Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C.[CH3:51][CH:52]([C:54]1[CH:60]=[CH:59][CH:58]=[C:57]([CH:61]([CH3:63])[CH3:62])[C:55]=1[NH2:56])[CH3:53]>O1CCCC1>[CH3:63][CH:61]([C:57]1[CH:58]=[CH:59][CH:60]=[C:54]([CH:52]([CH3:53])[CH3:51])[C:55]=1[NH:56][C:34](=[O:40])[N:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:62]
Reactant: CCCCCCCCCCCCn1nnc(Nc2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCn1nnc(N(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a stirred, cold (-78° C.) solution of 2-dodecyl-N-phenyl-2H-tetrazol-5-amine (2.2 g, 0.0067 mol) in anhydrous tetrahydrofuran (30 mL) under nitrogen atmosphere was added dropwise a 2.5 M solution of n-butyl lithium in hexanes (2.7 mL, 0.0068 mol), and the mixture was stirred for 25 minutes. To the mixture was added triphosgene (0.6385 g, 0.002152 mol) in one portion. The mixture was stirred for 1.5 hours and then allowed to warm to room temperature. The resulting orange solution was stirred for 3 days. To the mixture was added diisopropylethylamine (1.3 mL, 0.0069 mol) and 2,6-bis(1-methylethyl)aniline (1.3 mL, 0.0069 mol), and the mixture was refluxed for 3 days. The reaction mixture was allowed to cool and then rotoevaporated. The residue was partitioned between diethyl ether and saturated sodium bicarbonate. The organic layer was washed with additional saturated sodium bicarbonate, 1M hydrochloric acid, saturated sodium chloride, and was dried over magnesium sulfate. The organics were rotoevaporated to an oil. The oil was dissolved in PET ether and chromatographed on silica gel (360 g, 230-400 mesh) using PET ether-ethyl acetate (15:1, 3×300 mL; 11:1, 20×350 mL) as eluent. Fractions containing product were rotoevaporated from dichloromethane and dried in vacuo (50° C.), yield 2.798 g (78%) of the title compound. 1H NMR (CDCl3): δ 9.3 (s, 1H), 7.5 (m, 6H), 7.2 (d, 2H), 4.5 (t, 2H), 3.2 (septet, 2H), 1.9 (m, 2H), 1.2 (m, 18H), 0.9 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47](Cl)[C:42]=3[CH:41]=2)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]3[N:44]=[CH:45][N:46]=[C:47]([O:11][C:4]4[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=4)[C:42]=3[CH:41]=2)=[CH:38][CH:39]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: CN1CCCC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ncnc21
Temperature: 130 °C
Reaction time: 24 h
Yield: 76.5 %

Procedure:
After adding 248 mg of 3-fluoro-4-nitrophenol, 0.208 ml of 2,6-lutidine and 1 ml of N-methylpyrrolidine to 490 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 130° C. for 24 hours. After returning it to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (ethyl acetate) to obtain 472 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(F)cc1F
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
A solution of 2,4-difluorobenzoic acid (1.5808 g, 10.00 mmol) in methanol (15 ml) was cooled to 0° C. in ice-water bath. To the mixture was added dropwise a solution of thionyl chloride (1.46 ml, 20.02 mmol) in methanol (10 ml). The mixture was gradually warmed to room temperature and stirred for 24 hours. The mixture was added to sat. NaHCO3 aqueous solution, extracted three times with ether and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (1.6743 g; 97%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.N1C=CC=CC=1.[N:18]#[C:19][C:20]#[N:21]>CN(C)C=O>[C:19]([C:20]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:21]=1)#[N:18]
Reactant: NCC(=O)c1ccccc1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1nc(-c2ccccc2)c[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
0.85 g (5 mmol) of 2-aminoacetophenone hydrochloride and 1.98 g (25 mmol) of pyridine were dissolved in 30 ml of N,N-dimethylformamide in a four-necked flask equipped with a dry ice condenser. The solution was then cooled to a temperature of -50° C. To the solution was then added about 0.5 g (9.6 mmol) of cyanogen which had been cooled and solidified at a temperature of -50° C. The solution was heated at a temperature of 60° C. for 1 hour, and at a temperature of 80° C. for 1 hour. The reaction solution was then extracted with ethyl acetate and water. The resulting organic phase was then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and then concentrated. The material was then subjected to silica gel column chromatography to obtain 0.29 g (yield: 34 %) of 2-cyano-4-phenylimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>CCCCC>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[C:5]([CH2:2][CH2:3][CH:4]([CH3:5])[CH3:12])([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=2[CH:3]=1
Reactant: CC(C)CCBr
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Solvent: CCCCC
Product: CC(C)CCC1(CCC(C)C)c2cc(Cl)ccc2-c2ccc(Cl)cc21
Yield: 90 %

