Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]([C:31]2[CH:36]=[CH:35][C:34]([S:37][CH:38]3[CH2:40][CH2:39]3)=[CH:33][CH:32]=2)=[CH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[N:13][C:14]=1[O:15][CH3:16]>ClCCl>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[N:13][C:12]([C:17]([C:31]2[CH:32]=[CH:33][C:34]([S:37][CH:38]3[CH2:39][CH2:40]3)=[CH:35][CH:36]=2)=[CH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: COc1nc(C(=C[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(SC3CC3)cc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(C(=C[C@H]2CCNC2)c2ccc(SC3CC3)cc2)ccc1Cl
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl (3R)-3-{2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(cyclopropylsulfanyl)phenyl]ethenyl}pyrrolidine-1-carboxylate (EZ mixture) (296 mg) in dichloromethane (3 mL) under ice-cooling, followed by stirring for three hours. The reaction solution was concentrated under reduced pressure to give 3-chloro-6-{1-[4-(cyclopropylsulfanyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]ethenyl}-2-methoxypyridine (EZ mixture) as a crude product (235 mg).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>CO>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:26]/[C:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)=[O:27]
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=C/C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 1-(1-trityl-1H-imidazol-4-yl)ethanone (81.0 g, 230 mmol) and DMF-DMA (77.0 mL, 575 mmol) in MeOH (500 mL) was heated to reflux for 72 h. The mixture was then allowed to cool to RT and was then cooled to 0° C. the suspension was filtered and the filter cake was dried in vacuo at 40° C. to give the title compound (72.7 g) that was used as it is in the next step. UPLC-MS: MS 408.3 (M+H+); UPLC rt 1.08 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 0 °C
Yield: 30.9 %

Procedure:
To an ice-cold solution of 3-(tert -butyldimethylsilyloxymethyl)benzonitrile (4.5 g, 18 mmol) in THF (47 mL) was added LiAlH4 (27 mL, of a 1 M solution in THF, 27 mmol), and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was cooled to 0° C., and the reaction was quenched with water (25 mL) and 15% NaOH in water (75 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-(tert-Butyldimethylsilyloxymethyl)benzylamine (1.4 g, 30%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.22-7.10 (m, 4H), 4.57 (s, 2H), 3.74 (s, 2H), 0.84 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:22](=[O:24])[CH3:23]>C(O)(=O)C.ClCCl.[Zn]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:22](=[O:24])[CH3:23])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(OCc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reaction time: 3 h
Yield: 536.6 %

Procedure:
Add zinc (21.6 g, 331 mmol) slowly to a solution of 1-[2-hydroxy-4-(3-nitro-benzyloxy)-3-propyl-phenyl]-ethanone (10.9 g, 6.07 mmol) in glacial acetic acid (120 mL). Stir the mixture for 3 hours. Dilute with dichloromethane (600 mL). Filter the reaction mixture through celite. Wash the celite pad several times with dichloromethane. Concentrate the combined filtrates. Partition the residue between ethyl acetate and saturated sodium bicarbonate. Wash the organic layer with brine, dry and concentrate to afford the title compound as a yellow solid (9.75 g, 98%): 1H NMR (CDCl3) δ 0.96 (t, 3H), 1.58 (sextet, 2H), 2.54 (s, 3H), 2.71 (t, 2H), 5.07 (s, 2H), 6.46 (d, 1H), 6.62 (d, 1H), 6.71 (s, 1H), 6.78 (d, 1H), 7.16 (t, 1H), 7.54 (d, 1H), 12.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(Cl)c2)s1
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NCc3ccccc3)c2)s1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
With stirring, a mixture of 5.24 g (16.4 mmol) of 2-chloro-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine and 25 ml benzylamine is heated at 180° C. After 16 h, the reaction mixture is concentrated under reduced pressure, the residue is taken up in 100 ml of MTBE, the resulting precipitate is filtered off and the filtrate is concentrated again. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 4.75 g (88%) of the desired product; 1H-NMR(MeCN-d3) δ: 7.91 (d, 1H), 7.49 (m, 2H), 7.29 (m, 5H), 7.07 (m, 2H), 6.45 (d, 1H), 6.39 (s, 1H), 5.83 (br.s, 1H), 4.43 (d, 2H), 3.02 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[C:22](=[O:25])([O-])[OH:23].[Na+].CCOCC.O.[C:33]1(C)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:33]1[CH:38]=[CH:37][C:36]2[O:23][CH2:22][O:25][C:35]=2[CH:34]=1
Reactant: Cc1ccccc1
Reactant: O=C([O-])O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc2c(c1)OCO2

