Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[NH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH2:25]1>>[C:35]([O:34][C:32]([CH2:31][CH2:30][CH:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][NH:21][C:2]2[N:3]=[C:4]([NH2:20])[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:29][CH2:28]1)=[O:33])([CH3:37])([CH3:38])[CH3:36]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)OC(=O)CCC1CCC(CCN)CC1
Product: CC(C)(C)OC(=O)CCC1CCC(CCNc2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1

Procedure:
The reaction of 2-chloroadenosine with t-butyl 3-[4-(2-aminoethyl)-cyclohexyl]-propionate according to the procedure described in Example 14 yields 2-{2-[4-(2-t-butyoxycarbonyl-ethyl)-cyclohexyl] -ethylamino}-adenosine, [alpha]D25 =-22.3° in methanol, m.p. 118°-122°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OCCCCCCCCCCN)cc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCCCCCCCCCNC(=O)CCl)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
The crude product from (iii) above (5.62 g, 18.84 mmol) and triethylamine (2.6 mL, 18.7 mmol) were dissolved in chloroform (90 mL) and cooled in an ice bath. A solution of chloroacetyl chloride (1.5 mL) in chloroform (40 mL) was added dropwise with stirring. After the completion of the addition, the solution was stirred in the ice bath for 15 minutes and warmed to ambient temperature and stirred for 20 hours. The solution was washed with water (4×80 mL). Drying (MgSO4) and concentration yielded the product (6.71 g, 93%) which was used without further purification. 1H NMR (CDCl3, δ): 7.95 (d), 6.87 (d), 6.54 s, br), 4.01 (d), 3.96 (t), 3.86 (s), 3.28 (q), 1.76 (m), 1.55 (m), 1.45 (m), 1.29 (m). 13C NMR (CDCl3, δ): 130.71, 130.66, 121.52, 113.23, 75.37, 67.33, 50.95, 41.85, 39.04, 28.56, 28.53, 28.47, 28.43, 28.33, 28.25, 25.94, 25.11.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](Cl)[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:52][NH:53][CH3:54].O1CCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:53]([CH3:54])[CH3:52])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
After dissolving 1.01 g of 1-(4-benzylpiperazin-1-yl)-7-chloroisoquinoline as synthesized in above Step 1 in 30 ml of tetrahydrofuran, 20 mg of palladium acetate, 48 mg of 2-(di-tert-butylphosphino)biphenyl, 450 mg of sodium-tert-butoxide and 5 ml of 2.0 M dimethylamine-tetrahydrofuran solution were added to the solution and sealed in a tube. This mixture was stirred at 80° C. for 16 hours. Removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure and the residue was purified on silica gel column chromatography (methanol:chloroform=1:19) to provide 261 mg (25%) of 1-(4-benzylpiperazin-1-yl)-7-dimethylaminoisoquinoline.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Li]C(CC)C.[CH2:18]([O:20][Si:21]([O:34][CH2:35][CH3:36])(Cl)[C:22]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32])[CH3:19]>CCOCC>[F:8][C:7]1[C:2]([Si:21]([C:22]2[C:23]([F:32])=[C:24]([F:31])[C:25]([F:30])=[C:26]([F:29])[C:27]=2[F:28])([O:34][CH2:35][CH3:36])[O:20][CH2:18][CH3:19])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Reactant: CCO[Si](Cl)(OCC)c1c(F)c(F)c(F)c(F)c1F
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
39.52 g (0.195 mol) chloropentafluorobenzene is weighed to a 1000 mL vessel and 250 mL Et2O is added. The vessel is cooled down to −70° C. and 150 mL (0.195 mol) of sec-BuLi (1.3 M) is added dropwise during one hour. The temperature of the solution is kept below −50° C. all the time. The solution is stirred for 30 minutes and 62.54 g (0.195 mol) of diethoxychloropentafluorophenylsilane in Et2O (100 mL) is added in small portions. The solution is stirred for over night allowing it to warm up to room temperature. Formed clear solution is filtered and evaporated to dryness to result di(pentafluorophenyl)diethoxysilane, (C6F5)2Si(OEt)2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27][CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[N:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:26][CH2:25][C:24]=2[CH:23]=[N:22][CH:21]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1ccccc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2-chlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d] [1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:17]=2)(=[O:15])=[O:14])=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:24]1[CH:23]=[C:22]([C:18]2[CH:17]=[C:16]([S:13]([NH:12][C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:6]=3[S:8]([NH2:11])(=[O:10])=[O:9])(=[O:15])=[O:14])[CH:21]=[CH:20][CH:19]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: OB(O)c1ccccc1
Reactant: NS(=O)(=O)c1cc(Br)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(-c2ccccc2)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
5-Bromo-2-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]benzenesulfonamide (70 mg, 0.13 mmol) was dissolved in DMF (700 μl), then phenylboronic acid (20 mg, 0.16 mmol) was added followed by the addition of 2M sodium carbonate solution (260 μl). The mixture was subjected to vacuum/argon (×3), tetrakis(triphenylphosphine)palladium (8 mg, 0.05 mol %) was added and the reaction was allowed to stir at 80° C. overnight. The cooled reaction mixture was filtered and was then purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (23 mg, 32%).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:29])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:21]=2)=[CH:13][CH:12]=1>>[CH3:29][C:19]1[O:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[CH:12][CH:13]=2)=[N:21][C:20]=1[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1cncnc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 5-Pyrimidine boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 335.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[B-:10]([F:14])([F:13])([F:12])[F:11].[Na+].[F-:16].[Na+].N#N.FF.FF>C(#N)C>[F:11][B-:10]([F:14])([F:13])[F:12].[F:16][N+:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)nc(C)c1
Reactant: [F-]
Agent: FF
Agent: F[B-](F)(F)F
Agent: N#N
Solvent: CC#N
Product: Cc1cc(C)[n+](F)c(C)c1
Yield: 70 %

