Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([OH:17])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:18])[CH:3]=1.[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@@H:24]1Br)(=[O:21])[CH3:20].ClCCl.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O>[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[C@@H:26]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:25][C@H:24]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:18])=[C:13]([CH:14]([CH3:15])[CH3:16])[NH:12][N:11]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1cc(Br)ccc1Cc1c(O)n[nH]c1C(C)C
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a 1 L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazol-3-ol (24 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (5 g, 15.5 mmol), dichloromethane (250 mL), potassium carbonate (32 g, 323 mmol) and water (120 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (450 mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (36.5 g, 57 mmol). MS (m/z): 638.5 (M+1), 636.5 (M−1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Cl[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.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]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[CH:18][N:17]=2)[C:3]1=[O:14]
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(Cl)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)N(c2cc(C(F)(F)F)ncn2)CC1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (800 mg, 4.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-chloro-6-(trifluoromethyl)pyrimidine (729 mg, 4.00 mmol) in 1,4-dioxane (40 ml) was treated with cesium carbonate (1953 mg, 5.99 mmol), Xantphos™ (173 mg, 0.300 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction mixture was heated at reflux under argon overnight. After cooling the reaction was diluted with water and extracted with ethyl acetate (×2). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate and reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (983 mg, 67.5% yield). LC/MS [M+H]+=347. (ii) Trifluoroacetic acid (4 ml, 51.9 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (980 mg, 2.83 mmol) in dichloromethane (8 ml) and the solution was stirred at room temperature for 6 hours. The solvent was evaporated and the residue was co-evaporated with toluene. The residue was dissolved in saturated sodium hydrogen carbonate solution and the solution was loaded onto an amino column eluting with 10% 2N hydrochloric acid in methanol. Product-containing fractions were combined and reduced under vacuum and the residue was triturated with methanol and the solid was filtered off. The filtrate was reduced under vacuum to give 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid hydrochloride salt (893 mg, assume ˜2.8 mmol) which was used in the next step. LC/MS [M+H]+=291.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[H-].[Na+].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>C1COCC1.CCOCC.C(OCC)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:1][C:21](=[O:22])[NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:24])[F:23])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1nc(Cl)cc(Cl)n1
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 2-amino-4,6-dichloropyrimidine (4.10 g, 25 mmol) in anhydrous THF (125 mL), under an atmosphere of N2, at 0° C. was added NaH (25 mmol, 1.02 g, 60% in mineral oil) and the mixture was stirred for 20 min. To this mixture was added 4-trifluoromethylphenyl isocyanate (4.678 g, 25 mmol) and stirred at 0° C. for 2 h. The mixture was poured into a mixture of ethyl acetate and 2N aq. HCl and the organic phase separated. The organic phase was washed with sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated in vacuo to give a solid. This solid was mixed with ether and filtered to give N′-[4,6-dichloropyrimidin-2-yl]-N-[4-(trifluoromethyl)phenyl]urea (2.6 g, 30% yield): m.p. 99-101° C.; 1H NMR (DMSO-d6) δ 10.78 (bs, 1H), 10.55 (bs, 1H), 7.69 (m, 4H), 7.58 (s, 1H); ESI/MS 348.88 (M−H) 350.97 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([O:24]CC)=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:21][CH2:20]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1.[OH-].[Na+].C(O)C>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([CH3:18])=[C:16]3[C:11]([C:12](=[O:27])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:20][CH2:21]3)=[C:10]([CH3:28])[C:9]=2[F:29])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(N3CCN(C)CC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(F)c(N2CCN(C)CC2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 60.2 %

Procedure:
To ethyl 7-(4-methyl-l-piperazinyl)-l-cyclopropyl-6-fluoro-5,8-dimethyl-1,4-dihydro-4 -oxoquinoline-3carboxylate (25 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. The aqueous layer is made acidic with acetic acid and then made weak alkaline with an aqueous sodium hydrogen carbonate. The resultant is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added diethyl ether. The precipitated crystals are filtered and recrystallized from ethanol to give 7-(4-methyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5,8-dimethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (14 mg), as yellow crystals, m.p. 205°-206° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC#N>[C:13]([C:7]1[CH:6]=[C:5]([N:4]([CH2:3][C:2]([F:15])([F:16])[F:1])[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:10]=[CH:9][C:8]=1[C:11]#[N:12])#[N:14]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C#N)c1
Temperature: 85 °C
Yield: 56.7 %

