Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>O1CCCC1>[Cl:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:9]2)=[CH:6][CH:7]=1)=[O:32]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (2.93 g, 10 mmol) and triethylamine (3.0 g, 30 mmol) in tetrahydrofuran (50 ml) was added chloroacetyl chloride (2.26 g, 20 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and dichloromethane. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give 2-chloro-N-((2S)-4-(((1R)-1-phenylethyl) morpholin-2-yl)phenyl)acetamide (3.5 g, 97%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH3:13])([CH3:12])[NH:7][C:8](=[O:11])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)NC(=O)CCc2cc(N)ccc21
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)NC3(C)C)ncc1Cl

Procedure:
Following a procedure analogous to Example 1826d, 7-amino-1,1-dimethyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide were converted to 2-(5-chloro-2-(1,1-dimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)-N-methylbenzamide, TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.55 (d, 1H), 8.25 (s, 1H), 7.9 (dd, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.5-7.45 (m, 2H), 7.4 (td, 1H), 3.2 (m, 2H), 3.1 (s, 3H), 2.8 (m, 2H), 2.0 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].CCOCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Yield: 74 %

Procedure:
A solution of ethyl-4-oxocyclohexane carboxylate (28.9 g, 169 mmol), ethylene glycol (36.7 g, 33.0 mL, 592 mmol) and p-toluol sulphonic acid (380 mg, 2.0 mmol) in toluol (90 mL) was stirred overnight at room temperature. The reaction solution was poured into ether (150 mL) and washed with water and 5% sodium hydrogencarbonate solution (150 mL each). The organic phase was dried with sodium sulphate and concentrated to low volume in a vacuum. Since the raw product (26.8 g) was obtained in pure form, it could be directly converted further.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3OC)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:40]=[C:39](OC)[CH:38]=1>>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:42]=2)=[CH:9][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCCCOc1cc(CCl)cc(OC)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3)cc2)c1

Procedure:
Analogously to Method D, 0238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.122 g of 1-chloromethyl-3-methoxy-5-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=6.19.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([C:29]1[O:30][C:31]2[CH:37]=[C:36]([CH2:38]Br)[CH:35]=[CH:34][C:32]=2[N:33]=1)#[N:28]>CC(C)=O.CN(C)C=O>[C:27]([C:29]1[O:30][C:31]2[CH:37]=[C:36]([CH2:38][O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]4[CH:7]=[CH:6][C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=4)[CH:15]=3)[CH:35]=[CH:34][C:32]=2[N:33]=1)#[N:28]
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Reactant: Oc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc2ccc(COc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)cc2o1

Procedure:
To a stirred solution of the (E)-3-(7-chloro-2quinolinylethenyl)phenol (1.485 g, 5.28 mmol) in acetone (120 ml) and dimethylformamide (I5 ml) at room temperature are added successively potassium carbonate (1.09 g, 7.0 mmol) and 2-cyano-6-(bromomethyl)benzoxazole (1.25 g, 5.27 mmol). The resulting solution-suspension is refluxed for 16 hours and concentrated. Water (100 ml) and ethyl acetate (150 ml) are added. Extraction with ethyl acetate is followed by washing with water and brine, drying (MgSO4) and evaporation under reduced pressure. The residue is subjected to flash chromatography over silica gel. Elution is with 33% ethyl acetate in hexane and concentration of the appropriate fractions provides (E)-2-cyano-6-[3-(7-chloro-2-quinolinylethenyl) phenoxymethyl]-benzoxazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:15]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1-c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1ccccc1-c1ccccc1
Yield: 70.1 %

Procedure:
Under an atmosphere of argon, 2,2′-dibromobiphenyl (9.5 g, 30 mmole), phenylboronic acid (3.7 g, 30 mmole) and tetrakis(triphenyl-phosphine)palladium(0) (1.0 g, 0.87 mmole, 3% Pd) were dissolved into toluene (75 ml). To the obtained solution, an aqueous solution of sodium carbonate (9.7 g, 92 mmole, 3 eq/46 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a dark yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and a colorless oil (6.5 g, 70%) was obtained.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)S(C(F)(F)F)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([O:41][CH:42]=[CH2:43])(=[O:40])[CH3:39]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:38]([O:41][CH:42]=[CH:43][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(=[O:40])[CH3:39]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Reactant: C=COC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)OC=Cc1ccc2ccccc2c1
Yield: 50.6 %

