Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[NH:8]2.Cl.CN(C)CCCN=C=NCC.[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[N:8]2[C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:34]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC1Cc2c(cccc2OC(F)F)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(OC(F)F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole (reference example 11d) and 192.7 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 196.8 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 6 ml of N,N-dimethylformamide and 6 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 220 mg of 2-{2-[4-(difluoromethoxy)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][C@@H:33]([CH3:35])[N:11]2[C:12]3[CH:13]=[C:14]([N:19]=C(C4C=CC=CC=4)C4C=CC=CC=4)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:34][C@@H:33]([CH3:35])[N:11]2[C:12]3[CH:13]=[C:14]([NH2:19])[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)cc3N21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N)cc3N21
Temperature: 60 °C

Procedure:
A mixture of (4R,10aR)-7-(benzhydrylidene-amino)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (3.35 g, 7.2 mmol), ammonium formiate (6.8 g, 107 mmol) and palladium on carbon (1.5 g, 5%) in methanol (35 mL) was heated to 60° C. for 1 h. After cooling the mixture was diluted with dichloromethane (100 mL) and filtered. The filtrate was washed with water (100 mL), the water phase was extracted with dichloromethane, and organic phases were pooled and dried with MgSO4. The solvents were removed in vacuo and the residue was purified by chromatography on silica gel with ethylacetate/n-hexane (1:1). The title product was isolated as yellow foam (1.15 g, 53%); ISP-MS: m/e=304.4 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH3:8][N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[N:10]1.Br[C:24]1[CH:25]=[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=[CH:28][C:29]=1[F:30]>C(#N)C>[F:30][C:29]1[CH:24]=[CH:25][C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:28]=1[C:12]1[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1ccc(F)c(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Pd-118 (0.201 g) was dissolved in acetonitrile (20 mL) and stirred for 5 min before addition of potassium carbonate (5.34 g), water (20 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.95 g). The mixture was stirred for a further 5 min then methyl 2-(3-bromo-4-fluorophenyl)acetate [Example 13, Step i)] (3.18 g) in MeCN (2 mL) added and the reaction was heated at the heating block (80° C.) for 25 min. The mixture was cooled and extracted into DCM (100 mL). Organic was separated, dried over magnesium sulfate. Solvents were evaporated to give a brown oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% ethyl acetate in isohexane to afford the subtitled compound (3.36 g) as a gum. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.44 (dd, J=7.3, 1.5 Hz, 1H), 7.12-7.02 (m, 2H), 3.96 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H)
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:30]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]3[CH2:21][CH2:22][C@H:23]([O:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (775 mg, 1.54 mmol) in THF: H2O: MeOH (3:1:2) (10 mL), was added LiOH in water (1N) (4.6 mL, 4.6 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (380 mg, 50%) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:23])([CH3:24])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(CCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 96.4 %

Procedure:
13.9 g ethyl 2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionate, 100 ml methanol and 37 ml 2 N aqueous potassium hydroxide solution are maintained at reflux temperature for 9 hours, the methanol is then distilled off in a vacuum and the residue is diluted with water and extracted with diethyl ether. The aqueous phase is filtered and acidified. There are obtained 12.8 g (100% of theory) of crude product. After recrystallization from 130 ml glacial acetic acid, there are obtained 12.4 g (94% of theory) 2-{4-[2-(4-chlorobenzamido)-ethyl]-phenyl}-2-methylpropionic acid; m.p. 234°-235° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12](OCC)=[O:13])([O-])=O.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.CCCCCC.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Nc1ccccc1CCCO
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of ethyl 3-(2-nitrophenyl)acrylate (1.11 g) in diethyl ether (30 mL) was added a 1M diisobutylaluminum hydride solution in hexane (15.0 mL) under ice cooling. After stirring the solution under ice cooling for 1 hour, diethyl ether, water (0.6 mL) and a 15% aqueous sodium hydroxide solution (0.6 mL) were added thereto. The solution was stirred at room temperature for 15 minutes. Water (1.8 mL) was then added and the solution was stirred at room temperature for 15 minutes. Anhydrous magnesium sulfate was added to the solution and filtered. The filtrate was concentrated under reduced pressure. To a solution of the resulting residue in ethanol (50 mL) was added 10% palladium-carbon (200 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 89 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:2) to give the title compound (660 mg).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:29][C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][CH2:20][O:19][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=3[CH2:15][CH2:16][CH2:17][CH3:18])[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])[N:23]=2)=[CH:33][CH:32]=1
Reactant: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(OC(C)(C)C(=O)O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C
Yield: 75.5 %

