Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH:28]3[C:26]([N:30]([CH3:32])[CH3:31])([CH2:27]3)[CH2:25]2)[N:20]=[C:19]([Cl:33])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.Cl>CO.O1CCOCC1>[Cl:33][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH:28]3[C:26]([N:30]([CH3:32])[CH3:31])([CH2:27]3)[CH2:25]2)[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C12CC1CN(c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C12CC1CN(c1nc(Cl)nc(NN)c1F)C2
Reaction time: 72 h
Yield: 52.8 %

Procedure:
To a solution of racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (1.3231 g, 2.254 mmol) in MeOH (13 mL) was added 4 N HCl in dioxane (13 mL). The solution was stirred for 3 days, and was then concentrated in vacuo. The residue was partitioned between 10% aq. K2CO3 and DCM, and the aqueous phase was extracted with a fresh portion of DCM. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give racemic 3-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.3415 g, 53%) as a brown solid. LCMS: (M+H)+: 287.1.
Reaction SMILES: O[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.CN(C)C=O.S(Cl)([Cl:18])=O>>[Cl:18][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc(O)cn1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)cn1
Temperature: 0 °C
Yield: 75 %

Procedure:
5-Hydroxypyrazine-2-carboxylic acid (1.0 g, 0.007 mol) was taken in thionyl chloride (10 mL), to this solution dimethylformamide (0.1 mL) was added which was heated to reflux for 16 h. After this period, excess thionyl chloride was distilled off to get crude compound, which was added to ice (20 g) and extracted with ethyl acetate (2×70 mL). The organic layers were combined and dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain brown solid which was triturated with diethyl ether (30 mL) to afford 600 mg (75%) of 5-chloropyrazine-2-carboxylic acid.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl>C1COCC1>[CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)C(CCCCNC(=O)c1ccccc1)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCOP(=O)(OCC)C(CCCCNCc1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
A solution of tetraethyl N-benzoyl-5-aminopentane-1,1-bisphosphonate (0.63 g, 1.36 mmol) in THF (3.4 mL) was cooled to 0° C., and borane methylsulfide (0.34 ml, 3.4 mmol) was added via syringe. The reaction was stirred at 0° C. for 20 minutes, then warmed to 65° C. for 2.5 hours. The reaction mixture was cooled to 0° C. and 6N HCl (4.0 ml) was added carefully. The solvent was removed in vacuo, and the residue was concentrated repeatedly from methanol (2×5 mL). The residue was dissolved in water (10 ml) and extracted with diethyl ether (3×5 ml). The aqueous layer was made basic to phenolphthalein with solid KOH and saturated with NaCl. The product was extracted into dichloromethane (5×20 ml), dried (Na2SO4) and concentrated to give the title compound (0.28 g).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9]2)([O-:5])=[O:4].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl.Cl>CS(C)=O.O>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[C:10]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Fc1cccc(F)c1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 5.49 g (83.2 mmol, 85% pure) of potassium hydroxide (powder) are initially charged in 110 ml of dimethyl sulphoxide, 6.43 g (27.5 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate (A. Guy, J.-P. Guetté, Synthesis 1980, 222–223) are added at RT and the mixture is stirred for 30 min. With ice-cooling, at an internal temperature of 5–10° C., 2,6-difluorobenzyl chloride (10.0 g, 61.5 mmol) is then added dropwise over a period of 15 min, and the mixture is stirred at RT for 16 h. For work-up, the mixture is poured into 500 ml of water and acidified with dil. hydrochloric acid and the precipitated solid is filtered off with suction and pre-purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane→dichloromethane-methanol 3:1). The resulting product is recrystallized from ethanol. This gives 4.33 g (47% of theory) of a pale-yellow crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2)=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:17]
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CCC1(O)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(C(=O)OC)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 1H-indole-7-carboxylic acid methyl ester, the title compound is prepared as in example 1. 103 mg (75%). LC-MS m/z 338.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17].N1C=CN=C1.[CH:25]([Si:28](Cl)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>CN(C)C=O>[CH3:26][CH:25]([Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[O:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:18][O:19][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH:10][C:9]3=[O:17])[CH3:27]
Reactant: O=C1Nc2ccccc2C12COc1cc(O)ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc2c(c1)OCC21C(=O)Nc2ccccc21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.0 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (30 mL) under nitrogen were added imidazole (1.97 g, 28.9 mmol) and triisopropylsilyl chloride (6.03 mL, 28.5 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo to dryness. The residue was extracted twice with ethyl acetate (50 mL), the combined organic phases were dried over sodium sulfate, and the filtrate was concentrated and purified by flash chromatography with 30% ethyl acetate in hexanes to give 6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.68 g, 69% yield) as colorless solid: 1H NMR (300 MHz, CDCl3) δ8.48-8.08 (br, 1H), 7.29-6.90 (m, 4H), 6.10 (d, J=8.1 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.35 (dd, J=8.1, 2.1 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 1.34-0.98 (m, 21H).
Reaction SMILES: P([O-])([O-])([O-])=O.[F:6][C:7]([F:17])([F:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CC(O)C>C(OCC)(=O)C>[F:6][C:7]([F:16])([F:17])[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 30 °C
Reaction time: 18 h