Procedure:
In a 25 ml pear-shaped flask, 2,4,6-trimethylpyridine (1.21 g, 10 mmoles), sodium borofluoride (1.23 g, 10 mmoles) as the XM reactant and anhydrous sodium fluoride (2.1 g, 50 mmoles) were dissolved in 15 ml of anhydrous acetonitrile and to the resulting solution a mixed gas of nitrogen/fluorine (9:1) was introduced at a rate of 50 ml/min. at -40° C. under vigorous stirring. The amount of fluorine introduced was 20 mmoles. After the completion of the reaction, precipitates were filtered and then the solvent was distilled off. The resultant residue was recrystallized from acetonitrile/diethyl ether to obtain 1.59 g (yield: 70%) of N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate the physical properties of which are shown in Table 6.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:31])[C@H:6]([N:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[C:25]1=[O:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:14]([NH2:23])=[N:13][CH:12]=[CH:11]2.C(N(C(C)C)CC)(C)C.[N:41]1([C:46]2[S:47][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:49][N:50]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:31])[C@H:6]([N:24]1[CH2:28][CH2:27][C@H:26]([NH:29][S:51]([C:48]2[S:47][C:46]([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[N:50][CH:49]=2)(=[O:53])=[O:52])[C:25]1=[O:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([F:21])([F:22])[F:20])[C:14]([NH2:23])=[N:13][CH:12]=[CH:11]2
Reactant: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](N)C1=O
Reactant: O=S(=O)(Cl)c1cnc(N2CCCC2)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](NS(=O)(=O)c2cnc(N3CCCC3)s2)C1=O

Procedure:
To a suspension of 485 mg (1 mmol) of (R)-3-(1-Amino-7-trifluoromethoxy-isoquinolin-6-yl)-2-((S)-3-amino-2-oxo-pyrrolidin-1-yl)-propionic acid methyl ester bishydrochloride in 6 ml CH2Cl2, 873 μl (5 mmol) diisopropylethylamine and 379 mg (1.5 mmol) 2-Pyrrolidin-1-yl-thiazole-5-sulfonyl chloride, dissolved in 5 ml CH2Cl2, are added subsequently at 0° C. under stirring.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: CCI
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Fourteen g of 2-amino-3-(4-chlorobenzoyl)benzene acetic acid, sodium salt.H2O was dissolved in 150 ml of dimethylformamide and then treated with 30 g of ethyl iodide. The resulting solution was stirred at room temperature for 2.5 hours. The solution was then added to water and the mixture was extracted several times with benzene. The benzene layer obtained was washed with dilute base and water, dried over sodium sulfate and stripped to leave an oil which crystallized on trituration with pet. ether. Recrystallization from ethyl alcohol gave 11.6 g of the titled compound as yellow flakes, m.p. 101°-102° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]([CH3:18])([N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]1)[CH3:9])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][CH:25]([NH:31][CH:32]([CH3:36])[C:33](O)=[O:34])[CH2:24][CH2:23]2>>[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][CH:25]([NH:31][C@@H:32]([CH3:36])[C:33]([NH:15][C:13]1[N:12]=[CH:11][N:10]([C:8]([CH3:18])([CH3:9])[CH2:7][NH:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:14]=1)=[O:34])[CH2:24][CH2:23]2
Reactant: CC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CCOCCNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CCOCCNCC(C)(C)n1cnc(NC(=O)[C@H](C)NC2CCc3cc(F)cc(F)c3C2)c1