Procedure:
A solution of 4-[(2,2,2-trifluoroethyl)amino]-1,2-benzenedicarbonitrile (0.020 g, 0.089 mmol) in MeCN (3 mL) was treated with Cs2CO3 (0.078 g, 0.24 mmol) and methyl bromoacetate (0.037 g, 0.24 mmol) and heated at 85° C. under nitrogen for 8 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (20-100% CH2Cl2-hexanes gradient) and the product crystallized from CH2Cl2-hexanes to give 0.015 g (58% yield) of the title compound as a white solid: MS (ES) m/z 296 (M−1).
Reaction SMILES: [OH-].[Li+].CC([O:6][C:7]([C:9]1[N:44]=[CH:43][C:12]2[N:13]([CH2:30][C:31]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:32])[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:45][O:46][CH3:47])=[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])C.S(=O)(=O)(O)O>CO.O1CCCC1.C(OCC)(=O)C>[CH3:47][O:46][CH2:45][C:10]1[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[N:13]([CH2:30][C:31]([N:33]([CH3:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:32])[C:12]=2[CH:43]=[N:44][C:9]=1[C:7]([OH:8])=[O:6]
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1c(Oc3ccc([N+](=O)[O-])cc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1c(C(=O)O)ncc2c1c1c(Oc3ccc([N+](=O)[O-])cc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 63.4 %

Procedure:
10 ml of an aqueous 0.5N lithium hydroxide solution is added to a solution of 610 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid (1-methyl-ethyl)-ester in 10 ml of methanol and 10 ml of tetrahydrofuran, and it is stirred for 24 hours at 50° C. Then, it is cooled to 20° C., acidified with 10% aqueous sulfuric acid and diluted with ethyl acetate. The solution that is obtained is washed twice with saturated sodium chloride solution dried on sodium sulfate and evaporated to dryness in a vacuum. The crude product that is obtained is recrystallized from ethanol/tetrahydrofuran, and 360 mg of 4-methoxymethyl-5-(4-nitrophenoxy)-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid is obtained as pale yellowish crystals with a melting point of 231°-232° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[C:23]([F:32])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1>>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[C:23]([F:32])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:35][CH:36]=1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(C)(CO)O3)cc1F
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (229a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.57 (dd, J=8.46, 1.89 Hz, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.13 (s, 1 H) 7.10 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.71 (dd, J=10.61, 2.27 Hz, 1 H) 3.70-3.77 (m, 1 H) 3.57-3.66 (m, 1 H) 3.19 (d, J=16.67 Hz, 1 H) 3.13 (s, 3 H) 2.98 (d, J=1.52 Hz, 3 H) 2.81 (d, J=16.67 Hz, 1 H) 2.31 (s, 3 H) 1.46 (s, 3 H); LCMS for C26H26FN3O5 m/z 480.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10]Br)=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(#N)C>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[CH2:10][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][OH:21])[CH2:25][CH2:26]2)=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1cc(Cl)c(NC(=O)CBr)c(Cl)n1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Temperature: 5 °C
Yield: 90.2 %