Procedure:
Following the procedure of Example 1,2,7-dichloro-9,9-di(3-methyl-1-butyl)fluorene is prepared from 2,7-dichlorofluorene and 1-bromo-3-methylbutane as colorless crystals (recrystallized from pentane) in 90 percent yield, melting point 116° C. to 117.5° C. The spectral data is consistent with the title structure and HPLC analysis shows the purity as 99 percent and greater.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:16][CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CCC[C@H]2N4CCC3)c(C(F)(F)F)c1
Yield: 92.9 %

Procedure:
Tert-butyl(±)-cis-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (56 mg, 91%) was prepared by the general method of Example 319, step A from tert-butyl(±)-cis-2-bromo-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-11-carboxylate (50 mg, 0.12 mmol) and 4-methoxy-2-(trifluoromethyl)phenylboronic acid (54 mg, 0.25 mmol) as a white foam. MS (ESI): 503.6 (base, M+H).
Reaction SMILES: [OH-].[K+:2].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:12]([CH2:14][C:15]([O:17]C)=[O:16])#[C-:13]>CO>[F:3][C:4]1[CH:11]=[CH:10][C:7]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([O-:17])=[O:16])=[CH:6][CH:5]=1.[K+:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: [C-]#[N+]CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])[C@@H]1N=CO[C@H]1c1ccc(F)cc1
Yield: 106.4 %

