 min; MS m/z: 402.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][NH:20]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(NCC4CC(F)(F)CCN4C(OC(C)(C)C)=O)C(F)=CN=3)=CNC2=NC=1.CCN(C(C)C)C(C)C.[CH3:71][O:72][CH2:73][CH2:74][C:75](Cl)=[O:76]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][N:20]4[C:75](=[O:76])[CH2:74][CH2:73][O:72][CH3:71])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCC(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NCC1CC(F)(F)CCN1
Agent: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-[(4,4-difluoro-2-piperidyl)methyl]-5-fluoro-pyrimidin-4-amine, 13k, (0.086 g, 0.198 mmol) in CH2Cl2 (1 mL), DMF (0.5 mL) and iPr2NEt (0.10 mL, 0.57 mmol) was added 3-methoxypropanoyl chloride (2.43 g, 0.20 mmol). The reaction mixture was stirred at room temperature for 17 hours. All volatiles were removed at reduced pressure and the residue was purified via silica gel chromatography to give a mixture enriched in desired product, 13, which was repurified via preparatory HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 61.3 g of 2-(p-chlorophenoxy)ethanol, 73.5 ml of triethylamine and 900 ml of dichloromethane chilled at -10° C. is added dropwise a solution of 30.2 ml of methanesulfonyl chloride in 60 ml of dichloromethane. The mixture is stirred at -8° C. for 1 hour and worked up as described in Example 11 to give the product as a white solid. A dried sample of product melted at 75°-77° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])C.CO.O.O[Li].O>C1COCC1>[C:11]1([C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)[nH]n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%.
Reaction SMILES: CO[C:3]1[CH:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:14])[CH2:11][CH3:12]
Reactant: CCCC1CCCCN=C1OC
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCCC1CCCCNC1=N
Product: Cl
Yield: 89.9 %

Procedure:
The product of EXAMPLE 111 (415 mg, 2.45 mmol) in 20 mL of MeOH was reacted with ammonium chloride (111 mg, 2.1 mmol) by the method of EXAMPLE 27 to yield 360 mg (76%) of the title material.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.[Pd]>[NH:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:1])[C:12]=2[N:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cccc2[nH]cnc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2[nH]cnc12

Procedure:
4-Nitro-1H-benzimidazole was hydrogenated (48 psi) with 1 g 10% Pd/C in HOAc (100 mL) for 3 h. The crude mixture was filtered through a pad of Celite, washing with MeOH, and concentrated. The residue was taken up in 2 M aq HCl and applied to a Phenomenex Strata-X—C ion exchange column (5 g). The column was washed with H2O and MeOH. The washings contained additional material and were applied to another Strata X—C ion exchange column (5 g). The columns were washed with H2O and MeOH. Each of the columns containing product were washed separately with 10% concentrated NH4OH in MeOH and the product collected in fractions. The collected fractions were concentrated to give 1H-Benzimidazol-4-amine as a deep red solid. 1H NMR (500 MHz, d6-DMSO) δ 12.10 (bs, 1 H), 7.98 (s, 1 H), 6.87 (t, J=7.81 Hz, 1 H), 6.72 (d, J=7.82 Hz, 1 H), 6.34 (d, J=7.57 Hz, 1 H), 5.16 (bs, 2 H).
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][N:3]1C.Cl.[Cl:12][CH2:13][C:14](=N)OCC.Cl[CH:20](Cl)C>>[Cl:12][CH2:13][C:14]1[N:8]([CH3:20])[C:6]2[C:5]([N:9]=1)=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2
Reactant: CCOC(=N)CCl
Reactant: CC1N=C(N)C(N)=CN1C
Reactant: CC(Cl)Cl
Agent: Cl
Product: Cc1ncc2nc(CCl)n(C)c2n1

Procedure:
A solution of 2,N-Dimethyl-4,5-diaminopyrimidine (180 mg, 1.3 mmol) and ethyl chloroacetimidate hydrochloride (310 g, 2.0 mmol) in dichloroethane (10 mL) is heated at reflux for 17 h and cooled. The mixture is washed with aqueous NaHCO3, water, dried and concentrated to give 8-Chloromethyl-2,9-dimethyl-9H-purine.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CN(C)C=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1O.COS(OC)(=O)=O>O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1[O:4][CH3:1]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (59.25 g, 0.43 mol) is added slowly to a solution of dimethylformamide (200 mL) containing 2-fluoro-6-nitrophenol (10, 33.63 g, 0.21 mol) and dimethylsulfate (41.0 mL, 0.43 mol) at room temperature. The orange mixture is stirred at 80° C. for 6 h. The resulting yellow mixture is cooled to room temperature, diluted with water (500 mL), and extracted with hexanes (3×500 mL). The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure to give 1-fluoro-2-methoxy-3-nitrobenzene as a yellow oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 4.08 (d, JH-F=2.0 Hz, 3H, OCH3), 7.13 (apparent t of d, JH-H=8.5 Hz, JH-F=5.0 Hz, 1H, H-5), 7.34 (d, JH-F=10.5 Hz, JH-H=8.5 Hz, JH-H=1.5 Hz, 1H, H-6), 7.58 (d of apparent t, JH-H=8.5 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-4). 19F{1H} NMR (CDCl3): 8-126.7 (s). 13C{1H} NMR (CDCl3): δ 62.6 (d, JC-F=5.5 Hz, OCH3), 120.2 (d, JC-F=3.5 Hz, C-4), 121.1 (d, JC-F=19.5 Hz, C-6), 123.2 (d, JC-F=8.0 Hz, C-5), 142.2 (d, JC-F=14.5 Hz, C-2), 144.8 (br, C-3), 156.2 (d, JC-F=251.5 Hz, C-1). LCMS m/z calcd for C7H6FNO3 ([M]+) 171. Found 183 ([M−CH2O+H+ CH3CN]+, 26%), 183 ([M-CH2O+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[Br:10])=[O:4].C([O-])(O)=[O:14].[Na+].CCOC(C)=O>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:14])=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: COC(=O)c1sc(CBr)cc1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc(CO)cc1Br
Temperature: 115 °C
Yield: 24 %

Procedure:
A mixture of 3-Bromo-5-bromomethyl-thiophene-2-carboxylic acid methyl ester (0.99 g, 3.15 mmol) and NaHCO3 (4.5 g, 53.6 mmol) in DMSO (25 ml) was heated at 115° C. for 3 h. The reaction mixture was cooled. The reaction mixture was EtOAc (250 ml), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 0.19 g (24%) yellow solid product.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:11][CH:12]([C:15]1[CH:32]=[CH:31][C:18]([O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:21](O)=[O:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[N:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH:20]([O:19][C:18]2[CH:31]=[CH:32][C:15]([CH:12]([CH3:11])[CH2:13][CH3:14])=[CH:16][CH:17]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cnc2ccccn12
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1cnc2ccccn12

Procedure:
3-Aminoimidazo[1,2-a]pyridine, synthesized by reduction of the corresponding nitro compound according to Example 31, was coupled with 2-(4-(1-methylpropyl)-phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Solvent: CCOCC
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with diethyl ether was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.