Procedure:
N-(2,4-Dichloro-6-methylpyridin-3-yl)-2-bromoacetamide (70.0 g, 234.9 mmol) was dissolved in acetonitrile (105 mL), and potassium carbonate (39.0 g, 282.2 mmol) was added to the solution under stirring and under cooling with ice. While the inner temperature was maintained at 5° C. or lower, a solution of 1-(2-hydroxyethyl)piperazine (36.7 g, 281.9 mmol) in acetonitrile (140 mL) was added dropwise to the resultant mixture. Thereafter, the temperature of the mixture was elevated to room temperature, and the mixture was stirred for 4 hours. The reaction mixture was extracted with chloroform-water, and the aqueous layer was further extracted twice with chloroform. The combined organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, followed by condensation under reduced pressure. The residue was recrystallized from isopropanol and diisopropyl ether, to thereby yield 73.57 g of N-(2,4-dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (yield: 90%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](O)=[O:17]>O1CCCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a cooled solution (−40° C.) of 2-bromopyridine (1.68 mL, 17.6 mmol) in tetrahydrofuran (THF) (30 mL) was added n-butyllithium (nBuLi) (9.7 mL, 19 mmol, 2M in pentane) in a dropwise fashion and the resulting mixture was stirred for 30 min. 2-amino-5-chlorobenzoic acid (0.7 g, 4 mmol) was added and stirring was continued at 0° C. After 2 h, the mixture was quenched with trimethylchlorosilane (TMSCl) (10 mL), and hydrolyzed with 1N HCl (30 mL). The aqueous layer was separated from the organic phase, neutralized with 3N aq. sodium hydroxide, and extracted with ether (3×100 mL). The combined ether extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography on silica gel [hexanes:ethyl acetate (7:3)] to give (2-amino-5-chlorophenyl)-pyridin-2-yl-methanone (0.71 g, 76%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.CCOCC.C(=O)(O)[O-].[Na+]>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1ccc(CO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirring solution of Dess-Martin Periodinane (1.5 eq) in dichloromethane (0.3 M) at room temperature under nitrogen was added a solution of 29 in dichloromethane (0.2 M). After 4 hours the reaction was diluted with ether (0.1 M). The reaction mixture was then poured into a solution of sodium thiosulfate (10.5 eq) in saturated sodium bicarbonate (0.5 M) and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (1×), H2O (1×) and brine (1×) then dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (94%) 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.86 (d, 2H), 7.46 (d, 2H), 3.72 (m, 5H).
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1([Li])C=CC=CC=1.[CH2:39]([O:41][C:42]([C:44]1[S:48][C:47]([N:49]2[C:53]3[CH:54]=[C:55]([CH:58]=O)[CH:56]=[CH:57][C:52]=3[N:51]=[CH:50]2)=[N:46][C:45]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[CH:61]=1)=[O:43])[CH3:40]>O1CCCC1>[CH2:39]([O:41][C:42]([C:44]1[S:48][C:47]([N:49]2[C:53]3[CH:54]=[C:55]([CH:58]=[CH:12][CH2:11][CH2:10][O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:56]=[CH:57][C:52]=3[N:51]=[CH:50]2)=[N:46][C:45]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[CH:61]=1)=[O:43])[CH3:40]
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cnc3ccc(C=CCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
To a suspension of 0.983 g (2 mmole) of (3-benzyloxypropyl)triphenylphosphonium bromide and 20 mL of tetrahydrofuran at −78 degrees was added 1.33 mL (2.4 mmole) of 1.8 M phenyllithium solution. The mixture was stirred for 10 minutes and then 0.823 g (2 mmole) of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid ethyl ester (I.41a) was added. The reaction was allowed to warm up to room temperature, stirred for 2 hours and then quenched by the addition of 10 mL of saturated ammonium chloride solution. The layers were separated. The aqueous layer was extracted twice with 20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-1.5:98.5) to give 0.568 g of 2-[6-(-benzyloxy-but-1-enyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41b) as a yellow solid.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:18][Mg]Cl.ClC1C=C(C=C(F)C=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Cl[Mg]Cc1ccc(Cl)c(Cl)c1
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cc(F)cc(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dichlorobenzylmagnesium chloride (0.25 M in diethyl ether, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dichlorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pt2O). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.064 g.
Reaction SMILES: O.[CH3:2][N:3]([CH3:35])[CH2:4][CH2:5][N:6]([CH3:34])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)=[C:9]([O:32][CH3:33])[CH:8]=1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:35][N:3]([CH3:2])[CH2:4][CH2:5][N:6]([CH3:34])[C:7]1[C:12]([NH2:13])=[CH:11][C:10]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH:20]=[CH:19][N:18]=2)=[C:9]([O:32][CH3:33])[CH:8]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Yield: 95.8 %

Procedure:
Water (4 mL) was added in one portion to a mixture of N′-(2-dimethylaminoethyl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 169, 270 mg, 0.59 mmol), iron (196 mg, 3.51 mmol), NH4Cl (21.9 mg, 0.41 mmol) and ethanol (24 mL). The resulting mixture was heated at 105° C. for 3 h then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then part-purified by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to give the title compound (244 mg, 97%) as a brown solid which was used without further purification; 1H NMR: 2.18 (6H, s), 2.37 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.76 (3H, s), 6.77 (1H, s), 7.03-7.26 (3H, m), 7.46 (1H, d), 7.52 (1H, s), 7.74 (1H, s), 8.18-8.35 (2H, m), 8.42 (1H, d), 11.72 (1H, s); m/z: ES+ MH+ 432.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].I[CH2:32][C:33]([NH2:35])=[O:34].C1CCN2C(=NCCC2)CC1.O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24][CH2:32][C:33]([NH2:35])=[O:34])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(O)ccc2c1=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(OCC(N)=O)ccc2c1=O
Yield: 39.1 %

Procedure:
A solution of tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.43 g, 1 mmol), and 2-iodoacetamide (0.37 g, 2 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.30 ml, 2 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.19 g, 39.6%) as crystals.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[C:33]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[OH:39][C:33]1([C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:38]2[C:37](=[CH:27][CH:21]=[CH:22][CH:23]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: O=C1CCCCC1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C1(O)CCCc2ccccc21

Procedure:
By using a procedure similar to that described in Example 22 but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from cyclohexanone (5 cc), 1-(1-hydroxy-1-cyclohexyl)-3-dimethylamino-1-phenyl-1-propene (Z) hydrochloride (6 g) is obtained in the form of a white powder melting at 197° C. after recrystallisation from a mixture (50 cc) of isopropanol and isopropyl ether (60/40 by volume).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccc(C(F)(F)F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2ccc(C(F)(F)F)cc21
Yield: 44 %

Procedure:
In close analogy to the procedure described above, 1-methyl-7-trifluoromethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.