Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:53]1[CH:58]=[C:57]([Cl:59])[CH:56]=[C:55]([O:60][CH3:61])[C:54]=1[Cl:62].[CH3:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([CH2:71][SH:72])=[CH:67][CH:66]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[Cl:62][C:54]1[C:53]([S:72][CH2:71][C:68]2[CH:69]=[CH:70][C:65]([O:64][CH3:63])=[CH:66][CH:67]=2)=[CH:58][C:57]([Cl:59])=[CH:56][C:55]=1[O:60][CH3:61]
Reactant: COc1cc(Cl)cc(Br)c1Cl
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2cc(Cl)cc(OC)c2Cl)cc1

Procedure:
To a mixture of DIPEA (5.77 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.488 g), 1-bromo-2,5-dichloro-3-methoxybenzene (4.32 g) and (4-methoxyphenyl)methanethiol (2.47 mL) and toluene (100 mL) was added tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.773 g) at room temperature. The mixture was refluxed for 5 h. After cooling, water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (5.66 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1.[H-].[Na+].I[CH3:20].O>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1cccc(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-(methoxymethoxy)phenyl)acetate (8.06 g, 35.9 mmol) in DMF (50 mL) was slowly added sodium hydride (1.74 g, 43.5 mmol) and iodomethane (6.37 g, 44.9 mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. The mixture was added water (250 mL) and extracted with EtOAc. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=10/1.
Reaction SMILES: NCCC[NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7].FC1C=C[C:35]([C:38]2C(C3C=C4C(=CC=3)N(C(N3C5C(=CC(C6C(C7C=CC(F)=C(C)C=7)=NC=CC=6)=CC=5)C=N3)=O)N=C4)=CC=C[N:39]=2)=CC=1C>>[NH2:39][CH2:38][CH2:35][NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=4)=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7]
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)NCCCN)c2)ccc1F
Reactant: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)n3ncc4cc(-c5cccnc5-c5ccc(F)c(C)c5)ccc43)c2)ccc1F
Product: Cc1cc(-c2ncccc2-c2ccc3c(cnn3C(=O)NCCN)c2)ccc1F

Procedure:
N-(3-Aminopropyl)-5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-1-carboxamide (Compound 640).LCMS: rt 3.41 min (A), purity 99%, MS (m/e) 404 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[N+:58]([O-])([O:60]C(C)C)=[O:59].S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[C:3]([N+:58]([O-:60])=[O:59])=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2ccccc2)c([N+](=O)[O-])c1O

Procedure:
To a stirred solution of 1-(3-hydroxy4-methoxyphenyl-2-phenyl-ethanone (8.57 g, 35.4 mmol) in dichloromethane (90 mL) at room temperature was added tetrabutylammonium sulphate (0.6 g, 5 mol %) followed by isopropyl nitrate (7.44 g, 70.8 mmol). Sulphuric acid (96%, 8.5 mL) was then added dropwise causing a gently exothermic reaction, and after stirring for forty minutes, the reaction mixture was poured onto water (250 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was triturated with a small volume of diethylether (20 mL) to afford orange crystals, (6.9 g, 68%) of m.p. 176–177° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent trituration with diethyl ether (15 mL) allowed the isolation of a small amount of a minor product, which was recrystallised from a dichloromethane/heptane mixture to give yellowish crystals of m.p. 142–143° C., corresponding (TLC) to a standard of the para-nitrated product, 1-(3-hydroxy-4-methoxy-6-nitrophenyl)-2-phenyl-ethanone (1.22 g, 12%). (80% combined yield, Ortho:Para selectivity, 5.7:1)
Reaction SMILES: NC1(C[O:8]C2C=CC(C#N)=CC=2)CCCC1.[CH3:17][N:18]([CH3:34])[C:19]1([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:17][N:18]([CH3:34])[C:19]1([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:8])=[CH:28][CH:27]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#Cc1ccc(OCC2(N)CCCC2)cc1
Reactant: CN(C)C1(COc2ccc(C#N)cc2)CCCC1
Product: CN(C)C1(COc2ccc(C=O)cc2)CCCC1