Procedure:
To a stirred and cooled (4° C.) solution of KOH (3.04 g, 46.02 mmol) in MeOH (50 mL) were slowly added 4-fluorobenzaldehyde (4.13 mL, 38.35 mmol) and methyl 2-isocyanoacetate (4.00 g, 38.35 mmol). This mixture was stirred at RT under N2 atmosphere for 7 h. The solvent was evaporated and the residue was dried overnight under vacuum to give potassium (±)-threo-5-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate ANP 20162 (10.09 g, quantitative yield), as a beige powder. This material was used in the next reaction without further purification.
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[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C@H:20]([CH3:23])[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][C@@H:20]([OH:19])[CH3:23])=[O:14]
Reactant: C[C@@H](O)CN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: C[C@H](O)CNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-[(2S)-2-hydroxypropyl]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.4 mmol of 2-(R)-hydroxypropylamine. LC/MS [8.40 min; 416 (M+1)]
Reaction SMILES: [C:1](O)(=O)C.[CH:5]([NH2:7])=[NH:6].[C:8](#[N:12])[CH2:9][C:10]#[N:11].[O-]CC.[Na+].[Na]>C(O)C>[NH2:6][C:5]1[C:9]([C:8]#[N:12])=[CH:10][N:11]=[CH:1][N:7]=1
Reactant: N#CCC#N
Reactant: CC(=O)O
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#Cc1cncnc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Formamidine acetate (104.11 g., 1.00 mole) and malononitrile (33.03 g., 0.50 mole) are added to a solution of sodium ethoxide prepared from sodium (24.2 g., 1.05 mole) and absolute ethanol (750 ml.) in a nitrogen atmosphere. The mixture is stirred at room temperature for 48 hours. The off-white solid which separates is collected by filtration, washed with ice water then dried at 80° C./house vac. (ca. 200 mm.). The yield of product melting at greater than 340° C. (uncorr.) is 28.5 g. (47.0%). Recrystallization of this material from water (Darco G-60) affords cream-colored needles melting at 250° C. dec. (uncorr.) in a yield of 11.3 g. (18.8%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:25]([N:27]([CH2:42][CH3:43])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36]([CH:39]=O)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:26].N1CCCCC1>C(O)C>[CH2:42]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36](/[CH:39]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:43]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cccc(C(F)(F)F)c3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(C(F)(F)F)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3-Trifluoromethyl-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (75 mg, 0.28 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 105 mg (62%) of 2,4-dimethyl-5-[2-oxo-5-(3-trifluoromethyl-phenylmethanesulfonyl)-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.O>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: ClCCN1CCOCC1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(N(C)CCN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.13 g, 0.44 mmol) was dissolved in dimethylformamide (DMF) (5 ml). To this was added NaH (60%, 0.053 g, 1.3 mmol) as a suspension in DMF (2 ml). The mixture was stirred at room temperature for 30 minutes then 4-(2-Chloro-ethyl)-morpholine (0.12 g, 0.66 mmol) was added in one portion as a solution in DMF (1 ml) and the reaction mixture was heated to 70° C. for 24 hours. After this time, the reaction mixture was cooled to room temperature and water (10 ml) was added cautiously, the mixture was extracted with ethyl acetate (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 95% ethyl acetate, 5% methanol) gave the title compound (0.051 g, 30% yield) as a white solid.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O-:12])=[O:11].[Na+].[C:14]([O:20][CH2:21]Br)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1>[N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:21][O:20][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: CC(C)(C)C(=O)OCBr
Reactant: O=C([O-])C1C(=O)CC2CC(=O)N21
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)OCOC(=O)C1C(=O)CC2CC(=O)N21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of sodium 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (20 mg) in anhydrous hexamethylphosphoramide (0.5 ml) is added bromomethyl pivalate (35 mg). The resulting mixture is stirred at room temperature for 2 hrs, then diluted with benzene (5 ml) and washed thoroughly with H2O (5×2 ml) and brine. The benzene solution is dried with MgSO4, filtered, and concentrated under reduced pressure. Preparative tlc of the residue on a silica gel GF plate provides pivaloyloxymethyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2.[H-].[Na+]>CN(C=O)C>[CH:25]1[C:26]2[C:21](=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:21]=4[CH:22]=[CH:23][N:24]=[CH:25]5)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Oc1cccc2cnccc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cnccc34)nnc2Oc2cccc3cnccc23)cc1
Temperature: 140 °C

Procedure:
To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)), (100 mg, 0.3 mmol) and 5-hydroxyisoquinoline (112 mg, 0.7 mmol, Aldrich) in DMF (2.5 mL) was added NaH (32 mg, 0.8 mmol, 60 % suspension in mineral oil, Aldrich) and the reaction mixture was heated at 140° C. for 10 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and partitioned between H2O/CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were concentrated in vacuum. The residue was evaporated onto SiO2 and purified by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant to give the title compound as an white amorphous solid. Mp: 197-199° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([CH:18]=[O:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-c2c(C=O)nn3ccccc23)n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C(O)c3ccccc3)nn3ccccc23)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a cold (−78° C.) solution of 3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine-2-carbaldehyde (520 mg, 1.92 mmol) in tetrahydrofuran (40 mL) was added phenylmagnesium bromide (2.88 mL 1.0 M in tetrahydrofuran, 2.88 mmol). The reaction was warmed to 0° C. and stirred for 1 hour. The reaction mixture was then recooled to −78° C. and additional phenylmagnesium bromide (2.00 mL, 1.0 M in tetrahydrofuran, 2.00 mmol) was added and stirred at room temperature for 14 hours. The reaction was quenched with water and the resulting mixture was concentrated in vacuo to remove the excess tetrahydrofuran. The resulting aqueous mixture was extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (49:1 dichloromethane:methanol) provided {3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (550 mg, 82%) as a white solid. Rf 0.31 (49:1 dichloromethane:methanol); 1H NMR (CDCl3) δ 8.52 (d, 1H), 8.40 (d, 1H), 7.87 (d, 1H), 7.43–7.13 (m, 7H), 6.93 (t, 1H), 6.21 (s, 1H), 2.60 (s, 3H); MS m/349 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])N>C(#N)C.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2c(oc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Reaction time: 20 h
Yield: 22.3 %

