Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br-].[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>CN(C)C=O>[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[N:34][C:33]=1[CH2:43][CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:49](/[CH:50]=[CH:11]\[CH2:10][CH:5]2[O:4][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:52][CH:53]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C\CC2OCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Sodium hydride (60% in oil, 0.78 g) was added in limited amounts, at room temperature, to a solution of [2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (8.9 g) in N,N-dimethylformamide (100 ml). The mixture was stirred for 30 minutes at the same temperature range, to which was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g). The mixture was stirred for 15 minutes at room temperature, then for 5 hours at 70° C. The reaction mixture was poured into ice-water, which was acidified with 2N HC1,, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The residue was purified by means of a silica gel column chromatography. From the fractions eluted with hexane - ethyl acetate (3:1), (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane (5.1 g, 77%) was obtained as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[Cl:12][C:13]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16].ClCCl>CN1CCCC1=O>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:18]([NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:13]=1[Cl:12])=[O:19]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Yield: 22.7 %

Procedure:
150 mg (1 mmol) of 3,4-diaminobenzoic acid were dissolved in 2 ml of N-methyl-2-pyrrolidinone and, at 0° C., 1 ml (1.2 mmol) of the 2-chloro-4-fluorobenzoyl isocyanate/dichloromethane solution prepared in stage a was added. The resulting precipitate was filtered off with suction. The crude mixture (500 mg) was purified by column chromatography (dichloromethane/methanol=98/2 to 93/7). 80 mg (25%) of the desired product were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][NH:27]1.C(#N)C>C(Cl)Cl>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][N:27]2[CH2:28][CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26]2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: c1cc(OCCCN2CCc3ccccc3C2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 1,2,3,4-tetrahydroisoquinoline and acetonitrile essentially as described above in example 48 except that the crude product is dissolve in DCM and purified by using a step gradient of 50% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=96%, [M+H]+=391.
Reaction SMILES: [Cl:1][CH:2]([Si:4]([Cl:7])(Cl)[Cl:5])[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>>[Cl:1][CH:2]([Si:4]([Cl:7])([Cl:5])[C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CC(Cl)[Si](Cl)(Cl)Cl
Reactant: Fc1ccc([Mg]Br)cc1
Product: CC(Cl)[Si](Cl)(Cl)c1ccc(F)cc1

Procedure:
In the same apparatus and procedures as Example 6 were reacted 10.6 g (0.051 mol) of (α-chloroethyl)trichlorosilane and 26 ml of 4-fluorophenylmagnesiumbromide (2.0 M in diethylether) to give (α-chloroethyl)dichloro(4-fluorophenyl) silane.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=C)[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:23])([F:22])[F:21])=[C:4]2[CH2:3]1.C[N+]1([O-])CC[O:37]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:32][C:2]1([CH3:1])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:37])[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:21])([F:23])[F:22])=[C:4]2[CH2:3]1
Reactant: C=Cc1ccc2c(c1)C(C)(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 94 %

Procedure:
To a mixture of 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 1E, 0.036 g, 0.082 mmol) and NMO in water (0.017 mL, 0.082 mmol) in THF (1.5 mL) at room temperature was added osmium tetroxide in water (0.013 mL, 1.65 μmol). The reaction mixture was stirred at room temperature for 7 hours. A solution of sodium periodate (0.026 g, 0.124 mmol) in water (1 mL) was added via syringe. The resulting cloudy reaction mixture was stirred overnight at room temperature concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.034 g, 0.078 mmol, 94% yield) as a tan solid. The product had an HPLC ret. time=3.51 min. (condition A); LC/MS M+1=439.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[O-:13][C:14]#[N:15].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]([NH2:15])=[O:13])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
4-aminophenol (45 g, 0.4123 mol) was charged in water and acetic acid mixture (9:1) (450 vol) to obtain a clear solution. To this clear solution was added drop wise previously prepared solution of sodium cyanate (29.48 g, 0.45358 mol) in water over a period of 1 hour. The reaction mass obtained was stirred for 6 hours at ambient temperature and filtered to obtain solid. The solid was washed with water and vacuum dried to obtain the desired product, i.e., 1-(4-hydroxyphenyl)urea (48 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15]([C:18]1[O:22][CH:21]=[N:20][C:19]=1[CH3:23])(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]([C:18]1[O:22][CH:21]=[N:20][C:19]=1[CH3:23])([OH:17])[CH3:16]
Reactant: CC(=O)c1ocnc1C
Reactant: COc1ccccc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccccc1C(C)(O)c1ocnc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-Bromoanisole (4.86g) in anhydrous diethylether (10 ml) was added dropwise to a stirred solution of n-butyllithium (2.5M solution in hexane, 10.4 ml) in diethylether (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 45 minutes, 5-acetyl-4-methyloxazole (2.5g) in diethylether (loml) was added dropwise. After a further 1 hour at -70° C. the reaction mixture was allowed to warm to room temperature and was stirred overnight. Saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were further processed to give the title compound as a white solid, m.p. 74-75° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[CH2:7]2.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1>O>[CH:22]1[CH:21]=[CH:20][C:19]2[S:15][N:16]=[C:17]([N:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[CH:5]=[C:6]5[CH2:7][C:8](=[O:14])[NH:9][C:10]5=[CH:11][C:12]=4[Cl:13])[CH2:28][CH2:29]3)[C:18]=2[CH:23]=1
Reactant: O=C1Cc2cc(CCBr)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Temperature: 99 °C
Reaction time: 1.17 h