Procedure:
(2-Ethoxy-ethyl)-[2-methyl-2-(4-nitro-imidazol-1-yl)-propyl]-amine was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-propionic acid to afford the title compound: MS 464.6 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23]([OH:27])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of the alcohol 2 [(0.92 g, 2.68 millimoles (mM)] in acetone (25 ml) was added a 2N H2Cr2O7 (Jones Reagent) solution (3.02 ml, 6.04 mM) dropwise over a 10 minute time period. After stirring for 1 hour the reaction solution was decanted from the chromium precipitates on the sides of the reaction vessel. The reaction solution was concentrated in vacuo and taken up into ethyl acetate (EtOAc) (100 ml), washed with distilled H2O until the washes were clear, dried (MgSO4), filtered, and concentrated in vacuo. Crystallization from Et2O: hexane afforded 12 (0.88 g, 92%) as an off-white crystalline solid, mp=126°-128° C.
Reaction SMILES: C(=[N:14][CH:15]([CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.Cl>[NH2:14][CH:15]([CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]#[N:17]
Reactant: CC(c1ccnc2ccccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(c1ccnc2ccccc12)C(N)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To 2-(Benzhydrylideneamino)-3-quinolin-4-yl-butyronitrile (3.0 g, 7.3 mmol) in 30 ml dioxane, 1N HCl (30 ml, 29.99 mmol, was added and the reaction mixture stirred at room temperature overnight. The solution was then concentrated under reduced pressure, partitioned between water (10 ml) and EtOAc (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give 1.58 g (88%) of the product which was used as such for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27][CH3:28])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([OH:33])=O)[C:11]=2[CH:10]=1.[NH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:21]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:20]=2[C:19]2[C:18]3[CH:17]=[C:16]([O:27][CH3:28])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:29][CH2:30][C:31]([NH2:34])=[O:33])[C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(=O)O)C(=O)NC3=O
Reactant: N
Product: COc1ccc2c(c1)c1c3c(c(-c4c(Cl)cccc4Cl)cc1n2CCC(N)=O)C(=O)NC3=O
Yield: 73 %

Procedure:
Reaction of acid (244) (0.23 g, 0.48 mmol) prepared as described in example 204 according to the procedure described in example 207, except that concentrated ammonia (˜30%, 20 mL) was added as the amine, gave amide (250) (0.17 g, 73%) as a yellow powder, mp 261–264° C. 1H NMR δ [(CD3)2SO] 11.19 (br s, 1H), 8.50 (d, J=2.6 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.63 (m, 2H), 7.52 (dd, J=8.8, 7.3 Hz, 1H), 7.38 (br s, 1H), 7.33 (dd, J=9.0, 2.6 Hz, 1H), 6.87 (br s, 1H), 4.69 (t, J=6.7 Hz, 214), 3.91 (s, 3H), 2.57 (t, J=6.7 Hz, 2H). Found: C, 59.55; H, 3.79; N, 8.73. C14H17Cl2N3O4 requires: C, 59.75; H, 3.55; N, 8.71.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:5]=[O:6]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(N2CCOCC2)c(Br)c1
Yield: 58.2 %

