Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH3:2][C:3]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:13]([N+:18]([O-])=O)[CH:14]=[N:15]3)=[CH:10][C:9]=2[O:29][CH3:30])=[C:6]([CH3:31])[O:5][N:4]=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[CH3:2][C:3]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:13]([NH2:18])[CH:14]=[N:15]3)=[CH:10][C:9]=2[O:29][CH3:30])=[C:6]([CH3:31])[O:5][N:4]=1
Reactant: [H][H]
Reactant: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Yield: 88.6 %

Procedure:
10% palladium on carbon, 50% water paste, (300 mg, 20% wt) was added to a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitro-N-(2-pyridinylmethyl)-4-quinolinamine (1.5 g, 3.70 mmol) in ethyl acetate (90 ml) and ethanol (10 ml). The reaction mixture was stirred in an atmosphere of hydrogen for 3 h. The reaction mixture was filtered through Celite™. The solvent was evaporated from the filtrate. The residue was chromatographed [5% methanol/DCM] to give the title compound as a brown oil (1.23 g, 3.28 mmol, 89% yield). LCMS (formate) Rt 0.63 min, MH+ 376
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[CH2:17][C:16]2([F:19])[F:18])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>CCCCCC.C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:13][CH2:14][C@H:15]2[CH2:17][C:16]2([F:19])[F:18])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Solvent: CCCCCC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1

Procedure:
A racemate (48.4 g) of (2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate was resolved by HPLC (column: CHIRALPAK AD (trade name), 50 mmID×500 mL, DAICEL CHEMICAL INDUSTRIES, LTD., mobile phase:hexane/ethanol=50:50) to give the title compound having a shorter retention time (18.4 g). The steric configuration was determined by X ray structure analysis.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:4][C:5]1[C:10]([N:11]([CH3:21])[C:12]([C:14]2[C:15]([NH:3][CH2:1][CH3:2])=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:8]=[C:7]([O:22][CH3:23])[N:6]=1
Reactant: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Reactant: CCN
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCNc1ncccc1C(=O)N(C)c1ccc(OC)nc1Br
Temperature: 150 °C
Yield: 77.1 %

Procedure:
Ethylamine (0.7 g) was added to a solution of N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-N-methyl-3-pyridinecarboxamide (1.9 g) in xylene (5 ml), and the resulting mixture was sealed in a pressure bottle and heated at 150° C. for 4 hours. The solution was diluted with ethyl acetate, washed with water, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (ethyl acetate/hexane, 1:4) to give 1.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=1[CH:8]=[O:9])[CH2:2][CH2:3][CH3:4].CC(=CC)C.O.O.P([O-])(O)(O)=[O:28].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH2:1]([N:5]([CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:7]=1[C:8]([OH:28])=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCN(CC)c1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 2 h
Yield: 0.1 %

