Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([NH:21][C:22](=[O:31])[C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[CH3:32]>CN1CCCC1=O>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[CH:13][C:12]([CH3:32])=[C:11]2[O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:31]
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Oc1ccccc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a mixture of sodium hydride (60% in oil, 28.9 mg) and N-methylpyrrolidone (3 ml) was added phenol (113 mg) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (200 mg), and the mixture was stirred for 30 minutes at ambient temperature and for 4.5 hours at 120° C. The mixture was extracted with ethyl acetate, and the extract was washed with water, 1N sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-3-methyl-4-phenoxyquinoline (170 mg) as white crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[CH:16]=[C:17](C3C=CC(F)=C(C(F)(F)F)C=3)[N:18]=2)[CH2:10][CH2:9]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](C2N(C)C(C3CCNCC3)=NC=2)=[CH:35][C:34]=1[C:51]([F:54])([F:53])[F:52]>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH3:30])[C:16]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[C:34]([C:51]([F:54])([F:53])[F:52])[CH:35]=3)=[CH:17][N:18]=2)[CH2:12][CH2:13]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Reactant: Cn1c(-c2ccc(F)c(C(F)(F)F)c2)cnc1C1CCNCC1
Product: Cn1c(-c2ccc(F)c(C(F)(F)F)c2)cnc1C1CCN(c2ncnc(N)c2Br)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1.Cl>O>[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:13]1[S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9]
Reactant: CC1(C)C=CC(=O)CC1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CCC(=O)CC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Benzenesulfinic acid sodium salt (5.98 g) was added to a solution containing 3 ml of 4,4-dimethyl-2-cyclohexene-1-one and 20 ml of water. Forty ml of 1N hydrochloric acid were added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and the solid, washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 4,4-dimethyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals. Yield: 89%, Melting point: 84 to 86° C.
Reaction SMILES: C(OP([C:9](OC)(OC)[CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(OCC)=O)C.[Li]CCCC.[CH3:32][C:33]1([CH3:51])[CH:42]=[C:41]([C:43]2[S:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:49]=O)[CH:39]=2)[O:34]1.Cl[Sn](Cl)(Cl)Cl>C1COCC1.CCCCCC.C(OCC)(=O)C.ClCCl>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([C:11]2[CH:49]=[CH:38][C:37]3[CH:36]=[C:35]4[C:40]([C:41]([C:43]5[S:44][C:45]([CH3:48])=[CH:46][CH:47]=5)=[CH:42][C:33]([CH3:51])([CH3:32])[O:34]4)=[CH:39][C:9]=3[CH:10]=2)=[CH:22][CH:21]=1)[CH3:20]
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)s1
Reactant: CCOC(=O)c1ccc(CCC(OC)(OC)P(=O)(OCC)OCC)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(c2ccc(C)s2)=CC(C)(C)O4)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (-78° C.) solution of ethyl 4-(diethoxyphosphoryl-3,3-dimethoxypropyl)benzoate (Compound D, 690 mg, 1.75 mmol) in THF (8 mL) was added n-BuLi in hexane (1.6M solution, 1.1 mL). The mixture was gradually warmed to ambient temperature over 30 min and stirred for 5 minutes. The mixture was recooled to -78° C. and 2,2-dimethyl-4(5-methyl-thien-2-yl)-chrom-3-en-6-al (Compound S, 300 mg, 1.1 mmol) in THF (1 mL) was added to the reaction mixture. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (10 mL) dried and the solvent was removed by evaporation. The material was subjected to flash chromatography on silica gel to obtain the E and Z olefinic compounds, which were dissolved in dichloromethane (5 mL) and cooled to -78° C. A solution of SnCl4 in dichloromethane (52 mg in 0.2 mL) was added to the olefinic compounds. The resulting mixture was stirred for 30 minutes, quenched with methanol, water and diluted with ethyl acetate (100 mL). The organic layer was washed with brine and dried. Solvent was removed under reduced pressure and purified by silicagel chromatography to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)([OH:12])[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:19]>O1CCCC1.CCOCC>[ClH:19].[NH:11]=[C:10]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:12]1
Reactant: N#CCCC(O)(c1ccccc1)C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: N=C1CCC(c2ccccc2)(C2CCCCC2)O1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 1-phenyl-1-cyclohexyl-3-cyano-1-propanol (1.4 g) in anhydrous tetrahydrofuran (THF), a solution of HCl 10% w/v in ether (2.5 ml) was added dropwise. The mixture was stirred and cooled for 48 hours. The solvent was removed and the residue triturated with diethyl ether/THF to afford 0.8 g of 2-imino-5-phenyl-5-cyclohexyltetrahydrofuran hydrochloride. M.p. 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH2:11]([Mg]Br)[CH3:12].Cl.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH2:11][CH3:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC[Mg]Br
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(=O)c1cccc(OC)c1