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.894 g) in toluene (4 ml) containing tetrakis(tnrphenylphosphine)palladium(0) (0.04 g) was added saturated aqueous sodium hydrogen carbonate solution (3 ml) and a solution of 3.4-methylenedioxypheny,lboronic acid (0.600 g) in ethanol (2 ml). The mixture was heated under reflux for 4 hours, cooled and then poured into ether (40 ml) and water (40 ml). The organic layer was separated, washed with water (2×30 ml), brine (30 ml) and then dried (MgSO4) and evaporated. The residue %as purified by column chromatography on silica gel (30 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale brown crystalline solid, m.p. 222° C. with softening at 198° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1.Cl>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]1
Reactant: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 67.1 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was loaded 8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (1.30 g, 3.9 mmol) and methanol (15 ml). To the resulting stirred solution was added aqueous HCl (15 ml, 1M) in one portion. After stirring for one hr at room temperature the acid was quenched by adding saturated aqueous sodium bicarbonate solution (10 ml). After stirring vigorously for 10 min, the reaction mixture was transferred to a separating funnel and the phases separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine and the solvent evaporated. To the slightly wet crude product was added methanol (30 ml) and acidic ion exchange resin (4 g). The resulting mixture was heated under reflux, with stirring, for 5 hr. Filtering through a plug of Celite, washing with ethyl acetate, followed by removal of solvent in vacuo afforded an orange oil. Purification by flash column chromatography, (SiO2, ethyl acetate/petroleum ether, 1:1, v/v) furnished the title compound as a white powder (0.54 g, 68%). m/z (ES−) 411 (2M−1); δH (CD3OD) 1.94 (2H, ddd), 2.16-2.23 (2H, m), 2.41 (2H, dt), 2.62 (1H, t), 2.63 (1H, t), 6.24 (1H, dd), 6.31 (1H, d), 6.92 (1H, d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1)([O-])=O.CN(C)C=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:25])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(S(C)(=O)=O)cc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(S(C)(=O)=O)cc2C1=O