Procedure:
To a solution of 2-naphthyl triflate (90 g, 326 mmol) in DMF (240 ml), add triphenylphosphine (9.6 g, 36.6 mmol), vinyl acetate (149 g, 1862 mmol) and palladium acetate (3.8 g, 17 mmol). Reflux the reaction mixture for 1 h, then quench by addition of sat'd NaHCO3 solution. Extract the mixture with Et2O, dry and concentrate. Purify the residue by chromatography on silica gel (5% EtOAc in hexane) to obtain 35 g (165 mmol, 51%) 2-(2-naphthyl)vinyl acetate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]#[N:21]>CN(C)C=O.O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]#[N:21])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
10.88 g of a 50% sodium hydride suspension in mineral oil are diluted with 230 ml of absolute dimethylformamide and treated within 30 minutes with a solution of 50 g of p-(p-chlorophenoxy)phenol in 230 ml of absolute dimethylformamide while the temperature rises slightly. The mixture is then stirred at room temperature for 30 minutes. A solution of 18.8 g of chloroacetonitrile in 200 ml of absolute dimethylformamide is added dropwise while cooling the mixture in a water-bath. The mixture is stirred at 50° C. overnight, then cooled and diluted with 1 liter of water. This mixture is extracted five times with 200 ml of ethyl acetate each time. The organic phases are washed twice with 100 ml of 2-N sodium carbonate solution, once with 100 ml of saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The crude product (80 g of a dark oil) is purified by chromatography on silica gel using toluene for the elution to yield 45 g of [p-(p-chlorophenoxy)phenoxy]acetonitrile (76%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6].C(N(CC)CC)C.[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([N:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH3:6])=[O:25]
Reactant: CNc1ccccc1OC
Reactant: O=C(Cl)c1cc(Br)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Yield: 77.8 %

Procedure:
2-Methoxy-N-methylaniline (7.4 g, 53.8 mmol) and triethylamine (10.9 g, 107.7 mmol) were added to 5-bromo-4-chloro-2-fluoro-benzoyl chloride (Step 21D, 11.7 g, 43.1 mmol) in DCM (200 mL) at 0° C. The mixture was then allowed to warm to rt and concentrated. The mixture was partitioned in water and ethyl acetate. The organic layer was separated, washed with NaHSO4 solution, water and brine, and was dried. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with ethyl acetate in hexane (50%) to give 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (12.5 g). MS: [M+H]+374.0/372.0; tR=2.70 min (method 1)
Reaction SMILES: [OH-].[K+].[C:3]([OH:6])(=[S:5])[CH3:4].Br[CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>O.CC(C)=O>[C:3]([S:5][CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])(=[O:6])[CH3:4]
Reactant: O=C(CBr)OCCOc1ccccc1
Reactant: CC(O)=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SCC(=O)OCCOc1ccccc1
Yield: 98.1 %

Procedure:
The solution of potassium hydroxide (6.6g) in water (20 ml) was added under ice cooling to thioacetic acid (7.6g) and then the solution of β-phenoxyethyl bromoacetate (25.9g) in acetone (30ml) was added and treated for 6 hours at room temperature. Extracted twice with 200 ml of ethylether and the ether layer was washed with water, dried, and concentrated, giving colourless crystals (24.9g) which was then recrystallized from n-hexane. Thus colourless crystals (20.8g), m.p. 56.0°-57.0° C., of β-phenoxyethyl S-acetylthioglycolate was obtained.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:17]=[CH:16][N:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)[CH:19]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Clc1cc(-c2ccccc2OCc2ccccc2)ncn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-methanesulfonyl-phenylamine hydrochloride (4.98 g, 24 mmol) and 4-chloro-6-(2-benzyloxyphenyl)-pyrimidine (6.88 g, 23.2 mmol) in DMFA (50 mL) was stirred at 80° C. till the reaction completion (TLC control). The reaction mixture was diluted with water (200 mL), treated with NaHCO3 (4.2 g, 50 mmol). The resulting precipitate was filtered out, washed with water (2×200 mL), dried and purified by column chromatography on silica (eluent chloroform-ethanol 20:1) to yield [6-(2-benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonyl-phenyl)-amine as colorless solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CCOC(=O)c1cncc(-c2ccc(C(C)C)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCC(c2ccc(C(C)C)cc2)C1

Procedure:
2.4 g (8.9 mmol) of ethyl 5-[4-(1-methylethyl)phenyl]pyridine-3-carboxylate were dissolved in 60 ml of ethanol, 1.33 g Pd/C (10%) were added and the mixture was hydrogenated in an autoclave at 60° C. at a hydrogen pressure of 50 bar overnight. The reaction mixture was filtered through silica gel. The resulting solution was concentrated under reduced pressure. Water was added to the residue and the solution was adjusted to pH 8 using aqueous 1 N sodium hydroxide solution. The mixture was then extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Yield: 2.1 g (81% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]=2[F:16])[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Brc1cncc(Br)c1
Product: Fc1ccc(F)c(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 41, Step 1, using 3,5-dibromo-pyridine and 2,5-difluorophenylboronic acid.
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)=[O:19])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[CH2:4]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18]([C:20]4[N:21]=[CH:22][NH:23][CH:24]=4)([OH:19])[CH3:1])=[CH:17][C:11]=3[CH:10]=[CH:9][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: O=C(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methylmagnesium chloride in diethyl ether (3M; 3 mL) was added to a solution of (2,3-dihydro-1H-benzo[f]chromen-8-yl)(1H-imidazol-4-yl)ketone (0.50 g) in THF (20 ml) at 0° C. The mixture was stirred at room temperature for 3 h. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated. The residue was washed with ethyl acetate to give the titled compound (0.49 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[NH:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.[NH:16]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)(Cl)=O>>[Br:37][C:33]1[CH:32]=[C:31]([CH:23]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH2:11][NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:15])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)C(Nc1ccccc1)c1cccc(Br)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2cccc(Br)c2)c1
Yield: 51 %