Procedure:
EX-604A) To a pyridine (15 mL) solution of 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol) was added morpholine (0.5 mL, 5.7 mmol) and K2CO3 (0.69 g. 5.0 mmol), and the slurry was refluxed for 18 h. The solvent was removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 15% ethyl acetate in hexane gave 0.77 g (58%) of the desired 3-bromo-4-(4-morpholinyl)benzaldehyde product as an white solid. 1H NMR (CDCl3) δ3.18 (m, 4H), 3.90 (m, 4H), 7.10 (d, 1H), 7.78 (d, 1H), 8.07 (s, 1H), 9.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[CH3:11].CO[CH:14](OC)[CH2:15][NH2:16]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]2[C:6](=[CH:5][C:4]=1[CH3:11])[CH:7]=[N:16][CH:15]=[CH:14]2
Reactant: COC(CN)OC
Reactant: COc1ccc(C=O)cc1C
Solvent: c1ccccc1
Product: COc1cc2ccncc2cc1C
Temperature: -10 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
4-Methoxy-3-methylbenzaldehyde (3.00 g) was dissolved in benzene (30 ml) to prepare a solution. 2,2-Dimethoxy-ethylamine (2.10 g) was added to the solution, and the mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in tetrahydrofuran (30 ml), and the mixture was cooled to −10° C. Ethyl chloroformate (2.17 g) and trimethyl phosphite (2.97 g) were added thereto, and mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in dichloromethane (30 ml), titanium tetrachloride (22.7 g) was added to the solution, and the mixture was heated under reflux for 36 hr. The reaction solution was cooled to room temperature, was then neutralized with a 1 N aqueous sodium hydroxide solution, and was extracted with 3 N hydrochloric acid. The aqueous layer was made basic by the addition of a 3 N aqueous sodium hydroxide solution and was then extracted with dichloromethane. The solvent was removed by distillation under the reduced pressure to give 6-methoxy-7-methylisoquinoline (764 mg, yield 22%).
Reaction SMILES: [C:1]1([CH2:11][N:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH2:13][CH2:14][OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:1]1([CH2:11][N:12]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH2:13][CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-[Naphthalen-1-ylmethyl-(3-phenylisoxazol-5-yl)amino]ethanol (820 mg, 2.38 mmol) was dissolved in methylene chloride (15 ml), treated with triethylamine (592 μl, 4.25 mmol) followed by methanesulfonyl-chloride (265 μl, 3.42 mnmol) and the solution stirred at rt for 1.5 hr. The reaction was washed with 50% sodium bicarbonate (aq, 2×), water (1×), and brine (1×), dried over sodium sulfate, filtered and stripped to dryness in vacuo to give the product as a sticky, foam (1.07 gm, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]#[C:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1C#CCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1CCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
Dissolve 1-[3-(2-methoxy-4-nitro-phenyl)-prop-2-ynyl]-pyrrolidine (292 mg, 1.12 mmol) in EtOH (5 mL) and treat with 5% Pd/C. Purge the black mixture with hydrogen, then stir overnight at room temperature under a hydrogen atmosphere (1 atm). Filter the black mixture through a pad of Celite® and wash the solids with additional EtOH (20 mL). Concentrate the filtrate to give the title compound as an oil (240 mg, 91%). MS (ES+) 235.2 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 6.88 (d, 1H, J=8.3 Hz), 6.22-6.18 (m, 2H), 3.73 (s, 3H), 3.55 (s, 2H), 2.53-2.41 (m, 8H), 1.79-1.72 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](Cl)=[N:28][CH:29]=1>CN(C=O)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=3)[CH2:2][CH2:3]2)=[CH:8]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCC(c3c[nH]c4ccccc34)CC2)nc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3-piperidin-4-yl-1H-indole (0.5 g, 2.5 mmol) is suspended in 10 ml of DMF and is heated to 60° C. K2CO3 and 5-trifluoromethyl-2-chloropyridine (0.54 g, 3.0 mmol) are added and the reaction mixture is stirred at 95° C. for 1 hour. K2CO3 is removed by filtration and the filtrate is concentrated and purified with a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1>CC1C=CC=CC=1C.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:9][C:5]3[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=3[N:10]=2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Nc1cc(F)c(F)cc1N
Agent: [Ti+4]
Agent: CC[O-]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Yield: 15 %

Procedure:
To a solution of 4,5-difluoro-benzene-1,2-diamine (2.0 g, 6.94 mmol; CAS Reg. No. 76179-40-3) in o-xylene (25 ml) was added 4-chloro-2-nitro-benzoic acid (2.78 g, 6.94 mmol; CAS Reg. No. 6280-88-2) and titanium tetraethoxide (2.9 ml, 6.94 mmol) at 25° C., and the reaction mixture was allowed to stir at reflux temperature for 14 h. After the completion of reaction, solvents were evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (18-20% ethyl acetate/n-hexane) to afford the desired compound as a yellow powder (15%). MS (Turbo Spray): m/z=310.2 (M+H).