Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)(=[O:33])=[O:13]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(COc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)phenoxymethyl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Cl)cc1
Product: ClCc1coc(-c2ccc(Cl)cc2)n1
Yield: 46 %

Procedure:
This compound was synthesized from 4-chlorobenzamide and 1,3-dichloroacetone as described in example 74 step 1 (3.4 g, yield 46%). 1H NMR (300 MHz, CDCl3) δ 8.01-7.98 (d, J=8.8 Hz, 2H), 7.72 (s, 1H), 7.47-7.44 (d, J=8.8 Hz, 2H), 4.59 (d, J=0.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH3:20][O:21][CH2:22][C:23]#[C:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[N:29][CH:30]=1>>[CH:31]([OH:33])=[O:32].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([C:24]#[C:23][CH2:22][O:21][CH3:20])=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: COCC#Cc1ccc(C(=O)O)nc1
Product: COCC#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)COCC3(F)F)c2)nc1
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-(3-methoxy-prop-1-ynyl)-pyridine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as a white solid. MS (ISP): m/z=410.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[C:10]([C:12]1[C:13]([CH2:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:11].[C:20](C1C(CC2C=CC=CC=2)=NC=CC=1)#N.C(C1C(CCC2C=CC=CC=2)=NC=CC=1)#N.C(C1C(CC(C2C=CC=CC=2)C)=NC=CC=1)#N>>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:9]([CH3:20])=[C:10]([C:12]2[C:13]([CH2:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[N:11]=1
Reactant: N#Cc1cccnc1Cc1ccccc1
Reactant: Cc1ncccc1C#N
Reactant: CCc1ncccc1C#N
Agent: CC(Cc1ncccc1C#N)c1ccccc1
Agent: N#Cc1cccnc1CCc1ccccc1
Product: CCc1ncccc1-c1nc(N)c2cccnc2c1C

Procedure:
In a similar manner by substituting the 3-cyano-2-methylpyridine with equivalent quantities of 3-cyano-2-ethylpyridine, 3-cyano-2-benzylpyridine, 3-cyano-2-phenethylpyridine and 3-cyano-2-phenylpropylpyridine and by substantially following the procedure of this example there is produced 1-amino-3(2-ethyl-3-pyridyl)-4-methyl-2,5-naphthyridine; 1-amino-3-(2-benzyl-3-pyridyl)-4-phenyl-2,5-naphthyridine; 1-amino-3-(2-phenethyl-3-pyridyl)-4-benzyl-2,5-naphthyridine; 1-amino-3-(2-phenylpropyl-3-pyridyl)-4-phenethyl-2,5-naphthyridine, respectively. Similarly, in those instances wherein it is desired to produce those compounds bearing substituents on the pyridyl, phenyl and benzyl moieties of the foregoing then, as expected, the appropriately substituted starting reactants are then similarly reacted.
Reaction SMILES: C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C(C)C.Br[C:20]1[S:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.Br[C:39]1[CH:45]=[CH:44][C:42](N)=[CH:41][CH:40]=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[S:24][C:20]([C:39]4[CH:45]=[CH:44][CH:42]=[CH:41][CH:40]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Agent: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(-c2ccccc2)s1

Procedure:
The title compound was prepared as described in Example 51A, substituting 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.14 (t, J=6.0 Hz, 1H), 8.50 (dd, J=7.1, 0.7 Hz, 1H), 7.91-7.88 (m, 1H), 7.84 (d, J=3.9 Hz, 1H), 7.72 (dt, J=8.3, 2.4 Hz, 2H), 7.57 (d, J=3.9 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H), 7.49-7.33 (m, 4H), 6.86 (dd, J=7.0, 1.7 Hz, 1H), 4.50 (d, J=5.8 Hz, 2H); MS (ESI(+)) m/e 334 (M+H).
Reaction SMILES: CO.Cl.[C:4]([NH2:7])(=[NH:6])[CH3:5].[CH3:8][CH:9]([C:15](OCC)=[O:16])[C:10](OCC)=[O:11].O>C(O)(=O)C>[CH3:5][C:4]1[N:7]=[C:10]([OH:11])[C:9]([CH3:8])=[C:15]([OH:16])[N:6]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Yield: 49 %