Procedure:
Synthesized from 4-(1-aminocyclopentylmethoxy)benzonitrile according to an analogous synthetic method to Preparation Example 18, 4-(1-dimethylaminocyclopentylmethoxy)benzonitrile (1.2 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.2 g).
Reaction SMILES: CC([O:4][C@@H:5]1[C:19](=[O:20])[C@H:18]2[C@@:8]([CH3:27])([CH2:9][CH2:10][C@@H:11]3[C@:17]2([CH3:21])[CH2:16][C@@H:15]([C:22]2[CH:23]=[CH:24][O:25][CH:26]=2)[O:14][C:12]3=[O:13])[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)=O.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:31][O:30][C:28]([C@@H:7]1[CH2:6][C@H:5]([OH:4])[C:19](=[O:20])[C@H:18]2[C@@:8]1([CH3:27])[CH2:9][CH2:10][C@H:11]1[C@:17]2([CH3:21])[CH2:16][C@@H:15]([C:22]2[CH:23]=[CH:24][O:25][CH:26]=2)[O:14][C:12]1=[O:13])=[O:29]
Reactant: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of 1 (3.5 g, 8.0 mmol) and Na2CO3 (3.4 g, 32.2 mmol) in absolute MeOH (150 mL) was stirred at room temperature for 4 b. The solvent was removed under reduced pressure and CH2Cl2 (500 mL) was added to the crude residue. The organic extract was washed successively with 2N HCl (50 mL) and saturated NaCl (50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and MeOH (100 mL) was added to the residue. The resulting solid was collected by filtration and dried to afford 2.4 g (77%) of 8a as a white solid, mp 211-214° C. (Lit. 213-216° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C(Cl)Cl.O>[CH:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[N:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)OCc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)OCc1ccc(C#N)nc1
Temperature: 180 °C

Procedure:
In a microwave reaction tube was placed 2-chloro-5-isopropoxymethyl-pyridine (0.12 g, 0.66 mmol), Zn(CN)2 (0.077 g, 0.66 mmol), tetrakis(triphenylphosphino)dipalladium (76 mg, 0.066 mmol), DMF (2 mL). The reaction mixture was heated at 180° C. for 5 minutes. The resulted mixture was worked up by CH2Cl2/H2O. The CH2Cl2 layer was dried and concentrated to give the crude product. The crude was purified by column chromatography by using 30% EtOAc/Hexane. 1H NMR (CDCl3, 400MHz) δ 1.26 (d, 6H), 3.73 (m, 1H), 4.59 (s, 2H), 7.68 (d, 1H), 7.85 (m, 1H), 8.67 (s, 1H). Exact mass calculated for C10H12N2O 176.09, found 177.2 (MH+).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[I:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13])[CH:9]=[CH:10][CH:11]=1.P([O-])([O-])([O-])=O>C(#N)C>[I:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH:13][C:3]([NH:2][CH3:1])=[O:4])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CN(N)c1cccc(I)c1
Reactant: CN=C=O
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(I)c1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
Methyl isocyanate (1.24 g) was added to a solution of methyl [1-(3-iodophenyl)hydrazino]acetate (3.0 g) in acetonitrile (50 ml) and the mixture was stirred under nitrogen for 2 h. The mixture was added to pH 6.5 phosphate solution (150 ml) and extracted with ethyl acetate (200 ml). The organic phase was washed with brine (100 ml) and water (100 ml), dried and evaporated to give a solid (3.0 g) which was crystallised from ethyl acetate to give the title compound (2.0 g), m.p. 150°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ncnc2c1
Product: COc1ccc2c(Cl)ncnc2c1
Yield: 99.1 %

Procedure:
Step 2 A suspension of 7-methoxyquinazolin-4-ol (400 mg, 2.271 mmol) in phosphorus oxychloride (7 mL, 75 mmol) was heated at reflux for 3 h. The solution was concentrated and the residue was suspended in EtOAc and stirred on an ice bath with NaHCO3 (aq) until all the solid was dissolved and gas evolution ceased. The layers were separated and the organic phase was dried and concentrated to provide 4-chloro-7-methoxyquinazoline as a light yellow-tan solid (438 mg, 99%). 1H NMR (400 MHz, chloroform-d) δ 8.94 (1H, s), 8.15 (1H, d, J=9.7 Hz), 7.29-7.37 (2H, m), 4.00 (3H, s).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([O:7][C:16](=[O:17])[O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: CC/C=C\CCO
Reactant: O=C(Cl)OCc1ccccc1
Product: CCC=CCCOC(=O)OCc1ccccc1