Procedure:
A solution of 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-4-butylphenoxy}-2-methylpropionic acid ethyl ester (0.12 g, 0.258 mmol) in ethanol (3 mL) was treated with 2 N aqueous NaOH (0.64 mL), and heated at 55° C. for 8 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (25 mL) and water (20 mL) and acidified to pH 1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid (0.10 g, 88%). 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.3 Hz, 2H), 7.47 (t, J=7.8 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.81 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 4.24 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.60 (s, 6H), 1.51 (penta, J=7.6 Hz, 2H), 1.39-1.26 (m, 2H), 0.91 (t, J=7.3 Hz, 3H), MS (ES) m/e 514 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]#[C:14][CH:15]([NH:17][OH:18])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[N-:21]=[C:22]=[O:23].[K+]>C(OCC)(=O)C.O>[OH:18][N:17]([CH:15]([C:14]#[C:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:16])[C:22]([NH2:21])=[O:23]
Reactant: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)N(O)C(N)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
The N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]hydroxylamine prepared in step 3 above was taken up in ethyl acetate (36 kg) and cooled to 5° C. A solution of freshly prepared potassium isocyanate (10 kg) in water (18 kg) was slowly added and the exotherimic reaction was maintained below 10° C. The reaction mixture was agitated for 30 min. The layers were separated and the organic phase was dried over MgSO4 and filtered. The filtrate was diluted with heptane (58 kg) and agitated for one hour. The resulting crude product was filtered, dissolved in 45° C. ethyl acetate (42 kg). PWA carbon (0.5 kg) and Ultra Norit C (0.5 kg) were added and the mixture was agitated for 30 minutes and filtered. The combined filtrate and washings were diluted with heptane (68 kg) and filtered to provide N-hydroxy-N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]urea (2.94 kg). m.p. 139°-40° C.; 1H NMR (d6Me2SO) 1.33 (d, 3, J=7 Hz), 5.10 (q, 1, J=7 Hz), 6.55 (s, 2), 6.87 (m, 1), 7.03 (m, 1), 7.13 (m, 3), 7.25 (t, 2, J=8 Hz), 7.37 (t, 1, J=8 Hz), 9.33 (s, 1) ppm; mass spectrum m/e (rel intensity) 332 (80, M+ +NH4), 315 (75, M+ +H), 289 (80), 272 (100). Analysis calculated for C17 H15FN2O3 : C, 64.95, H, 4.81, N, 8.91; found: C, 64.67, H, 4.76, N, 8.81.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:54])/[C:10](/[C:52]#[N:53])=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[C:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH:23]=[C:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH:21]=2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[C:10](\[C:52]#[N:53])/[C:9]([O:8][CH3:7])=[O:54])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH:25]=1)[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6]
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C(\C#N)C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Reactant: C=C(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOc1cc(COc2ccc(/C=C/C(=O)OC)cc2OC)cc(COc2ccc(/C=C(\C#N)C(=O)OC)cc2OC)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
0.32 ml (2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 2 ml N,N-dimethylformamide (DMF) were added dropwise to a solution of 0.2 ml (1.9 mmol) 2-methylacrylic acid in 2 ml DMF. After addition of 2 mg phenothiazine, 60 mg tetrabutylammonium iodide and 1.1 g (1.6 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy]-3-methoxyphenyl]-2-cyanoacrylic acid methyl ester in 7 ml DMF the resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into an ice cold 1 M HCl solution. The aqueous phase was extracted three times with ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. The crude product was filtered through a thin silica gel layer. (eluent: ethyl acetate). The filtrate was evaporated to dryness and recrystallized from ethanol to yield 0.35 g (30%) of 2-methylacrylic acid 6-[3-[2-methoxy-4-[2-cyano-(E)-2-(methoxycarbonyl)vinyl]phenoxymethyl]-5-[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxymethyl]phenoxy]hexyl ester as slightly yellow crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[CH:6][C:5]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29].OS([O-])(=O)=O.[K+]>>[CH2:9]([N:8]1[C:4]([NH:3][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[N:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 520 mg, 13 mmol) was added portionwise to a suspension of ethyl 5-amino-1-benzylpyrazole-4-carboxylate (2.2 g, 9 mmol) in anhydrous THP (30 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h then 1-fluoro-2-nitrobenzene (1.26 g, 9 mmol) was added and the resultant deep purple suspension was stirred at room temperature for 18 h. 1 M KHSO4 was added to quench the reaction and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.3 M KHSO4, sat. NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant 75% pet. ether/25% ethyl acetate) to yield ethyl 1-benzyl-5-(2′-nitrophenylamino)pyrazole-4-carboxylate (2.5 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]2[C:7](=[CH:8][C:9]([C:17](=[O:20])NC)=[CH:10][CH:11]=2)[N:6]=1.S(=O)(=O)(O)[OH:27]>O>[C:17]([C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:16])[N:14]([CH3:15])[C:5]([CH2:4][C:3]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])=[N:6]2)=[CH:11][CH:10]=1)([OH:20])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CNC(=O)c1ccc2c(=O)n(C)c(Cc3ccc(Cl)cc3Cl)nc2c1
Solvent: O
Product: Cn1c(Cc2ccc(Cl)cc2Cl)nc2cc(C(=O)O)ccc2c1=O
Temperature: 100 °C
Reaction time: 7 h
Yield: 81.2 %