Procedure:
A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0° C. with an ice bath, 9.72 g of sodium methylate (i.e. a solution of concentration c=3 mol.l−1) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0° C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up in a minimum amount of water, followed by cooling down to 0° C. then acidifying with pure acetic acid to a pH of between 4 and 5. The white precipitate formed is filtered and rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g (Yield=49%) of expected product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=O)[NH:5][C:3]1=[O:4].[CH2:11]=[O:12].[BrH:13]>C(O)(=O)C.C(Cl)Cl>[Br:13][CH2:6][N:5]1[C:11](=[O:12])[C:8]([CH3:10])([CH3:9])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: C=O
Reactant: CN1C(=O)NC(=O)C1(C)C
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)N(CBr)C(=O)C1(C)C
Temperature: 0 °C
Yield: 88 %

Procedure:
A suspension of 21.3 g of 1,5,5-trimethylhydantoin, 5.86 g of paraformaldehyde and 34 ml of hydrogen bromide in acetic acid (33%) was heated to 80° for 2 hrs., again treated with 7.9 ml of hydrogen bromide in acetic acid and heated for a further 2.5 hrs. The solution was cooled to 0°, diluted with 100 ml of methylene chloride and subsequently treated at 0° with 100 ml of ice-cold water. The methylene chloride phase was washed with water, dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 30.9 g (88%) of pure 3-bromomethyl-1,5,5-trimethylhydantoin, m.p. 86-88°. IR (KBr): 1780s and 1732s (C=O).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH2:16]>N1C=CC=CC=1.O>[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:27])([F:28])[F:29])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH:16][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
4-Nitrobenzoyl chloride (4.55 g) was dissolved in a pyridine (30 ml) solution of 2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)aniline (2.7 g). The solution was refluxed under heating for 3 hours. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml), and an aqueous solution (5 ml) containing sodium hydroxide (2.0 g) was added, and then stirred at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with 1 N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (i.e., anhydrous magnesium sulfate) was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-nitrobenzamide (3.27 g, yield 83.4%).
Reaction SMILES: [CH2:1]([Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1>>[CH2:3]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)[CH:2]=[CH2:1].[CH2:5]([Sn:4]([I:24])([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:7][CH3:8]
Reactant: Brc1ccc(I)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1ccc(Br)cc1
Product: CCCC[Sn](I)(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a Stille coupling reaction, 1-bromo-4-iodobenzene and allyltri-n-butyltin were reacted to yield Compound 1. Thus, tetrakistriphenylphosphine palladium(0) (1.976 g, 1.710×10−3 mol) was weighed out in a nitrogen-filled glove box and transferred to a Schlenk line. Allyltri-n-butyltin (10.60 mL, 3.419×10−2 mol) and 1-bromo-4-iodobenzene (9.680 g, 3.422×10−2 mol) were added along with 115 mL distilled, degassed 1,4-dioxane to yield a yellow reaction mixture that darkened to orange as the reaction progressed. The reaction mixture was stirred at 70° C. for 46 h until analysis by TLC (hexanes) and GC/MS showed that reaction was complete. The mixture was next cooled to room temperature, filtered through Celite (rinsing with hexanes), and resulting solution washed with both hexanes and water, to remove PPh3. Then the organic portion was dried over MgSO4. Filtration through Celite and removal of the solvent in a rotary evaporator at <75° C. yielded an orange oil. Column chromatography on silica gel with hexanes as eluant afforded only Compound 1 and tri-n-butyltin iodide. These were separated via vacuum distillation at 160 mTorr, where Compound 1 distills at about 50° C. (never exceed 75° C., which can potentially cause allyl group isomerization) as a clear colorless oil (2.810 g, 42% yield). GC/MS: single peak; m/z (rel. intensity) 198 (M+, 46), 196 (M+, 46), 117 (100), 115 (86). 1H NMR (CDCl3): δ7.41 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 5.90 (m, 1H), 5.09 (m, 2H), 3.36 (d, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[CH3:9][NH:10][NH2:11]>>[CH3:9][N:10]([C:3]1[N:2]([CH3:1])[CH2:6][CH2:5][N:4]=1)[NH2:11]
Reactant: CNN
Reactant: CSC1=NCCN1C
Product: CN(N)C1=NCCN1C