Procedure:
Starting Material: cis-3-hexenol and benzylchloroformate.
Reaction SMILES: [CH2:1]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([C:31]([NH2:33])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:33][CH2:31][C:28]1[CH:29]=[CH:30][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([N:8]([CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:26][C:25]=2[CH:27]=1
Reactant: NC(=O)c1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Yield: 94.6 %

Procedure:
To a solution of 8-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide (3.00 g) in dry tetrahydrofuran (90 ml) was gradually added lithium aluminum hydride (1.02 g) under ice-cooling and nitrogen atmosphere. The mixture was then heated to reflux for 3 hours. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture under ice-cooling, and the resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1 to 5:1) to afford (2S)-1-[N-(3-aminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (2.75 g).
Reaction SMILES: [Na].[Br:2][C:3]1[N:11]([CH3:12])[C:10]2[C:9](=[O:13])[NH:8][C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1.Cl[CH2:17][P:18](=[O:21])([CH3:20])[CH3:19]>>[Br:2][C:3]1[N:11]([CH3:12])[C:10]2[C:9](=[O:13])[N:8]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1
Reactant: CP(C)(=O)CCl
Reactant: Cn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Product: Cn1c(Br)nc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 28 g (0.1 mol) of 8-bromo-3,7-dimethylxanthine sodium salt and chloromethyldimethylphosphine oxide analogously to Example 59 and chromatographed on silica gel.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])=[CH:11][N:10]=1)(C)(C)C.[ClH:37]>CCOC(C)=O>[ClH:37].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N3CCc4ccccc4C3)cnc(CN)c2cc1OC
Yield: 99 %

Procedure:
As described in Example 1, 84 mg of {4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 74 mg (99%) of 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-1-(3,4-dihydro-1H-isoquinolin-2-yl)-ethanone hydrochloride. MS: APCI (M+H) calc'd for C23H25N3O3+H 392.5; found 392.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[CH3:1][C:2]1[N+:7]([O-:20])=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCCO)cn1
Solvent: ClCCl
Product: Cc1ccc(OCCO)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.00 g of the crude product from example 23A are dissolved in 45.6 ml of dichloromethane, and 9.91 g (43.09 mmol) of meta-chloroperbenzoic acid are added a little at a time. The reaction mixture is stirred at RT for 8 h. The solvent is then removed on a rotary evaporator, and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→5:1). The product obtained in this manner is used without further purification for the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:20][S:21]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[N:7]=1)(=[O:23])=[O:22]
Reactant: Cc1nc(CO)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(COS(C)(=O)=O)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
(6-Methyl-5-nitropyridin-2-yl)methanol (12 g, 71 mmol), and triethylamine (9.4 g, 93 mmol) in THF (300 mL) was chilled in an ice bath to 10° C. and methanesulfonyl chloride (9.0 g, 79 mmol) was added dropwise and the solution was stirred for one hour, then filtered to remove triethylamine HCl, and the solvent was removed under reduced pressure on the rotovap (with the bath temperature at 35° C.) and (6-methyl-5-nitropyridin-2-yl)methyl methanesulfonate (17 g, 97%), a brown oil which was directly used as such. 1HNMR (CDCl3, 400 MHz) δ 2.87 (s, 3H), 3.16 (s, 3H), 5.83 (s, 2H), 7.55 (d, J=8.34, 1H), 8.38 (d, J=8.34, 1H); Exact mass calculated for C8H10N2O5: 246.03. found: 247.10 MS m/z (MH+).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([O:24][CH3:25])[C:5]2[N:6]([CH2:18][CH2:19][O:20]C)[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:20][CH2:19][CH2:18][N:6]1[C:5]2[C:22]([O:24][CH3:25])=[CH:23][C:2]([C:26]#[N:27])=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)cc2nc(-c3ccc(C(C)C)cc3)n(CCO)c12
Temperature: 180 °C