Procedure:
The mixture of 2.5 g of N-(4- nitro-o-tolyl)-4-methylsulfonylphthalimide, 0.1 g of palladium on carbon, 80 ml of dimethylformamide and 200 ml of ethyl acetate is hydrogenated at 2.7 atm. and room temperature until the hydrogen uptake ceases. It is filtered, the filtrate extracted with hydrochloric acid, washed with ethyl acetate, basified with sodium carbonate, reextracted with ethyl acetate, the organic solution washed with water, dried filtered and evaporated. The residue is triturated with ethyl acetate-diethyl ether, to yield the N-(4-amino-o-tolyl)-4-methylsulfonylphthalimide melting at 214°-220°.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCOCC1>[CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:34](=[O:35])[O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:25][CH:26]=2)[N:9]=1)(=[O:5])=[O:6])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
(4-{4-[(Isopropylsulfonyl)methyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)amine (1.5 g, 3.84 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (485 mg, 5.76 mmol) was added, followed by phenyl chloroformate (0.484 mL, 3.84 mmol) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the resultant oil partitioned between 10 mL DCM and 10 mL water. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The cream solid obtained was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM, to give the desired material as a white solid (1.8 g).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(O[CH:43]([CH3:45])[CH3:44])=O)=NC(OC(C)C)=O.[N:46]1[CH:51]=CC=[CH:48][CH:47]=1>C1COCC1>[N:46]1[CH:51]=[CH:45][C:43]([CH2:44][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2](=[O:3])[O:4][C:5]2=[O:12])=[CH:48][CH:47]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc(=O)n(Cc2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of isatoic anhydride (72.60 g/445.0 mmol) and triphenylphosphine (116.74 g/445.1 mmol) in THF (1 L) at 0° C. was added diisopropyl azodicarboxylate drop-wise over ca. 50 min. The resulting pale yellow reaction mixture was stirred for 10 min. before drop-wise addition of a solution of 4-hydroxmethyl pyridine (48.57 g, 445.1 mmol) in THF (250 ml). The reaction mixture was stirred at room temperature for 2 hours. The resulting red solution was filtrated through a pad of silica gel, and the filtrate was evaporated under reduced pressure. The residue was treated with EtOAc and the resulting precipitated material was isolated by filtration and re-crystallised from EtOAc affording the title compound as a white solid material (37.5 g). The filtrate from this crystallisation was extracted with 0.1M HCl aq. The pH of the aqueous layer was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The precipitated material was isolated by filtration and washed with water to yield more of the title compound (9.8 g). The combined aqueous filtrates were extracted several times with EtOAc. The combined organic layers were evaporated under reduced pressure. The residue was re-crystallised from EtOAc affording an additional amount of the title compound (20.3 g). 13C-NMR (DMSO-d6) δ 158.7, 149.7, 148.2, 144.5, 141.1, 136.9, 129.5, 123.8, 121.5, 114.8, 112.1, 46.7.
Reaction SMILES: [F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3](O)=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C@:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([Cl:19])=[O:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCC[C@@](F)(C(=O)O)C(F)(F)F
Product: CCCCCCCC[C@@](F)(C(=O)Cl)C(F)(F)F
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
2.0 g (7.7 mmol) of (R)-(+)-2-fluoro-2-(trifluoromethyl)-decanoic acid was cooled with ice, and 1.8 g (8.5 mmol) of phosphorus pentachloride was added to the acid. The resulting mixture was stirred for 30 minutes while being cooled with ice, and then stirred at room temperature for 8 hours. Subsequently, the resulting reaction mixture was distilled under reduced pressure, thereby obtaining 1.4 g of (S)-(+)-2-fluoro-2-(trifluoromethyl)decanoyl chloride having the physical properties as mentioned hereinbefore, in a yield of 66%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][CH2:12][C:13](O)=O>>[Cl:11][CH2:12][C:13]1[N:8]([CH3:9])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[N:10]=1
Reactant: CNc1ccc(F)cc1N
Reactant: O=C(O)CCl
Product: Cn1c(CCl)nc2cc(F)ccc21
Yield: 7.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from 4-fluoro-N1-methylbenzene-1,2-diamine (2.5 g, 17.84 mmol) and 2-chloroacetic acid (2.50 g, 27 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt:60/40 as eluent) to afford 277 mg of 2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (Yield: 8%) as a semi-solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C(OC)=O)=[CH:3][N:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(Cl)Cl>C(OCC)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cnnc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C1=NNc2ccccc2C1

Procedure:
A solution of 1.00 g of methyl cinnolin-4-carboxylate in 15 ml diethyl ether is added dropwise at 0° C. to a suspension of 222 mg of lithium aluminium hydride in 5 ml of diethyl ether. After 1.5 hours water is carefully added dropwise to the reaction mixture, this is stirred with methylene chloride and suction filtered through a glass fibre filter. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate and evaporated down. According to 1H-NMR a mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained as a yellow oil which is reacted further without any more purification.
Reaction SMILES: C[C:2]1(C)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[C:7]([S:13][CH2:14][N+:15]([O-:17])=[O:16])[C:8]=2[CH3:12])O1.CC1C(SC#N)=C(C)C=C2C=1CCC[S:26]2>>[CH3:12][C:8]1[C:7]([S:13][CH2:14][N+:15]([O-:17])=[O:16])=[C:6]([CH3:18])[CH:5]=[C:4]2[C:9]=1[CH2:10][CH2:11][CH2:2][S:26]2
Reactant: Cc1cc2c(c(C)c1SC[N+](=O)[O-])CCC(C)(C)O2
Reactant: Cc1cc2c(c(C)c1SC#N)CCCS2
Product: Cc1cc2c(c(C)c1SC[N+](=O)[O-])CCCS2
Yield: 44 %

Procedure:
Using similar procedures to that described in parts (ii) and (iii) of Example 8, but starting from 5,7-dimethyl-6-thiocyanatothiachroman (J), 5,7-dimethyl-6-(nitromethylthio)thiachroman was obtained in 44% yield as a pale yellow gum which slowly solidified; NMR: 2.17(2H,m), 2.4(3H,s), 2.43(3H,s), 2.69(2H,t), 2.95(2H,m), 5.19(2H,s), 6.91(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:3]=12.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:17]3[CH:36]=[CH:35][C:20]4/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=5[O:24][CH2:25][C:19]=4[CH:18]=3)[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:10][C:3]=12
Reactant: Clc1ccnc2[nH]c(C3CCC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CCC4)nc4c(Cl)ccnc43)cc2COc2cc(F)ccc21
Yield: 62.8 %

