Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.[CH3:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][CH2:35][C@H:31]3[CH3:30])[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCCN1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1

Procedure:
Heat a mixture of 4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 12.3 mmol), 2-(R)-methyl-pyrrolidine hydrobromide (Nijhuis et. al. (1989) J. Org. Chem. 54:216-220) (3.0 g, 16.0 mmol), and K2CO3 (5.2 g, 37.8 mmol) in DMA at 120° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[N:16][C:10]3[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:18][C:17]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][C:9]2[NH:14][C:13](=[O:15])[CH2:12][O:11][C:10]=2[N:16]=1
Reactant: O=C1COc2ncc(-c3ccccc3)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
In a 10 ml microwave vial was 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.221 mmol) and N-bromosuccinimide (78.6 mg, 0.441 mmol) in dimethylformamide (1 ml). The reaction mixture was heated to 80° C. under microwave irradiation for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 ml). The organic solution was washed with water (2×10 ml) and brine (2×10 ml). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified via Biotage chromatography (gradient 0% to 5% methanol in dichloromethane) to give the title compound as a yellow solid (61 mg, 90%). 1H NMR (500 MHz, CD3OD) δ 7.48-7.32 (5H, m), 7.12 (1H, s), 4.82 (2H, s).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>C1COCC1.C(N(CC)CC)C>[CH:14]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([CH3:10])[C:2]=1[OH:1])=[O:15]
Reactant: C=O
Reactant: Cc1c(O)cccc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C#N)ccc(C=O)c1O
Yield: 15.3 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzonitrile (7.00 g) in THF (100 mL) were added triethylamine (13.1 g), magnesium chloride (12.4 g) and paraformaldehyde (6.60 g), and the mixture was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.30 g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH:9](Br)[O:10][CH2:11][CH3:12].O.Cl>CCOCC>[Br:7][CH2:8][CH:9]([O:10][CH2:11][CH3:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCOC(Br)CBr
Reactant: CCCC[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCC(CBr)OCC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.68 moles of n-butylmagnesium bromide, as a 1.7M solution in ether, is added dropwise a solution of 300 g. of 1,2-dibromo-2-ethoxyethane in 750 ml. of ether during a period of 2 hours at -15° C. The resulting mixture is stirred for one hour while warming to 20° C., then cooled to 0° C., and treated while stirring with 500 ml. of water, followed by 100 ml. of 4N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The residue is distilled to provide a colorless liquid, b.p. 83°-84° C., 18 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:26]([O-:28])=[O:27])[CH2:13][CH2:14][C:15](=[O:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][OH:42]>C1CCCCC1>[CH2:41]1[O:42][C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:14][CH2:13][CH:12]([N+:26]([O-:28])=[O:27])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:25][CH2:40]1
Reactant: OCCO
Reactant: COc1ccc(CC(CCC(=O)CCc2ccc(Cl)cc2)[N+](=O)[O-])cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: COc1ccc(CC(CCC2(CCc3ccc(Cl)cc3)OCCO2)[N+](=O)[O-])cc1OC

Procedure:
Into 1 l. r.b. flask equipped with a Dean Stark trap was placed 65 g (0.16 mole) of 1-(3',4'-dimethoxyphenyl)-7-(4'-chlorophenyl)-2-nitro-5-heptanone, 2 g p-toluenesulfonic acid, 100 ml ethylene glycol and 400 ml of cyclohexane. The mixture was allowed to reflux overnight, then concentrated in vacuo. Dil NaHCO3 solution was added to the residue and extracted with methylene chloride. The organic layer was backwashed with water, dried over anh MgSO4, filtered and concentrated under reduced pressure to obtain 45.3 g of an oil which solidified on drying at room temperature under vacuum.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:6]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:26])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:13]([CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:14]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.49 mmol) in 1,4-dioxane:H2O (2:1) was added 1N aqueous lithium hydroxide (10 eq), and the reaction was stirred overnight at room temperature. The pH was adjusted to pH 6 with 10% aqueous HCl, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product (0.2 g)
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[C:17]([C:21](Cl)=[O:22])[CH:16]=1.C1(C)C=CC=CC=1>[OH-].[Na+].O>[C:1]([N:5]([C:21]([C:17]1[CH:16]=[C:15]([CH3:24])[CH:20]=[CH:19][CH:18]=1)=[O:22])[NH:6][C:7](=[S:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=S)c1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C(=O)N(NC(=S)c2ccccc2)C(C)(C)C)c1
Reaction time: 3 h

Procedure:
N't-butyl-N-(thiobenzoyl)hydrazine (ca. 1 g), m-toluoyl chloride (approx. 0.7 g) and 50% aqueous sodium hydroxide (6 drops) were mixed in 1 ml water and 10 ml toluene at 23° C. After stirring for 3 hours, ether-hexane was added and the product was isolated by filtration (0.25 g). m.p. 165-168° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:34]=[C:35]1[NH:39][CH:38]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1>ClCCl.CN(C)C1C=CN=CC=1>[O:43]=[C:42]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH2:8][S:9][CH3:10])[CH2:41][CH2:40][CH:38]1[CH2:37][CH2:36][C:35](=[O:34])[NH:39]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.025 mol) L-methionine methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.028 mol) of triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes, filtered, and a mixture of the following is added in a single addition: 6.32 g (0.03 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 3.85 g (0.025 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 19:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields crystalline analytically pure N-[1-oxo- 3-(5-oxo-2-pyrrolidinyl)propyl]-L-methionine, methyl ester with a melting point of 98°-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.NC1C=NC=CN=1.[CH3:16][S-:17].[Na+]>>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:17][CH3:16])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: Nc1cnc(Br)cn1
Agent: Nc1cnccn1
Agent: [Na+]
Product: CSc1cnc(N)cn1

Procedure:
2-Amino-5-bromopyrazine can be prepared from aminopyrazine as described (Tetrahedron, Vol. 44, pp. 2977-2984 (1988)). Reaction of 2-amino-5-bromopyrazine with sodium methanethiolate proceeds to form 2-amino-5-methylthiopyrazine (J. Het. Chem., Vol. 28, pp. 1131-1137 (1991)). Oxidation of 2-amino-5-methylthiopyrazine with m-chloroperbenzoic acid produces 2-amino-5-methanesulfonylpyrazine. 2-Hydrazino-5-methanesulfonylpyrazine can be prepared by known procedures (J. Het. Chem., Vol. 27, pp. 2151-2163 (1990)). Subsequent reaction of 2-Hydrazino-5-methanesulfonylpyrazine with 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (made from 4-methoxyacetophenone and ethyl trifluoroacetate via Scheme 1) can then produce the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11]
Reactant: OC[C@@H]1CCCN1
Reactant: Clc1ccccn1
Solvent: O
Product: OC[C@@H]1CCCN1c1ccccn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyridine (118 g) and L-prolinol (70 g) was heated under nitrogen atmosphere at 160° C. with stirring for 4 h. The mixture was cooled to room temperature and poured into water and the solution was extracted with chloroform repeatedly. The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using 2% MeOH in CHCl3 as eluent to get 67.3 g (54.5%) of the title compound as a syrupy liquid.
Reaction SMILES: C([O:8][CH2:9][CH3:10])(OCC)OCC.[CH3:11][C:12]1[NH:13][CH:14]=[C:15](C)[C:16]=1[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1[C:16]([C:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH:18]=2)=[C:12]([CH3:11])[NH:13][C:10]=1[CH:9]=[O:8]
Reactant: Cc1c[nH]c(C)c1C1=CCN(C)CC1
Reactant: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(C=O)c(C)c1C1=CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethyl orthoformate (6 mL) was added to a solution of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine (360 mg) in TFA (6 mL) at 0° C. The mixture was stirred at 0° C. for 10 mins and then at rt for 40 mins. The solvent was removed and to the residue was added NaHCO3, extracted with ethyl acetate, dried and concentrated to give 356 mg of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carbaldehyde.
Reaction SMILES: [ClH:1].[CH:2]1([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=[O:26])[C:14]([C:24]#[N:25])=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][NH:21][CH2:20]3)=[CH:11][C:10]=2[F:27])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH2:25][CH2:24][C:14]1[C:13](=[O:26])[C:12]2[C:17](=[CH:18][C:9]([NH:8][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:10]([F:27])[CH:11]=2)[N:16]([CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)[CH:15]=1
Reactant: N#Cc1cn(C2CCNC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: NCc1cn(C2CCNC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To 0.31 g of 7-(cyclohexylamino)-6-fluoro-4-oxo-1-pyrrolidin-3-yl-1,4-dihydroquinoline-3-carbonitrile hydrochloride were added 5 ml of ethanol, 0.2 ml of concentrated hydrochloric acid and 0.10 g of platinum oxide, followed by overnight stirring in an atmosphere of hydrogen. After adding water, celite filtration was carried out and the solvent was evaporated under a reduced pressure. By purifying the resulting residue by an ODS column chromatography, 256 mg of 3-(aminomethyl)-7-(cyclohexylamino)-6-fluoro-1-pyrrolidin-3-ylquinolin-4(1H)-one hydrochloride was obtained.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:40]=[C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[C:44]([NH:43][C:41]1[N:40]=[C:39]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:38]=[C:37]([C:33]2[CH:34]=[N:35][CH:36]=[C:31]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[O:8])=[CH:14][CH:13]=3)[CH:32]=2)[CH:42]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.25 mmol, 0.079 g) and 2M Na2CO3 (3 eq, 0.624 mmol, 0.3 ml) in dry DME (1.5 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-tert-butyl-amine (Ex. 2.48; step 1) (1 eq, 0.208 mmol, 80 mg) and PdCl2dppf (0.1 eq, 0.0208 mmol, 15 mg). The reaction mixture is heated using microwave radiation at 90° C. for 1 hour. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 493.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: CSc1ccc(CC(=O)O)cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)c(Cl)c1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid (8.00 g, 36.92 mmol) in methanol (200 mL) was treated slowly with concentrated sulfuric acid (1 mL). The resulting reaction mixture was heated under reflux overnight. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was dissolved with ethyl acetate (50 mL). The organic layer was washed with water (1×50 mL). The water layer was further extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (7.28 g, 85.5%) as a yellow oil which was used without further purification: EI-HRMS m/e calcd for C10H11ClO2S (M+) 230.0168, found 230.0166.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][CH2:16][C:17](Br)=[O:18].O>CN(C=O)C>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:18]
Reactant: Cc1cnc(N)cn1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2 g) dissolved in dry DMF (30 mL) was added by dropwise addition bromoacetylbromide (2.89 g) and the mixture stirred at rt for 2 hours. Water (200 mL) was added and the mixture extracted with ethyl acetate (2×100 mL) and dried over magnesium sulfate. Concentration of the extract to ˜50 mL and addition of isohexane (100 mL) gave the sub-titled compound as a solid (1.64 g).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]4[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 40.4 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide formate (0.77 g, 1.85 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.671 g, 1.66 mmol) according to Procedure G to give the title compound (0.53 g, 0.67 mmol).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]=[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([NH2:29])=[O:28])[C:15]([C:30]([F:33])([F:32])[F:31])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:36][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]3[N:17]=[C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([NH2:29])=[O:28])[C:15]([C:30]([F:32])([F:33])[F:31])=[CH:14][N:13]=3)[CH:6]=2)[CH2:1]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCNC3)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
2-(2-(2-(2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (21) (25 mg, 0.055 mmol) was suspended in methanol (2 mL) and 37% aqueous formaldehyde (0.016 mL, 0.22 mmol) was added. The mixture was stirred for five minutes then sodium tri(acetoxy)borohydride (58 mg, 0.27 mmol) was added. After stirring for 2 hours at room temperature the mixture was concentrated and the residue treated with 10% aqueous NaOH (1 mL) for five minutes. Brine (2 mL) was added, and the mixture was extracted with ethyl acetate (5×5 mL). The combined ethyl acetate extracts were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (28) (22.8 mg, 88% yield) as an off-white solid; 1H NMR (400 MHz, d4-MeOD) δ 8.54 (d, J=0.5 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.47 (dd, J=8.3, 2.2 Hz, 1H), 7.28-7.16 (m, 4H), 7.04 (d, J=8.3 Hz, 1H), 3.66 (s, 2H), 3.60 (s, 2H), 3.21-3.11 (m, 2H), 3.11-3.02 (m, 2H), 2.96 (t, J=6.0 Hz, 2H), 2.76 (t, J=6.1 Hz, 2H), 2.46 (s, 3H). LCMS Method C: rt 4.78 min; m/z 470.1 [M+H]+; m/z 468.1 [M−H]−.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH3:21][C:22]1([C:37](Cl)=[O:38])[CH2:26][C:25]2[C:27]([CH3:36])=[C:28]([N+:33]([O-:35])=[O:34])[C:29]([CH3:32])=[C:30]([CH3:31])[C:24]=2[O:23]1>CN(C=O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:37]([C:22]1([CH3:21])[CH2:26][CH:25]2[CH:27]([CH3:36])[C:28]([N+:33]([O-:35])=[O:34])=[C:29]([CH3:32])[C:30]([CH3:31])=[C:24]2[O:23]1)=[O:38]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)Cl)C2
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C2OC(C)(C(=O)N3CCc4c([nH]c5ccccc45)C3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-carboxylic acid, 20 ml of methylene chloride and 0.27 g of thionyl chloride were added, followed by heating at reflux for 2 hours. After returning the temperature to room temperature, the solvent was distilled off to obtain 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride. To 0.33 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 0.23 g of triethylamine and 15 ml of DMF, a solution prepared by dissolving 2,4,6,7-tetramethyl-5-nitro-2,3-dihydrobenzofuran-2-carbonyl chloride in DMF was added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and a crystal was collected by filtration. The crystal was dissolved in chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain 0.54 g of the objective product.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 2-amino-5-bromopyridine (43 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (9 mg, 9%). MS (ISP) 420.2 [(M+H)+]; mp 228-231° C.