Procedure:
2-(Butyl-ethyl-amino)-5-trifluoromethyl-benzaldehyde (1.72 g) is dissolved in a mixed solvent of tert-butanol (8 ml) and water (2 ml), and thereto are added 2-methyl-2-butene (4 ml), sodium dihydrogenphosphate dihydrate (1.37 g) and sodium chlorite (1.82 g) under ice-cooling, and the mixture is stirred for 2 hours. Thereto are added ethyl acetate and a 1N-hydrochloric acid and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 2-(butyl-ethyl-amino)-5-trifluoromethyl-benzoic acid (1.29 mg). MS (m/z): 290 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:30][C:28]1[CH:27]=[C:4]([CH:3]=[C:2]([N:33]2[CH2:34][CH2:35][CH2:36][CH:32]2[CH3:31])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Reactant: CC1CCCN1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCCC2C)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 2-methylpyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.26 (d, 1H), 8.22 (m, 1H), 7.84 (m, 1H), 7.57 (m, 2H), 7.45 (d, 1H), 7.39 (s, 1H), 7.13 (d, 1H), 7.05 (d, 1H), 4.41 (d, 2H), 4.31 (t, 2H), 3.60 (m, 4H), 2.88 (m, 4H), 2.58 (m, 4H), 1.7 (m, 4H), 1.11 (m 1H), 0.95 (d, 3H). MS: 475.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:18]([F:27])([F:26])[C:19]([O:21]C(C)(C)C)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=[O:4].[S:35]1[CH:39]=[C:38]([CH:40]=O)[N:37]=[CH:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:18]([F:26])([C:8]1[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:11]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:40][C:38]2[N:37]=[CH:36][S:35][CH:39]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: O=Cc1cscn1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1cc(NC(=O)[C@@H](N)Cc2ccccc2)cc(-c2ccncc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1cc(-c2ccncc2)cc(C(F)(F)C(=O)O)c1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of (S)-tert-butyl 2-(3-(2-amino-3-phenylpropanamido)-5-(pyridin-4-yl)phenyl)-2,2-difluoroacetate 52.F (300 mg, 0.64 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (73 mg, 0.64 mmol). The mixture was stirred for 1 h at room temperature, then acetic acid (30 μL, 0.64 mmol) and sodium triacetoxyborohydride (408 mg, 1.93 mmol) were added and the mixture stirred at room temperature for an additional 2 hours. The mixture was then concentrated and the residue was stirred in THF (5 mL) and concentrated HCl (5 mL) at 50° C. overnight. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (S)-2,2-difluoro-2-(3-(3-phenyl-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)acetic acid 52 as a white solid (140 mg, 43% yield). LCMS ESI (pos.) m/e: 509.0. (M+1). 1H NMR (500 MHz, MeOH-D4) δ ppm 9.14 (d, J=1.96 Hz, 1H), 8.81-8.87 (m, 2H), 8.16 (t, J=1.83 Hz, 1H), 8.12-8.15 (m, 2H), 7.88 (s, 1H), 7.81 (d, J=1.96 Hz, 1H), 7.72 (s, 1H), 7.24-7.37 (m, 5H), 4.46-4.59 (m, 2H), 4.27 (dd, J=9.29, 5.87 Hz, 1H), 3.40-3.51 (m, 1H), 3.27 (dd, J=13.45, 9.29 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.[H-].[Li+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.051 g, 4.070 mmol) in anhydrous t-butyl methyl ether (16 ml), lithium hydride (30.3 mg, 3.81 mmol) was added and the mixture was stirred for approximately 6 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in anhydrous t-butyl methyl ether (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g/15 g/18 g; ethyl acetate:hexane=1:4) three times, to give methyl 7-[(1R,2R,3R,5S) -5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.257 g; 0.484 mmol; yield: 21.3%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1>C(N)CN.C(Cl)(Cl)Cl.C(O)(C)C>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:3][CH2:4][CH2:5][NH2:6]
Reactant: Clc1nc2ccccc2[nH]1
Solvent: NCCN
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NCCNc1nc2ccccc2[nH]1
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-1H -benzoimidazole (1 g) in 4 mL of ethane-1,2-diamine was heated to 100 C. for several hours until complete by HPLC. The reaction was allowed to cool and diluted with a mixture of chloroform and isopropanol (3:1). The organic phase was washed with water then dried and concentrated to give 216 mg of product as a solid which was used in the next step without further purification. MS(ES): m/c (EI*) 177.1 [M+H]
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH3:7])[C:3]#[N:4].ClCCl.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[C:3]([CH:2]([O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][O:6][CH3:7])#[N:4]
Reactant: CS(=O)(=O)Cl
Reactant: COCC(O)C#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C#N)OS(C)(=O)=O