Procedure:
Using 7-chloro-2-cyclobutyl-3H-imidazo[4,5-b]pyridine (WO2009/29592, 69 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (102 mg, 62%) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([C:21]2[CH:22]=[C:23]([C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:14]=1.[CH3:33]O>>[CH3:33][O:29][C:28](=[O:30])[C:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:15]2[CH:14]=[C:13]([NH:12][CH2:11][CH2:10][C:4]3[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=3[Cl:2])[N:18]=[C:17]([O:19][CH3:20])[N:16]=2)[CH:22]=1)([CH3:32])[CH3:31]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Hydrochloric acid (81.46 μL, 4M solution in 1,4-dioxane, 0.33 mmol) is added to a stirred solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.22 mmol, Example 49(b)] in MeOH (8 mL), and the reaction mixture is stirred overnight at 65° C. The reaction is cooled to room temperature and concentrated in vacuo. The residue is purified by chromatography to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (34 mg, Example 79). LCMS: RT=2.79 minutes; MS: 475 (M+H); 1H NMR (300 MHz, CDCl3): □7.98 (1H, s), 7.88 (1H, b), 7.42 (3H, d, J=2 Hz), 7.2 (2H, s), 6.4 (1H, s), 5.08 (1H, b), 4.05 (3H, s), 3.7 (2H, b), 3.65 (3H, s), 3.1 (2H, t, J=2 Hz), 1.65 (6H, s).
Reaction SMILES: C(N1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])C1C=CC=CC=1.[CH2:30]([NH2:32])[CH3:31].O[NH-].O=[N-]>>[CH2:30]([N:32]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([C:18](=[O:22])[C:19]([NH:16][CH2:14][CH3:9])=[O:21])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:31]1[CH:24]=[CH:23][CH:17]=[CH:18][CH:19]=1
Reactant: CCN
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: CCNC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
Coupling of 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenyl-butanoic acid with ethylamine and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[CH2:23]([NH2:25])[CH3:24]>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]=[C:2]([CH2:24][CH2:23][NH2:25])[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c1
Reactant: CCN
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-(4-chloro-phenyl)-7-trifluoromethylquinazoline (52.0 g, 0.15 mol) in THF (400 mL) at 0° C. was added dropwise a solution of ethylamine (0.45 mol, 230 mL, 2 M in THF. The ice-bath was then removed and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure then partitioned between ethyl acetate (400 mL) and water (400 mL) removing any undissolved solid by vacuum filtration. The filtrate was concentrated to approximately 200 mL and the resultant precipitate was removed by vacuum filtration. The filtrate was again concentrated to approximately 100 mL volume and the resultant precipitate was removed by vacuum filtration. Finally the filtrate was cooled to 0° C. upon which [2-(4-chloro-phenyl)-7-trifluoromethyl-quinazolin-4-yl]ethylamine precipitated from solution. The precipitate (30 g) was isolated by vacuum filtration and dried under vacuum (10 mbar, 50° C.). A second amount of the precipitate of equal purity (19.6 g) was obtained following concentration of the filtrate to approximately 50 mL volume, cooling to 0° C., filtration and drying under vacuum. Combined yield=49.6 g, 93%; LC-MS: 2.9 min, 352 (M+); 1H NMR (DMSO-d6): δ 1.38 (t, 1 H, J=7 Hz), 3.77-3.85 (m, 2 H), 7.46 (d, 2 H, J=8.7 Hz), 7.64 (dd, 1 H, J=8.3, 1.8 Hz), 7.72-7.78 (br s, 1 H), 8.09 (s, 1 H), 8.17 (d, 1 H, J=8.3 Hz), 8.59 (d, 2 H, J=8.7 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[NH:29]C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2].[OH-].[Na+]>Cl.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:38])[CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=2[NH2:29])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)C2)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The resulting (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzyl)glycyl}amino]pyrrolidine was dissolved in 50% 6 N hydrochloric acid in dioxane and the solution was stirred at room temperature for 2 h. The mixture was adjusted to pH 10 with 5 M NaOH solution, and extracted with ethyl acetate. The organic layer was evaporated and preparative TLC (SiO2, AcOEt/MeOH=4:1) afforded (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2152) (3.7 mg, 8%): The purity was determined by RPLC/MS (100%); ESI/MS m/e 508.3 (M++H, C24H28F3N5O4).