Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1.CCCCCC>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
1.0M LHMDS in hexane (153 mL, 153 mol) was added drop wise to a solution of 2-fluoro-4-iodoaniline (30.0 g, 128 mol) in dry THF (600 mL) at −78° C. over a period of 30 minutes and the resulting mixture was stirred at −78° C. for 30 minutes. This was followed by the addition of 2,3,4,6-tetrafluoronitrobenzene (25 g, 128 mol) in dry THF (150 mL) and stirring was continued for a further 1 hour at room temperature. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mixture was quenched with 2N HCl (100 mL), concentrated and the concentrate was partitioned between water (500 mL) and ethyl acetate (300 mL). The aqueous layer was washed with ethyl acetate (2×200 mL). The combined organic phase was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated to afford 38 g of the crude product. Purification by column chromatography on silica gel (0-5% ethyl acetate in hexane) afforded 31 g of the product (58.8% yield). LCMS: 95.5%, m/z=410.9 (M−1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=[O:3])[CH3:2].[C:18](OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][CH:8]([N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCOCn1cc(F)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(C)n1cc(F)c(=O)[nH]c1=O

Procedure:
1-[1-(2-Hydroxyethoxy)ethyl]-5-fluorouracil (2 g) obtained in Example 2 was treated with acetic anhydride and pyridine as in Example 2 to give 2 g of 1-[1-(2-acetoxyethoxy)-ethyl]-5-fluorouracil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[NH2:23])(=[O:3])[CH3:2].[C:24](OCC)(OCC)(OCC)[CH3:25]>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]=2[N:23]=[C:24]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Temperature: 95 °C
Yield: 97.4 %

Procedure:
1-[(3-Amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]eth-2-yl acetate (10.5 g, 33.29 mmol), toluene (100 mL), pyridine hydrochloride (0.077 g, 0.6659 mmol), and triethyl orthoacetate (9.1 mL, 49.94 mmol) were combined with stirring and the resulting mixture was heated to a gentle reflux (about 95° C.) for 1.5 hours. The reaction was complete. The resulting reaction mixture was concentrated under reduced pressure to white solids, which were dissolved in ethyl acetate. The ethyl acetate solution was washed with water (3×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether, filtered off, and dried at 60° C. overnight to provide 11 g of pure product, which was carried on to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CNc1ccccc1C(N)=O
Temperature: 160 °C
Yield: 23.3 %

Procedure:
To 2 g of ortho-aminobenzamide were added 4.04 g (2 equivalents) of potassium carbonate, 4.94 g (2 equivalents) of ethyl bromoacetate, and the mixture was stirred under heating at 160° C. for 3 hours. After cooling to room temperature, water was added and the mixture extracted with ethyl acetate. After washing with aqueous sodium chloride, the mixture was dried over anhydrous magnesium sulfate, followed by evaporation of the solvent. The residue was developed with hexaneethyl acetate (1:2) by silica gel column chromatography to obtain 760 mg of the desired compound (yield 23.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (251 mg).
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([OH:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].[CH2:13](I)[CH3:14].C(O)C>C1C=CC=CC=1.O>[CH2:13]([N:3]1[C:2](=[O:1])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([OH:10])=[N:4]1)[CH3:14]
Reactant: Oc1nnc(O)c(Cl)c1Cl
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCn1nc(O)c(Cl)c(Cl)c1=O
Reaction time: 4 h

Procedure:
A mixture comprising 5.00 g of 3,6-dihydroxy-4,5-dichloropyridazine, 2.21 g of sodium hydroxide, 5.60 g of ethyl iodide, 40 ml of ethanol and water, was stirred at a temperature of from 60° to 70° C. for 4 hours. Most ethanol was distilled off under reduced pressure. Then, dilute hydrochrolic acid and chloroform were added to the residue, and the mixture was vigorously shaked. The chloroform layer was separated and washed with water, followed by drying over sodium sulfate. Then, the solvent was distilled off to obtain a light orange solid substance. The solid substance was treated with benzene to obtain 3.56 g of the above identified compound as colorless crystals.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].COC[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19](O)=O.[C:22]1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:22][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOCCOCCOCC(=O)O
Solvent: c1ccncc1
Product: COCCOCCOCCCOCC(=O)Cl
Yield: 99 %