Procedure:
27.3 gr (0.27 Mol) of 2-hydroxy-3-methoxy-propionitrile was dissolved dichloromethane (250 ml) and treated first with 56.4 ml (0.40 Mol) triethylamine keeping the temperature below −8° C., followed by dropwise addition of 23.1 ml (0.297 mol) methansulfonyl chloride keeping the temperature below +7° C. under cooling. After the exothermic reaction ceased the mixture was left to reach room-temperature. Water was stirred in, and the mixture was extracted with tert.-butylmethylether, washed with brine, dried and evaporated. To remove some polar side-products the crude liquid obtained was filtered through silica gel (eluent: cyclohexane/ethylacetate 1:1). Methanesulfonic acid 1-cyano-2-methoxy-ethyl ester of 89% purity (GC-MS) was obtained; 1H-NMR (CDCl3): 5.33, t, 1H, 3.81, d, 2H, 3.48, s, 3H, 3.21, s, 3H.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:37]1[O:40][C@@H:38]1[CH3:39]>>[Cl:1][C:2]1[C:3]([NH:26][C@@H:27]2[C@@H:32]3[CH2:33][C@@H:29]([CH:30]=[CH:31]3)[C@@H:28]2[C:34]([NH2:36])=[O:35])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH2:37][C@H:38]([OH:40])[CH3:39])[CH2:20][CH2:19]4)=[CH:13][C:12]=3[O:24][CH3:25])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@H]1CO1
Reactant: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Product: COc1cc(CN2CCN(C[C@@H](C)O)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 32 %

Procedure:
In a similar fashion as for the synthesis of Compound XLIII, (1S,2S,3R,4R)-3-[6-Chloro-2-(2-methoxy-4-piperazin-1-ylmethyl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide was reacted with (R)-(−)-propylene oxide to afford the title compound as an orange solid (32%). Mp 157-9° C. 1H NMR (d-chloroform): 10.72 (br s, 1H), 8.35 (d, J=9 Hz, 1H), 8.05 (s, 1H), 7.04 (m, 2H), 6.37 (m, 3H), 5.56 (d, J=9 Hz, 1H), 5.20 (t, J=8 Hz, 1H), 5.12 (s, 1H), 4.08 (s, 3H), 3.84 (m, 1H), 3.59 (s, 2H), 3.48 (m, 1H), 3.18 (s, 1H), 2.92 (s 1H), 2.88 (d, J=8 Hz, 1H), 2.73 (m, 2H), 2.61-2.41 (m, 5H), 2.37-2.22 (m, 3H), 2.19 (s, 1H), 1.76 (d, J=9 Hz, 1H), 1.15 (d, J=7 Hz, 3H). MS: 566.23 (M+H). HPLC retention time: 1.71 minutes (G Method).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=O)[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=[S:28])[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=O)C1CCCC21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1cc2c(cc1[N+](=O)[O-])NC(=S)C1CCCC21
Yield: 74.7 %

Procedure:
As described for Example 4, 8-methyl-7-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (60 mg, 0.24 mmol) is reacted with Lawesson's reagent (105 mg, 0.26 mmol) to form 47 mg (75%) of product.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C=O)C>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20](=[O:21])[NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)#[N:16]
Reactant: CCOC(=O)CN=C=O
Reactant: N#Cc1ccc(CNOCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)N(Cc1ccc(C#N)cc1)OCc1ccccc1
Temperature: 50 °C

Procedure:
2.73 g (11 mmol) of 4-(benzyloxyaminomethyl)benzonitrile are dissolved in 75 ml of DMF and added dropwise at 0° C. to a solution of 1.48 g of ethyl isocyanatoacetate in 75 ml of DMF. The mixture is heated at 50° C. for 3 d, then concentrated in vacuo. The residue is taken up in ethyl acetate and the solution is washed with water. The organic phase is dried (MgSO4) and concentrated in vacuo. The residue is dissolved in a little ethyl acetate and precipitated with ether/petroleum ether. The precipitate produced is reacted without further purification.
Reaction SMILES: [C:1]1([C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH:12]=[N:11][C:10]([CH2:13][CH2:14][C:15](OCC)=[O:16])=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:26]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:8]2[CH:12]=[N:11][C:10]([CH2:13][CH2:14][CH2:15][OH:16])=[N:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
A solution of ethyl 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoate obtained in Reference Example 24 (700 mg, 1.70 mmol) in THF (5 mL) was added to a suspension of lithium aluminum hydride (84.0 mg, 2.21 mmol) in THF (5 mL) at 0° C., and the mixture was stirred at 0° C. for 5 hr, and then at room temperature for 15 hr. Water and 1N aqueous sodium hydroxide solution were added to the mixture, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-80% ethyl acetate/hexane) to give the title compound as a white powder (289 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6]Br)=[C:4]([CH3:11])[CH:3]=1.ClC1C=C(C)C=C(C)C=1CBr.[NH2:23][C:24]1[C:25]2[N:26]([C:30]([CH3:34])=[C:31]([CH3:33])[N:32]=2)[CH:27]=[CH:28][CH:29]=1.[I-].[K+].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[CH3:33][C:31]1[N:32]=[C:25]2[C:24]([NH:23][CH2:6][C:5]3[C:8]([CH3:10])=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:11])=[CH:29][CH:28]=[CH:27][N:26]2[C:30]=1[CH3:34]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: Cc1cc(Cl)cc(C)c1CBr
Agent: Cc1cc(C)c(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Product: Cc1cc(Cl)cc(C)c1CNc1cccn2c(C)c(C)nc12