Procedure:
To 0.02 g of the aforementioned wet bodies was added 500 μl of 50 mM phosphate buffer (pH 7.0) containing 1% 2,2,2-trifluoroacetophenone and 5% 2-propanol, followed by stirring at 30° C. for 18 hours. Then, after adding 500 μl of ethyl acetate to the reaction mixture, the mixture was subjected to centrifugal separation to obtain the organic phase. The organic phase was subjected to an analysis of the content by way of gas chromatography under the following condition. 2,2,2-Trifluoro-1-phenylethanol was produced at a ratio of 49.4% based on the amount of 2,2,2-trifluoroacetophenone used in the reaction. Furthermore, optical purity of 2,2,2-trifluoro-1-phenylethanol in the organic phase was measured under the following condition. The (S)-form of 99% e.e. was demonstrated.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:29])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)C#N)[CH2:16][CH2:15]1)=[O:13])=[CH:5][NH:6]2.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.O=[Mn]=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11](=[O:29])[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:19]1)=[O:13])=[CH:5][NH:6]2
Reactant: N#CC(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Reactant: Nc1ccccc1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=Nc2ccccc2)c2ccccc2)CC1)c1c[nH]c2cccc(F)c12
Reaction time: 48 h

Procedure:
An excess amount of MnO2 (500 mg) was added into a solution of 2-(4-(2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)-2-phenylacetonitrile (100 mg) and aniline (0.5 ml) in DMF (10 ml), and the reaction was kept stirring for 2 days. The solids were removed by filtration. The filtrate was concentrated under vaccum to give a residure which was purified by using Shimadzu automated preparative HPLC System to afford 1-(4-fluoro-1H-indol-3-yl)-2-(4-(phenyl(phenylimino)methyl)piperazin-1-yl)ethane-1,2-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].I[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1cc(N2CCNCC2)ccc1Cl
Reactant: CCCI
Product: CCCN1CCN(c2ccc(Cl)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-methanesulfonyl-phenyl)-piperazine and 1-iodopropane, the titled compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV)) 316 (M+, 25), 289 (41), 287 (bp), 70 (59), 56 (23)
Reaction SMILES: [N:1]1([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>>[N:1]1([C:10]2[N:11]=[CH:12][C:13]([C:14]([N:34]3[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)=[O:16])=[CH:19][CH:20]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(-n2cnc3ccccc32)nc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5ccccc54)nc3)CC2)cc1
Yield: 45.6 %

Procedure:
Using ethyl 6-(benzimidazol-1-yl)nicotinate (300 mg) described in Preparation Example 78, (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (269 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (217 mg) was obtained.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 79 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 79% of theory, C35H34N6O4 (602.7); Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=603; (M+Na)+=625.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH3:2].[N:15]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[N+:16]=[N-:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:15]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:16]=[N:17][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:14])[CH3:2]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: CCOC(=O)C#Cc1ccc(F)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)nnn1C[Si](C)(C)C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
To a solution of (4-fluoro-phenyl)-propynoic acid ethyl ester (1.45 g, 7.55 mmol) in benzene (25 mL) was added azidomethyl-trimethyl-silane (1.17 g, 9.05 mmol) and the reaction mixture was refluxed under nitrogen for 72 h. A subsequent batch of azidomethyl-trimethyl-silane (0.29 g, 2.26 mmol) was added and refluxing was continued for 5 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.0 g, 41%) as a yellow oil. MS: m/e=322.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[CH3:16]CCCC=C>>[CH3:16][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: C=CCCCC
Agent: C=O
Product: CN(C1CCCCC1)C1CCCCC1
Yield: 195 %