Procedure:
(CH3(OCH2CH2)3CH2OCH2COCl) was prepared according to Procedure 1. Oxalyl chloride (3.6 mL, 0.041 mol); {2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-acetic acid (3.3 g, 0.15 mol); pyridine (0.1 mL, 1 mmol) and anhydrous toluene (10 mL) to give CH3(OCH2CH2)3CH2OCH2COCl as yellow oil (3.5 g, 99%). This compound was used without any further purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Propionyl chloride (2.02 mL, 23.1 mmol) and DIPEA (14.4 mL, 84.0 mL) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (195 mL). The mixture was stirred for 15 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (1×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→3:2) yielded the title compound (5.08 g, 71%). LC-MS: tR=1.09 min; ES+: 383.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[C:7]2[C:13]([OH:15])=[O:14].C(Cl)(=O)[C:17](Cl)=[O:18].Cl[CH2:23]Cl>CN(C)C=O>[CH3:23][O:15][C:13]([C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([O:18][CH3:17])[CH:8]=1)=[O:14]
Reactant: ClCCl
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)nc2c(F)cccc12
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nc2c(F)cccc12
Reaction time: 2 h

Procedure:
8-Fluoro-2-chloroquinoline-4-carboxylic acid (0.986 g) suspended in dichloromethane (50 ml) was treated with dimethylformamide (3 drops) and oxalyl chloride (0.76 ml) and the mixture stirred for 2 h. Solvent was removed at reduced pressure. The residue was dissolved in methanol (50 ml) containing sodium methoxide (0.54 g) and stirred for 16 h. The solvent was removed at reduced pressure and the residue triturated with water. The precipitate was collected by filtration and column chromatographed (silica gel, 10→50% ethyl acetate/hexane) to give the title compound (0.184 g) as a colourless solid. m/z (API+): 236 (MH+). 1H NMR (CDCl3) δ: 4.02 (3H, s), 4.14 (3H, s), 7.36-7.41 (2H, m), 7.49 (1H, s), 8.37 -8.41 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCCCN)CC1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: O
Product: CN1CCN(CCCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 0.50 g (2.70 mmol) of 1-(5-aminopentyl)-4-methylpiperazine was heated with stirring in a 180° C. to 185° C. oil bath. After 2 minutes, solution was complete. After 0.5 hour, the solution was cooled to room temperature, and 5 mL of water was added to precipitate a taffy-like gum. Decanted and triturated gum again with 5 mL of water. Decanted and took up gum into 35 mL of ether. The ether solution was washed with 2×50 mL of water, dried (potassium carbonate), and concentrated to 5 mL volume. Petroleum ether was added to slight turbidity. The crystals that separated on inducement were filtered and washed with 80% ether/petroleum ether; wt 0.060 g; mp 110°-112° C.;
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:16][NH:15][C:14](=[N:17][N+:18]([O-:20])=[O:19])[NH:13][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:21]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH:11]2[CH2:16][N:15]([CH3:27])[C:14](=[N:17][N+:18]([O-:20])=[O:19])[NH:13][CH2:12]2)=[O:9])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CI