Procedure:
A mixture of 4-chloro-2,6-dimethylbenzylbromide and 2-chloro-4,6-dimethylbenzylbromide (1.1 g, 4.68 mmol) and 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (4.65 mmol) was dissolved in 15 ml dimethoxyethane. Potassium iodide (0.5 g, 3.0 mmol) and Na2CO3 (1 g, 9.4 mmol) was added. The mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel. The product was eluted with a mixture of methylene chloride and ethyl acetate (70:30). 70 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH2:27][CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[Li:10]CCCC>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Li:10]
Reactant: COc1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]c1ccccc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Methoxybromobenzene (8.44 g 45.1 mmol) was dissolved in dry diethyl ether (15 mL). The mixture was cooled to −78° C. n-BuLi (17.8 mL, 45.0 mmol) was added and the mixture was stirred for one hour at −78° C. and then for 20 min. at −10° C. The aryl lithium solution was used immediately.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=CC(CC3C(Cl)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1.N1(C2C=CC(CC3[C:63]([O:74]C)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:74][CH3:63])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Agent: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by using 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (Intermediate 19: step a) in place of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c) then following the procedure described for the preparation of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (Intermediate 16).
Reaction SMILES: [C:1]1([C@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:11]1([C@@:7]([OH:17])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([OH:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)[C@](O)(C1=CCCCC1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reaction time: 22 h

Procedure:
(S)-cyclohex-1-enyl-hydroxy-phenyl-acetic acid (120 g, 0.517 mol) is dissolved in methanol (678 ml) under an inert atmosphere of Argon and then treated with palladium on carbon (6 g, 10% w/w). The resulting suspension is stirred under an atmosphere of hydrogen for 22 hours and then filtered through celite. The solvent is removed in vacuo to yield the titled product.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:6][CH:5]=1)([O-])=O.NC1C=CC(OC2C=CN=C3C=C(C4C=CC(O)=CC=4)SC=23)=C(F)C=1>>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)cc1
Agent: Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)cc1
Yield: 83 %

Procedure:
Starting from the compound 198 and following the procedure described above for the synthesis of compound 154 (scheme 28), title compound 199 was obtained in 83% yield. LRMS (M+1) 335.0 (100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:14]2CCCC2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:22]=[C:23]([C:29](=O)[C:30]([F:33])([F:32])[F:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])C.C([O-])(=O)C.[NH4+]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
A solution of the crude enamine (2.67 g, 10.6 mmol) from Step A above in 30 mL of dry 1,4-dioxane was cooled to approximately 10° C. and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (2.3 mL, 11.7 mmol) was added dropwise. The resultant orange solution was allowed to warm to room temperature overnight. Ammonium acetate (1.78 g) was added to the blood-red solution, and the mixture was heated at reflux for 2 h, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ether and water, and the ether layer was washed with saturated brine, dried over magnesium sulfate and concentrated to a red oil. Purification by flash chromatography (silica gel; 12% ethyl acetate/hexanes as eluant) followed by preparative TLC (silica gel; 15% ethyl acetate/hexanes as eluant) afforded the title compound as a light yellow oil. LC/MS 365.2 (M+1).