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-(methyloxy)benzaldehyde (0.895 mL, 7.34 mmol) in diethyl ether (10 mL) cooled in an ice bath was added ethylmagnesium bromide (1.0M solution in THF) (11.02 mL, 11.02 mmol), the solution was stirred for 3 h in an ice bath, after which aqueous HCl (0.6M) (20 mL) was added. The aqueous layer was then extracted with DCM (4×30 mL), the combined organic extracts were dried over a phase separating column and concentrated. The residue was used in the next step without any further purification. To a solution of oxalyl chloride (0.964 mL, 11.02 mmol) in DCM (4 mL) cooled to −78° C. was added DMSO (1.042 mL, 14.69 mmol) dropwise, followed by a solution of the material isolated in the first step in DCM (6 mL). The resulting mixture was stirred for 1 h at −78° C. before the addition of triethylamine (5.12 mL, 36.7 mmol), after which the reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched at −78° C. by water (20 mL). The aqueous layer was then extracted with DCM (3×50 mL), the combined organic extracts were dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-25% ethyl acetate in cyclohexane, afforded the title compound (1.126 g). LCMS (A) m/z: 165 [M+1]+, Rt 1.32 min (basic).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][O:18][C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][C:12]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2ccc(COC(=O)c3ccccc3)cc2c1=O
Product: CCCC(=O)c1cnc2ccc(COCc3ccccc3)cc2c1Cl
Yield: 67 %

Procedure:
3-Butyryl-6-(benzoyloxymethyl)-4(1H)-quinolone (30 g) was heated under reflux in phosphorus oxychloride (200 ml) for 30 minutes. The solvent was evaporated and the residue partitioned between dichloromethane and ammonia solution. The organic layer was washed successively .with sodium hydrogen carbonate solution and 50% brine. Dried (anhyd. MgSO4), filtered and evaporated to an oily solid which crystallized on trituration with petroleum ether to give 3-butyryl-4-chloro-6-(benzyloxymethyl)quinoline (21.2 g, 67%), m.p. 85°-6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:23])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cc(Br)cc(NC(=O)OCc2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)c1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a stirring solution of 773 mg (2.33 mmol) of benzyl 3-bromo-5-cyanophenylcarbamate in 10 mL of THF at 0° C. was added 231 mg of NaH (60% dispersion in mineral oil). After 1 h, 300 μL (4.82 mmol) of methyl iodide was added, the ice bath was removed, and the red mixture was stirred at r.t. with the light off. After 17 h, saturated NH4Cl, H2O, and EtOAc were added and the layers separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 195 mg of benzyl 3-bromo-5-cyanophenyl(methyl)carbamate in 24% yield.
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[CH:13]=1)(OC)OC.[C:27](=O)([O-:29])[O-:28].[K+].[K+].CO>O>[C:27]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:29])=[O:28]
Reactant: COC(=O)Cc1cc(C(OC)(OC)C(C)Br)ccc1Sc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A mixture of 4.39 g (10 mmol.) of methyl 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 3.45 g (10 mmol.) of anhydrous potassium carbonate, 26 ml of methanol and 13 ml of water was heated under reflux and stirring for 2 hours. The reaction mixture was distilled to remove distillates having boiling points of below 100° C. To the residue was added 10 ml of water, and the mixture was heated under reflux and stirring for 12 hrs. The reaction mixture was treated in the same manner as in Example 6-(1) to obtain 2.46 g of the desired product as white crystals (yield 78%), m.p. 145°-146° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]2([CH2:15][CH2:14]2)[C:3]1=[O:16].O.O.Cl[Sn]Cl>CCOC(C)=O>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3](=[O:16])[C:4]12[CH2:14][CH2:15]1
Reactant: CN1C(=O)C2(CC2)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)C2(CC2)c2cc(N)ccc21
Yield: 85 %

Procedure:
1′-Methyl-5′-nitro-spiro[cyclopropane-1,3′-indoline]-2′-one (3 g) is dissolved in EtOAc (105 ml) and SnCl2.2H2O (9 g; 46.5 mmol) is added. The reaction mixture is refluxed overnight, cooled and filtered over Al2O3. After an aqueous work-up of the filtrate the compound (2.2 g) is obtained.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[CH2:38][CH2:39][CH2:40]I>C(C(C)=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:40][CH2:39][CH2:38][C:37]([F:43])([F:42])[C:36]([F:45])([F:44])[F:35]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
500 mg of 11β-fluoro-3-hydroxy-7α-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-trien-17-one is dissolved in 15 ml of ethylmethylketone, mixed with 1.1 g of potassium carbonate and 1.5 ml of 1,1,1,2,2-pentafluor-5-iodo-pentane and refluxed for 2.5 hours. For working-up, the reaction mixture is cooled to room temperature, stirred into saturated common salt solution, extracted with ethyl acetate, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Preparative column chromatography on silica gel with a methylene chloride-methanol gradient provides 397 mg of 11β-fluoro-3-hydroxy-7α-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-trien-17-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([CH:33]=[O:34])=[CH:31][N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:45])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33]([OH:45])=[O:34])=[CH:31][N:30]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C=O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