Procedure:
In a similar manner to Example 1, 204.0 g (1.13 mol) of dicyclohexylamine and 185.5 g (1.80 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.4 MPa is established at a temperature of 160° C. After the end of the reaction, 50 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently distilled. 226.3 g of N-methyldicyclohexylamine having a purity of 93.7% are isolated, corresponding to a yield of 96.1% of theory.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[F:12]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1
Yield: 86 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-methoxyphenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 5-fluoro-6-(2-fluoro-5-methoxyphenyl)picolinic acid in 86% yield. LC/MS=266.1 (M+H), Rt=0.79 min.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:27])([OH:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@:11]3([CH3:27])[O:26][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:10]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: C[C@](O)(CN1CCN(c2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(c3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.4 %

Procedure:
(S)-1-(2-Chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-chlorophenyl)piperazin-1-yl]propan-2-ol prepared in Example 370 (33.0 g, 79.7 mmol) was dissolved in DMF (300 ml). To the solution, sodium hydride (3.7 g, 91.6 mmol) was added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, ice-water and ethyl acetate were added, and the solution was vigorously stirred. The precipitates were filtered off, washed with water and ethyl acetate, and dried under reduced pressure to afford 23.2 g of a crude light yellow powder. The crude powder was combined with another crude powder synthesized in the same manner (50 g), and the mixture was purified by silica gel column chromatography (methylene chloride/ethyl acetate=50/1) and crystallized from methylene chloride-ethyl acetate to afford (S)-2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (45 g, yield 90%) as a white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)(=[O:4])=[O:3].[OH-].[K+].[I:16]I.O>CS(C)=O>[I:16][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[NH:10][N:9]=1
Reactant: II
Reactant: CS(=O)(=O)c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a solution of 5-(methylsulfonyl)-1H-indazole (430 mg, 2.19 mmol) in DMSO (10 mL) at 0° C., were added KOH (0.4 g, 6.57 mmol) and I2 (1.2 g, 4.38 mmol) successively, then the reaction mixture was stirred at room temperature for 3 hours. Water (40 mL) was added, product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=20:1) to give 3-iodo-5-(methylsulfonyl)-1H-indazole (410 mg, 59.9%) as an off-white solid. LCMS: (M+H)+=323; 1H NMR (300 MHz, DMSO): δ 7.98-7.95 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCBr
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetic acid salt (for example, as prepared for Intermediate 8) (701 mg, 2.001 mmol) and potassium carbonate (690 mg, 4.99 mmol) were suspended in DMF (10 mL) and the mixture heated at 50° C. under nitrogen for 2 hours. The mixture was allowed to cool and then 1-bromo-3-chloropropane (198 μL, 2.002 mmol) was added and the reaction mixture stirred at ambient temperature overnight. After 16 hours the reaction mixture was partitioned between water and DCM (25 mL of each). The aqueous phase was extracted with further DCM (2×20 mL). The combined DCM extracts were dried over magnesium sulphate and concentrated in vacuo to give the impure title compound as a pale yellow oil with some solid present (0.76 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:34][C:35](Cl)=[O:36])=[CH:28][C:27]=2[O:26]1.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[CH2:34][C:29]3[CH:30]=[CH:31][C:32]4[O:33][CH2:25][O:26][C:27]=4[CH:28]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nc(C2CCN(C(=O)Cc3ccc4c(c3)OCO4)CC2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 3,4-methylenedioxyphenylacetic acid (569 mg, 3.16 mmol) in chloroform (6 ml) was added thionyl chloride (1.2 ml). The mixture was refluxed for about 3 hours, and was evaporated. Toluene was added to the residue and the mixture was evaporated to remove the excess of thionyl chloride. To the residue was added dichloromethane (3 ml) to give a dichloromethane solution of 3,4-methylenedioxyphenylacetyl chloride. To an ice-cold mixture of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) and triethylamine (319 mg, 3.16 mmol) in dichloromethane (16 ml) was added dropwise the solution of 3,4-methylenedioxyphenylacetyl chloride prepared above under a nitrogen atmosphere. The mixture was stirred for about two hours and to the reaction mixture was added dichloromethane and saturated sodium hydrogencarbonate aqueous solution followed by extraction. The organic layer was washed with water, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). Crystallization from methanol gave the titled compound (617 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[O:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccncc1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccncc1

Procedure:
The title compound is prepared by reacting (2-aminophenyl)(4-pyridinyl)methanone as prepared by Nann, A. J. and Schofield, K., J. Chem. Soc. 1952, 583-9 with 3-amino-2-chloropyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(F)c1

Procedure:
3,4-Difluoronitrobenzene was reacted with 1-(2-hydroxyethyl)pyrrolidine by method D1. The product with the molecular weight of 254.26 (C12H15FN2O3) was obtained in this way; MS (ESI): 255 (M+H+).