Procedure:
N-Methyl-N-(1-methyl-4,5-dihydro-1 H-imidazol-2-yl)-hydrazine is prepared according to Step B of Example 25 using 1-methyl-2-methylsulfanyl-4,5-dihydro-1 H-imidazole and methyl hydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:25]([N:17]1[C:18]2=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]2[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])=[N:16]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cccc(B(O)O)c1OC
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: COCCOC
Solvent: CCO
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1OC
Temperature: 80 °C
Yield: 87.4 %

Procedure:
A solution 2,3-dimethoxyphenylboronic acid (105 mg, 0.58 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.23 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA65 (63 mg, 88% yield). ESI-MS (M+H)+ m/z calcd 314.1, found 314.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[NH2:38])=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccccc2N)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 2-aminobenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 1.27 (t, 3H) 4.21-4.37 (m, 2H) 4.45 (q, 2H) 6.33-7.25 (m, 5H). MS (ESI) negative ion 310 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25](=[O:41])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[NH2:40].[CH:42](OCC)(OCC)OCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[N:24]1[C:25](=[O:41])[C:26]2[C:27](=[CH:28][CH:29]=[C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]3)[CH:31]=2)[N:40]=[CH:42]1
Reactant: CN1CCCN(c2ccc(N)c(C(=O)Nc3cc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)ccc3F)c2)CC1
Reactant: CCOC(OCC)OCC
Product: CN1CCCN(c2ccc3ncn(-c4cc(NC(=O)c5cc(F)cc(N6CCOCC6)c5)ccc4F)c(=O)c3c2)CC1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 18, N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamide was reacted with triethyl orthoformate to give the title compound in 63% yield; NMR Spectrum: (DMSOd6) 1.92 (m, 2H), 2.25 (s, 3H), 2.46 (m, 2H), 2.64 (m, 2H), 3.21 (t, 4H), 3.53 (t, 2H), 3.6 (m, 2H), 3.72 (t, 4H), 6.99 (d, 1H), 7.12 (d, 1H), 7.23 (m, 1H), 7.3 (s, 1H), 7.36 (m, 1H), 7.48 (t, 1H), 7.58 (d, 1H), 7.87 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+ 575.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].CC(C)=O.C(=O)=O.[H-].[Na+].[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[CH2:22]Cl)([O-:18])=[O:17]>C1COCC1.C(O)(=O)C>[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[CH2:22][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: COC(=O)CO
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COC(=O)COCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
To a solution of methyl glycolate (10 mL, 130 mmol) in THF (50 mL) at -70° C. (acetone-dry ice) was added in small portions, with stirring 60% NaH in oil (1.6 g, 111 mmol). To the resulting white suspension was added a solution of 3,5-dinitrobenzylchloride (5.0 g, 23 mmol). The reaction was allowed to warm to room temperature and acetic acid (2 mL) was added to quench excess NaH. The reaction mixture was concentrated and the residual tan oil was partitioned between water and CH2Cl2. The organic phase was washed with water and dried over Na2SO4. The crude product obtained after concentration was chromatographed on a silica gel column (4×25 cm) eluting with 33% ethyl acetate in hexane. Concentration of appropriate fractions followed by drying in vacuo gave 5.1 g (93%) of the desired product 2.1 as a pale yellow crystalline solid: 1H NMR (CDCl3) δ 8.98 (s, 1H, C4 --H), 8.59 (s, 2H, C2 --H), 4.85 (s, 2H, CH2), 4.29 (s, 2H, CH2), 3.81 (s, 3H, CH3); 13C NMR (CDCl3) δ 170.16, 148.58, 142.33, 127.30, 118.15, 71.10, 68.07, 52.18.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[CH3:16][OH:17]>[Na]>[CH2:12]([N:11]([CH2:14][CH3:15])[C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:17][CH3:16])[N:3]=[CH:4][N:5]=1)[CH3:13]