Reactant: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(OC(=O)C(c2ccccc2)c2ccccc2)CNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-nitroiminohexahydropyrimidin-5-yl diphenylacetate (0.4 g) and methyl iodide (0.16 g) in DMF (4 ml), 80% sodium hydride (0.06 g) was added. The mixture was then stirred at room temperature overnight. The solvent was removed and the residue taken up with methylene chloride/water. The organic layer was evaporated and the residue was purified by column chromatography (eluent methylene chloride/methanol 98:2) to afford 1-methyl-2-nitroiminohexahydropyrimidin-5-yl diphenylacetate. M.p. 187° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:29]([O-])=O)=[C:13]([CH:28]=2)[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[CH3:27])=[N:3]1.O.O.Cl[Sn]Cl>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:28]=[C:13]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][C:17]=3[CH3:27])[C:12]([NH2:29])=[CH:11][CH:10]=2)=[N:3]1
Reactant: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(OC(F)(F)F)ccc1CNc1cc(OCc2ccn(C)n2)ccc1N
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N-(2-methyl-4-(trifluoromethoxy)benzyl)-2-nitroaniline (187 mg, 0.43 mmol) in ethanol (30 mL) was added SnCl2.2H2O (482 mg, 2.21 mmol). The resulting mixture was heated at 90° Celsius. After overnight, the mixture was cooled to RT and diluted with saturated NaHCO3 (40 mL). The resulting mixture was extracted with DCM (3×50 mL). The combined organics were concentrated to dryness to provide the title compound, which was used without further purification. MS (ESI): mass calcd. for C20H21F3N4O2, 406.16; m/z found, 407 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:20][C:21]1[C:26](O)=[C:25]([Cl:28])[C:24]([Cl:29])=[C:23]([Cl:30])[C:22]=1[Cl:31].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Cl:20][C:21]1[C:26]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:25]([Cl:28])[C:24]([Cl:29])=[C:23]([Cl:30])[C:22]=1[Cl:31]
Reactant: N#CC(C(=O)O)c1ccccc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in 80 ml. of dichloromethane, 10.2 g. (0.05 moles) of phosphorous pentachloride are added and the mixture is stirred for 2 hours at the boiling point of the dichloromethane. The reaction is completed when the hydrochloric acid evolution ceases. The solvent is distilled off and the residue containing the obtained acid chloride and phosphoroxychloride is taken up in carbontetrachloride and the solution is added dropwise to 13 g. (0.05 moles) of pentachlorophenol and 4 ml. (0.05 moles) of pyridine dissolved in 200 ml. of carbontetrachloride. The reaction mixture is cooled and the precipitated pyridine chlorohydrate is removed by washing twice with 50 ml. of water, dried, distilled off and the residue is distilled off with diisopropyl ether. The precipitated crystalline product is cooled and filtered. The α-cyanophenylacetic acid pentachlorophenyl ester is air-dried.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:8]1[S:7][C:6]([CH3:9])=[N:5][C:4]=1[CH2:3][Cl:2]
Reactant: Cc1nc(CCl)cs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(CCl)c(Br)s1
Reaction time: 2.5 h
Yield: 61.1 %