Procedure:
The procedure is as in Example 1, but using 1.04 g of 2-[3-(3-methylphenyl)ureido]acetic acid, 1.8 g of tert-butyl (RS)-2-anilino-2-(3-bromophenyl)acetate and 0.36 cm3 of thionyl chloride as starting materials The product obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1/99 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 11 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. and the residue obtained is recrystallized from cyclohexane. 1.4 g of tert-butyl (RS)-2-(3-bromophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 103° C. are then obtained.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>>[CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:37]3[CH2:38][CH2:39][N:34]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36]3)=[NH:29])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccccc4)cc3)c2)CC1
Yield: 6 %

Procedure:
The title compound was prepared from N-benzyl-4-(3-(3-cyanophenyl)ureido)benzenesulfonamide following procedure C and using 3 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH3:22].O1CCOCC1>O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:22])[N:7]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: Cc1cc(-c2ncccc2-c2ccnc(Cl)n2)ccc1F
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ncccc2-c2ccnc(N)n2)ccc1F
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine (Compound 919) was prepared as follows: A screw capped vial was charged with 2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine (125 mg), 28% aq. Ammonia (3 mL), 1,4-dioxane (3 mL) and a stir bar. The vial was capped tightly, heated and stirred at 60° C. for 12 h. The heterogeneous solution was cooled to room temperature, diluted with water, filtered. The solid (90 mg) was suspended in 50% EtOAc/hexanes, stirred and heated at 80° C. for 30 min. Upon cooling to room temperature, the suspension was filtered and the solid was suction dried to provide 4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine as a white solid (73 mg). 1H NMR (300 MHz, DMSO-d6): δ 8.69 (dd, J=4.7, 1.7 Hz, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.93 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (dd, J=7.8, 4.8 Hz, 1H), 7.38 (dd, J=7.4, 1.6 Hz, 1H), 7.18-6.95 (m, 2H), 6.70 (s, 2H), 6.20 (d, J=5.0 Hz, 1H), 2.19 (s, 3H). 19F NMR (282 MHz, DMSO-d6): δ −118.16 (q, J=7.7 Hz).LCMS: rt 4.40 min (A), purity 99%, MS (m/e) 281 MH+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:25](O)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27].CC1C=CC=C(C)N=1>ClCCl>[Br:16][C:17]1[C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][CH2:20][C:21]2=[O:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2c1ccc(O)c2Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (4.0 mL) is added dropwise to a solution of 4-bromo-5-hydroxy-indan-1-one (5.0 g) and 2,6-dimethylpyridine (5.1 mL) in dichloromethane (50 mL) cooled to 0° C. The cooling bath is removed and the mixture is stirred for 2 h at room temperature. The solution is partitioned between saturated aqueous NH4Cl solution and dichloromethane. The organic phase is separated, washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=359/361 (Br) [M+H]+.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[O:11]=[C:12]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:13]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[O:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To triethyl orthoformate (85 mL, 510 mmol) in dry dichloromethane (460 mL) under nitrogen at −10° C. was added dropwise BF3OEt2 (65 mL, 510 mmol). The solution was allowed to warm to 0° C. and was stirred for 10 minutes. The solution was cooled to −78° C. prior to the slow dropwise addition of tert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (55 g, 170 mmol) in dichloromethane (25 mL). N-ethyl-N-isopropylpropan-2-amine (100 mL, 600 mmol) was added over a 30 minutes period, and the mixture was slowly warmed to 25° C. and was stirred at this temperature overnight. The reaction mixture was diluted with dichloromethane (500 mL) followed by saturated aqueous sodium bicarbonate solution (500 mL). The layers were separated, and the organic layer was washed with additional sodium bicarbonate (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in hexane) to provide tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 91%) as an orange oil. ESI-MS m/z calc. 419.5. found 420.3 (M+1)+; Retention time: 2.50 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][NH:5][C:4]=1[CH3:10].[CH2:11](I)[CH2:12][CH3:13]>CN(C)C=O.C(Cl)(Cl)Cl.[Ag]=O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:11][CH2:12][CH3:13]
Reactant: CCCI
Reactant: COc1c(C)[nH]ccc1=O
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccnc(C)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Methoxy-2-methyl-4(1H)-pyridone(1.39 g) and propyl iodide (2.0 ml) were dissolved in dimethylformamide (20 ml), to which silver oxide (2.31 g) was added in small portions and stirred vigorously at room temperature for 5 hours. The reaction mixture was diluted with chloroform (100 ml), washed with water, dried and evaporated. The residue was purified by flash chromatography (chloroform) on silica gel, to give 3-methoxy-2-methyl-4-propoxypyridine (1.7 g) as a light brown oil.