Procedure:
Ethyl 3-cyano-2-{[(1E)-(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.20 g, 4.14 mmol) and 3-chloro-4-fluoroaniline (1.20 g, 8.27 mmol) were heated in a mixture of acetonitrile (20 mL) and acetic acid (10 mL) in a microwave oven for 30 min to 160° C. The mixture was then concentrated in vacuo, diluted with water, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was triturated with dichloromethane and left to stand for 20 h. The precipitate was collected by suction filtration. Subsequently, the solid was triturated with methanol. The crystals were collected by suction filtration and washed with diethyl ether to yield 360 mg (22%) of the title compound. A second batch of 159 mg (10%) was obtained from the mother liquor after purification by preparative HPLC.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12](O)[CH3:13])[CH:11]=1.C(Cl)[Cl:31]>CN(C)C=O>[Cl:5][C:6]1[C:7]([C:28]#[N:29])=[C:8]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:21][CH:22]=2)[C:9]([O:15][CH3:16])=[C:10]([CH:12]([Cl:31])[CH3:13])[CH:11]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1c(C(C)Cl)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 5 h
Yield: 80 %

Procedure:
Thionyl chloride (800 μL, 10 mmol) was added dropwise to a solution of 5-[3-chloro-2-cyano-5-(1-hydroxyethyl)-6-methoxyphenyl]N,N-dimethylpyridine-2-carboxamide (2 g, 6 mmol), methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 5 hrs and was complete by LC/MS. The reaction mixture was partitioned between EtOAc and water. The combined organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give crude 5-[3-chloro-5-(1-chloroethyl)-2-cyano-6-methoxyphenyl]-N,N-dimethylpyridine-2-carboxamide as an oil (1.8 g, 80%). LCMS calculated for C18H18Cl2N3O2(M+H)+: m/z=378.1; found: 378.1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:21][CH2:22][CH3:23])[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[N:3]=1
Reactant: CCCBr
Reactant: COC(=O)c1cccc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(C)nc2c(C(=O)OC)cccc21
Reaction time: 48 h

Procedure:
To a solution of methyl 2-methyl-1 H-benzimidazole-4-carboxylate (250 mg) in N,N-dimethylformamide (4 ml) were added potassium carbonate (363 mg) and n-propyl bromide at ambient temperature and the mixture was stirred at the same temperature for 2 days. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:1˜1:2˜1:3˜ethyl acetate only) to give methyl 2-methyl-1-propyl-1 H-benzimidazole-4-carboxylate (173 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Cl>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: N#Cc1ccccc1
Agent: Cl[Cu]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Clc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 79 %

Procedure:
A mixture of 2-amino-4-chloropyridine (5.00 g, 38.9 mmol), copper (I) chloride (195 mg, 1.97 mmol), 1,10-phenanthroline monohydrate (390 mg, 1.97 mmol) and benzonitrile (65 mL) was heated in a 100 mL 4-necked flask to 130° C. During 23 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (50 mL) and dried to yield crude 7-chloro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (7.09 g, 79%) as a green solid with 100% purity (HPLC area-%, method see below).