Procedure:
To 11 g of 4-chloromethyl-2-methylthiazole, hydrochloride (0.06 mol), dissolved in 150 ml of glacial acetic acid are added while stirring, 11.5 g of anhydrous sodium acetate (0.14 mol) and at 45°-50°, 9.6 g of bromine (0.12 mol) in 50 ml of glacial acetic acid. Stirring is continued for an additional 2.5 hours at 60°-80° C. Then the solution is evaporated in vacuo to dryness and the residual product is extracted with ether. Evaporation of the solvent gives 8.3 g oil which is then dissolved in hexane. Charcoal treatment, evaporation of the solvent, dissolving of the oil again in 100 ml of ether and addition of ethereal hydrochloric acid, yield the hydrochloride. Yield: 6.5 g (41%), m.p. 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C([Li])CCC.CO[C:17]1[C:18]([CH:23]=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=1.[Cl-].[NH4+].C[CH2:28][O:29]CC>CCCCCC.C1COCC1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:29][CH3:28])[C:2]=1[CH:23]([C:18]1[CH:17]=[CH:22][CH:21]=[CH:20][N:19]=1)[OH:24]
Reactant: COc1cccnc1C=O
Reactant: CCOCC
Reactant: OCc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 14.5 %

Procedure:
To a mixture of 3.59 g (0.019 mol) of o-bromobenzyl alcohol in 100 ml of ether cooled to -20° C. was added in portions 4.1 ml (0.0412 mol) of n-butyllithium (10M) in hexane over a 6 min period, and the reaction mixture was stirred 20 min. The above reaction mixture was cooled to -20° C., 3 g (0.021 mol) of 3-methoxy-pyridine-2-carboxaldehyde in 5 ml of THF was added in one portion to the mixture, and the resulting reaction mixture was allowed to warm to room temperature and stirred for 20 min. Ammonium chloride solution (30 ml) was added to the mixture and the mixture was extracted with ethyl acetate (3×50 ml). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was triturated with 100 ml of ether, filtered, and purified by chromatography on silica gel eluting with 4% methanol/hexane. The solvent was concentrated in vacuo to afford 0.68 g (14.5%) of 2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-methoxypyridine (Formula XIII: R1 =3--OCH3 ; R2 =R7 =H), as a white solid, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:30]>C(#N)C.O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][Cl:30])=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 3.28 g (9.1 mMol) of {4-[4-(6-methoxy-pyridin-3-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 40 ml of acetonitrile, 40 ml of dioxane and 4 ml of SOCl2 is stirred for 1 h at RT. The mixture is dissolved in EtOAc and NaHCO3-solution, the aqueous layer separated off and extracted with EtOAc. The organic layers are washed with NaHCO3-solution, water and brine, dried (Na2SO4) and partially concentrated. The crystallized title compound can be filtered off; elemental analysis for C, H and N within 0.4% of calculated value.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:14]=[N:15][CH:16]=2)=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)NS(C)(=O)=O)ccc4N3)c2)cc1
Yield: 19.9 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.48 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (130 mg, 0.72 mmol), 4-dimethylaminopyridine (88 mg, 0.72 mmol), methane sulfonamide (140 mg, 1.44 mmol) in dichloromethane (20 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-{2-[5-(4-tert-Butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (47 mg, 20%) as a light yellow solid: MS (ESI) M+1=492.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5][C:4]=2[C:3]=1[C:17]([NH2:19])=[O:18].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[CH3:22][N:23]([CH3:25])[CH:24]=[N:19][C:17]([C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2)=[O:18]
Reactant: COc1nc2cc(Cl)c(Cl)c(C(N)=O)c2nc1OC
Reactant: COC(OC)N(C)C
Product: COc1nc2cc(Cl)c(Cl)c(C(=O)N=CN(C)C)c2nc1OC
Yield: 92 %

Procedure:
6,7-Dichloro-2,3-dimethoxyquinoxaline-5-carboxamide (Preparation 24, 1.96 g, 6.49 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated under reflux for 2 hours. After being cooled the mixture was concentrated under reduced pressure and the residue triturated with diethyl ether to afford N1,N1-dimethyl-N2-[6,7-dichloro-2,3-dimethoxyquinoxalin-5-ylcarbonyl]formamidine (2.14 g, 92%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14]Br>CS(C)=O>[C:1]1([C:7]2([C:8]#[N:9])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CC1
Yield: 91.9 %

Procedure:
Phenylacetonitrile (5.85 g, 50 mmol) in DMSO (dimethylsulfoxide) (20 mL) is added dropwise over 45 min to a slurry of oil-free NaH (3.0 g, 125 mmol) in stirred DMSO (100 mL) at 25° under N2. Vigorous gas evolution occurs. After a further 30 min 1,2-dibromoethane (14.1 g, 75 mmol) in DMSO (20 mL) is added dropwise over 1 h. The reaction mixture turns purple, heats up to about 50°, and further gas evolution occurs. After a further 1 h the reaction mixture is poured slowly onto ice water (250 mL, gas evolution), and is extracted with ether (3×50 mL). The combined extracts are washed with water (2×100 mL) and saturated brine (100 mL) and dried (MgSO4). The solvent is removed under reduced pressure to give 1-phenylcyclopropane carbonitrile (6.58 g, 92%) as a mobile brown oil. Nmr δ (CDCl3) 7.25-7.40 (5H, m), 1.6-1.8, 1.2-1.45 (2H and 2H, AA'BB').