Procedure:
2-(2,4-Dichlorobenzyl)-3-methyl-7-(methylcarbamoyl)-4(3H)-quinazolinone (0.88 g) in a mixture of concentrated sulfuric acid (2.0 g) and water (2.0 g) was stirred at 100° C. for 7 hr. After cooling of the reaction mixture, water (5 ml) was added. The precipitate was collected by filtration, washed with methanol and dried to give the objective compound (0.69 g) as white crystals.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([Cl:18])[CH:12]=1)=[O:7])(C)(C)C.Cl[C:21]1C=C(C=C(C)N=1)C(O)=O.N(C(OC(C)(C)C)=O)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:18][C:13]1[CH:12]=[C:11]([C:10]2[O:19][C:6](=[O:7])[N:8]([CH3:21])[N:9]=2)[CH:16]=[C:15]([CH3:17])[N:14]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)cc(Cl)n1
Agent: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C)c(=O)o2)cc(Cl)n1
Yield: 45 %

Procedure:
Step-1: t-Butyl-2-(2-chloro-6-methylisonicotinoyl)hydrazinecarboxylate: To a stirred solution of 2-chloro-6-methylisonicotinic acid (4.0 g, 23.3 mmol) in DMF (40 mL) was added successively tert-butyl hydrazine carboxylate (3.0 g, 23.3 mmol), TBTU (6.0 g, 18.6 mmol) and DIPEA (12.2 mL, 69.9 mmol). After stirring for 12 hat RT, water (20 mL) was added to the reaction followed by ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 3.0 g (45%) of the title compound as white solid. 1HNMR (400 MHz, CDCl3) δ 8.65 (s, D2O exchangeable, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 6.77 (s, D2O exchangeable, 1H), 2.59 (s, 3H), 1.53 (s, 9H); GC-MS (m/z) 185 (M)+
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[N:51][CH:52]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.C(C1C=CC=CC=1)C.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O.O>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:10]2[N:9]=[C:8]([C:7]3[C:2]([NH:46][C:47]4[CH:52]=[N:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=4)=[N:3][CH:4]=[C:5]([C@H:34]([N:36]4[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:43])=[O:44])[CH2:38][CH2:37]4)[CH3:35])[CH:6]=3)[N:13]=[C:12]([CH3:14])[N:11]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
(R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (19.64 g, 30.9 mmol) and 5-amino-2-methoxypyridine (4.13 mL, 33.3 mmol) were dissolved in THF (300 mL) in a 2-necked round bottomed flask equipped with a stirbar and a dropping funnel. To the dropping funnel was added lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran/ethylbenzene (Acros; 96.0 mL, 96 mmol) via cannula, and the reaction flask was cooled in an ice water bath under nitrogen. Then, the LiHMDS solution was added to the reaction mixture dropwise over 20 min. The reaction mixture was subsequently stirred for 30 min and saturated ammonium chloride (40 mL) was then added dropwise via the dropping funnel, followed by water (200 mL). The reaction was warmed to room temperature and diluted with EtOAc (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatogtraphic purification of the residue (silica gel, 75:1 DCM/MeOH to 50:1 DCM/MeOH to 50:1 DCM/2N ammonia in MeOH to 40:1 DCM/2N ammonia in MeOH) provided (R)—N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (18.47 g).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=O)=[O:5].[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[NH2:13].O>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1C>[F:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:12]=1[N:13]1[C:7](=[O:6])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC1=C(C)C(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1=C(C)C(=O)N(c2ccc(Cl)cc2F)C1=O

Procedure:
A mixture of 126 g (1.0 mol) of dimethylmaleic anhydride, 145.5 g (1.0 mol) of 2-fluoro-4-chloroaniline and 2 g of 4-dimethylaminopyridine is heated under reflux in 800 ml of o-xylene for 16 hours using a water separator. The whole is then evaporated to dryness in vacuo and the residue is dissolved in a 1:1 mixture of ethyl acetate:ether and washed with each of 1N hydrochloric acid, 1N sodium hydroxide solution and water. After drying over sodium sulphate and evaporating off the solvent, the residue (227.5 g) is recrystallised from methanol. In this manner there are obtained 211.1 g (84% of the theoretical yield) of the title product in the form of colourless crystals which melt at 96°-97°.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN1CCOC(=O)OCC1
Yield: 239.2 %

Procedure:
The procedure of Example 1 was followed using N-butyl diethanolamine (13.5 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a yellow/brown oil product (12.9 g, 82%).