Procedure:
A solution of 1.42 g (3.52 mmol) of 5-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole and 455 mg (3.87 mmol) zinc cyanide in 15 ml DMF is stirred under argon for 10 min at RT. Tetrakis(triphenylphosphine)palladium (214 mg, 0.176 mmol) is added and the reaction is heated to 180° C. for 90 min. After cooling to RT, ice/water is added and the reaction mixture is extracted with ethyl acetate (3×). The organic layer is washed with water, dried (Na2SO4) and concentrated in vacuo and the material is used without further purification.
Reaction SMILES: [CH2:1]1[NH:6][C@H:5]([CH2:7][OH:8])[CH2:4][N:3]2[CH2:9][CH2:10][CH2:11][C@H:2]12.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:6]3[C@H:5]([CH2:7][OH:8])[CH2:4][N:3]4[CH2:9][CH2:10][CH2:11][C@@H:2]4[CH2:1]3)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@@H]1CN2CCC[C@@H]2CN1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2C[C@H]3CCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 0.02 h
Yield: 4.4 %

Procedure:
(3S,8aR)-Octahydropyrrolo[1,2-a]pyrazin-3-ylmethanol (Tetrahedron Asymmetry, 1996, 7(7), 1999-2005, 230 mg, 1.47 mmol) and 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (570 mg, 1.07 mmol) were dissolved in 12 mL of toluene. 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (ligand) (78 mg, 0.20 mmol), Pd(dba)2 (45 mg, 0.08 mmol) and, at last, caesium carbonate (697 mg, 2.14 mmol) were added. The reaction vessel was sealed and nitrogen bubbled through the solution for 15 min. The reaction mixture was heated to 140° C. for 15 h. The mixture was diluted with 100 mL of EtOAc and extracted with water. The aqueous phase was extracted again with dichloromethane. The combined organics were dried and the solvent removed. Product purified by flash chromatography: silica, cyclohexane:EtOAc 50:50 to 0:100. Further purification by HPLC (prep. conditions: Column: Gemini C18 5 μm, 100×19 mm; Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN, Gradient: 50% (B) for 1 min, from 50% (B) to 65% (B) in 12 min, 95% (B) for 6 min; Flow rate: 17 ml/min; UV wavelength range: 210-350 nm; Mass range: 100-900 amu; Ionization: ES+. Isolated 31 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:20])([F:19])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1.[Br:24]Br>ClCCl.CCCCCC>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([Br:24])=[C:12]([C:14]#[N:15])[C:11]([S:16][C:17]([F:19])([F:20])[F:18])=[C:10]2[NH2:21])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(N)c1SC(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1c(SC(F)(F)F)c(N)n(-c2ccc(C(F)(F)F)cc2)c1Br
Yield: 52 %

Procedure:
To a suspension of 1.17 g (3.30 mmoles) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.46 ml (0.34 g, 3.3 mmoles) of triethylamine in 20 ml of chloroform cooled to -20° C. was added a solution of 0.19 ml (0.59 g, 3.7 mmoles) of bromine in 5 ml of chloroform. The reaction mixture was stirred at -20° C. for 1 hour and then allowed to warm to 0° C. Another 0.04 ml (0.13 g, 0.8 mmole) of bromine was then added and after 15 minutes of additional stirring, the reaction mixture was diluted with dichloromethane and partitioned with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 1.11 g of a brown solid. This material was combined with that from a previous reaction of 1.00 g (2.8 mmoles) of 1-(4-trifluoromethylphenyl)- 2-amino-3-trifluoromethylthio-4-cyanopyrrole and 0.15 ml of bromine. Chromatography on silica gel eluting with 3:1 v/v dichloromethane-hexane furnished 1.40 g (52%) of 1-(4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyano-5-bromopyrrole (EXAMPLE 14A) as a yellow solid. Recrystallization from hexane-ethyl acetate provided the product as light yellow platelets, melting point about 175° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (47 mg, 0.11 mmol), 5-aminovaleric acid (4.46 g, 38.1 mmol) and NaOMe solution (57 mL, 28.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 50 mg of the title compound as a brown oil. MS: (+) m/z 497.17 (M+1).