In a 50 ml round-bottomed flask, 4-{6-fluoro-3-[7-formyl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (190 mg, 0.32 mmol) was dissolved in THF (7 ml) and water (1.4 ml). The light yellow solution was cooled to 0° C. and sulfamic acid (186 mg, 1.92 mmol) was added. Then, a solution of sodium chlorite (80%, 50 mg, 0.44 mmol) and potassium dihydrogen phosphate (522 mg, 3.83 mmol) in water (4.2 ml) was added dropwise via pipette. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with hexanes to afford 176 mg (90%) of 2-[1-(1-tertbutoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a light yellow powder.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]>>[NH2:30][C:29]1[S:28][C:27]([C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH:39]([CH3:41])[CH3:40])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: CC(C)c1cccc(B(O)O)c1
Product: CC(C)c1ccccc1-c1nc(C(=O)Nc2cnn(C)c2N2CCC(CN)CC2)c(N)s1
Yield: 41 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-isopropylbenzene boronic acid gave 269 as a red gum (38 mg, 41% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.55 (s, 1H), 7.54-7.33 (m, 6H), 7.28 (t, J=7.5 Hz, 1H), 3.71 (t, J=9.2 Hz, 1H), 3.62 (s, 3H), 3.11-2.93 (m, 4H), 2.42 (d, J=5.4 Hz, 2H), 1.73 (d, J=11.3 Hz, 2H), 1.27-1.21 (m, 9H). Alkyl NH2 not seen. LCMS (ES+) m/z 454 (M+1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]1[C:34](=[NH:36])[NH2:35]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][N:27]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC1=CC(C(=N)N)N(O)C=C1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cc(C)ccn4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-4-methylpyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 35 mg (38% of theory)
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[CH3:60][N:61]([CH3:88])[C:62]([N:64]1[CH2:69][CH:68]=[C:67]([C:70]2[NH:87][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[C:82]([F:84])[CH:81]=[C:80]([NH2:85])[C:79]=4[CH3:86])[C:72]=3[CH:71]=2)[CH2:66][CH2:65]1)=[O:63].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[F:103][C:104]([F:118])([F:117])[C:105]([C:108]1[CH:116]=[CH:115][C:111]([C:112](O)=[O:113])=[CH:110][CH:109]=1)([OH:107])[CH3:106]>>[CH3:88][N:61]([CH3:60])[C:62]([N:64]1[CH2:65][CH:66]=[C:67]([C:70]2[NH:87][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[C:82]([F:84])[CH:81]=[C:80]([NH:85][C:112](=[O:113])[C:111]5[CH:115]=[CH:116][C:108]([C:105]([OH:107])([CH3:106])[C:104]([F:103])([F:117])[F:118])=[CH:109][CH:110]=5)[C:79]=4[CH3:86])[C:72]=3[CH:71]=2)[CH2:68][CH2:69]1)=[O:63]
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Reactant: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: Cc1c(NC(=O)c2ccc(C(C)(O)C(F)(F)F)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12

Procedure:
Example 18 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 6 and Intermediate 8 with 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoic acid (WO2007/145834).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][CH:6]=1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([Cl:20])=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnco1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(Cl)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of oxazole-5-carboxylic acid methyl ester (1.4 g, 11 mmol) in anhydrous THF (50 mL) at −40° C. under an argon atmosphere was slowly added a solution of LiHMDS (13.3 mL, 1 M in THF). After 1 h at −40° C., solid hexachloroethane (3.91 g, 16.5 mmol) was added. The mixture was then allowed to slowly warm to room temperature and stir for 16 h. The reaction was diluted with AcOEt/H2O (30 mL/10 mL). The organic layer was washed with brine, dried with MgSO4 and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Cyclohexane: 1/1) to give 1.1 g of 2-chloro-oxazole-5-carboxylic acid methyl ester (62%) as a white solid. m.p.=35-50° C.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.ClC1N=CN=C(N2CCCN3C(=O)C=C(C4C=CC=CC=4)C=C23)C=1.[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][CH2:65][NH2:66]>>[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][CH2:65][NH:66][C:12]1[N:11]=[CH:10][N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Reactant: NCCc1ccccc1Cl
Agent: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(Cl)ncn1
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(NCCc2ccccc2Cl)ncn1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, 1-(6-chloro-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one (0.136 g, 0.40 mmol) was reacted with 2-(2-chlorophenyl)ethylamine (0.17 mL, 1.2 mmol) to give the title compound as a yellow solid. MS m/e 458 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CC[CH:35]([N:38]=C=NC2CCCCC2)CC1.C1COCC1.CN>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:38][CH3:35])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid (Example 59) (21.2 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with DMAP (˜1 mg) and DCC (11.3 mg, 0.055 mmol) followed 5 min later by a 2 M THF solution of methylamine (30 μL, 0.06 mmol). The reaction mixture was stirred for 16 h, evaporated, and purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, then 5% Me0H/Et0Ac as eluant to afford product as an oil (6.4 mg, 29%). LC/MS 5.09 min, [M+1]+ 438.