Reactant: CO
Reactant: CCN(CC)c1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Na]
Product: CCN(CC)c1ncnc(OC)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a sulphonation flask are dissolved 17.25 g sodium metal in 1000 ml absolute CH3OH. The reaction mixture is cooled to ambient temperature and then a solution of 116 g 4 -chloro-6-diethylamino-5-nitropyrimidine in 500 ml absolute CH3OH is added dropwise thereto. The reaction temperature rises from 22° to 32°. The reaction mixture is then heated for one hour under reflux. The reaction mixture is cooled and concentrated. The residue is taken up in diethylether, washed with water, the organic phase is partitioned off and dried over Na2SO4, concentrated, chromatographed on a silica gel column (elution with diethylether/hexane 1:10) to give a yellow, clear oil (4-diethylamino-6-methoxy-5-nitropyrimidine), Rf=0.3 in ether/hexane 1:3.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH3:32]>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:20]([C:27]2[NH:28][C:29]3[C:25]([C:26]=2[CH3:32])=[CH:24][C:23]([F:22])=[CH:31][CH:30]=3)[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1cccs1
Product: Cc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2cccs2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, rac-5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with thiophene-2-carbaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a red solid. MS: 434.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:24][N:23]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=323.4 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.O>CCOC(C)=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:26])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCNC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
tert-Butyl 5-aminopentylcarbamate (2.02 g, 10 mmol) was dissolved in EtOAc, 4-nitrophenyl carbonochloridate (2.22 g, 11 mmol) was added, the mixture cooled on an icebath, DIEA (2.05 mL, 12 mmol) was added with stirring and the mixture gradually allowed to reach rt and stirred for 3 h. The mixture was transferred to a separatory funnel with EtOAc and H2O, and shaken. The organic phase was extracted with 1N HCl, H2O, 5% NA2CO3, H2O (three times), brine, dried over Mg2SO4, filtered and concentrated to yield compound 9.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH2:1]([O:9][C:10]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(C(=O)OC)c1OCc1ccccc1
Yield: 90.1 %

Procedure:
Benzyl bromide (0.34 ml, 0.49 g, 2.89 mmol, 1.5 eq) was added to a stirred suspension of dimethyl 2-hydroxyisophthalate (0.4045 g, 1.92 mmol, 1 eq) and K2CO3 (0.5317 g, 3.85 mmol, 2 eq) in anhydrous DMF (2 ml) under Ar. After 48 h the reaction was diluted with Et2O. The mixture was washed with water (×4), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.5207 g (1.73 mmol, 90% yield) of dimethyl 2-(benzyloxy)isophthalate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CO>[CH3:27][O:26][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:28][CH3:29])[N:4]=[C:3]([CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Reactant: C1COCCN1
Solvent: CO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.5 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline-3-carboxylate (2.0 g), morpholine (2.5 g) and methanol (30 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane was added to the residue. The mixture was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The resulting crystals were separated by filtration and recrystallized from ethanol to give ethyl 6,7-dimethoxy-4-(4-methoxyphenyl)-2-morpholinomethylquinoline-3-carboxylate (1.65 g, 74%). Colorless prisms, mp. 165°-166° C.