Procedure:
To de-ionized water (1.5 Lit), was added 5-(2-bromoethyl)-6-chloro-oxindole (75 g) and 1-(1,2-benzisothiazol-3-yl)piperazine (132 g) at 30-35° C. The mixture was slowly heated under stirring to 98-100° C. over 60-80 minutes. The resultant mass was stirred for 4-5 hours at 98-100° C. After completion of reaction as monitored by HPLC, the suspended solid material was filtered at 98-100° C. The wet cake so obtained was suspended in de-ionized water (1.5 Lit) and heated to 90-95° C. and further maintained at this temperature for 30 minutes. The solid suspension was filtered at 90-95° C. The wet cake was further added to isopropyl alcohol (1.5 Lit) and the resultant mass was heated to reflux and maintained at reflux for 1 hour. The mass was further cooled to 30-35° C. and stirred for 2 hours at 30-35° C. The solids were filtered and washed with isopropyl alcohol (75 ml) and dried under vacuum at 50-55° C. for 7-8 hours till moisture content was not more than 1.0% w/w.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[N:12]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=3)=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.25 h

Procedure:
To a solution of the compound obtained in Example 29 (3) (0.0457 g) in N,N-dimethylformamide (1.4 ml), 60% sodium hydride (0.006 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 15 minutes, followed by addition of 4-fluorobenzyl bromide (0.02 ml), and the mixture was stirred for 1 hour. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.0403 g of the desired product as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[O:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[O:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Reactant: c1ccc(OC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(CN1CCC(Oc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-phenoxy-piperidine according to the method described in Example 142b. Melting Point: 206-208° C. (diethylether)
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12].C(I)[I:14].C(ON=O)CC(C)C>C(Cl)(Cl)Cl>[I:14][C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12]
Reactant: CC(C)Cn1cnc(C#N)c1N
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1cnc(C#N)c1I
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 5-amino-1-isobutyl-1H-imidazole-4-carbonitrile S10 (410 mg, 2.5 mmol, 1 equiv) and CH2I2 (2 mL) in CHCl3 (25 mL) at 80° C. was added a solution of isoamylnitrite (1.36 mL, 10.2 mmol, 4.0 equiv) in CHCl3 (5.0 mL) over 20 min. The reaction was heated for additional 30 min, then cooled to 25° C. and concentrated in vacuo. Purification by silica gel column chromatography (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (536 mg, 78%) as an orange solid: 1H NMR (CDCl3, 600 Hz) δ 0.92 (d, J=7.2 Hz, 6H), 2.12 (non, J=10.2 Hz, 1H), 3.76 (d, J=7.8 Hz, 2H), 7.62 (s, 1H); 13C NMR (CDCl3, 150 Hz) δ 19.6, 29.5, 56.1, 82.7, 114.6, 122.5, 141.3; LRMS (APCI+): calcd C8H111N3 [M+H]+ 276.1. found 276.0.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[NH:7][C:6]1=[O:12]
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Reactant: C#C[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a degassed solution of 5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline (1.Og,4.Ommol) in 20 ml of DMF and 20 ml of triethylamine was added trimethylsilylacetylene (1.6ml,12mmol), 50mg of triphenylphosphine, 20mg of palladium(Il)acetate, and 1 mg of cuprous(I)iodide. The mixture was stirred under nitrogen, at 70° C.. After 7h additionally 0.4ml of trimethylsilylacetylene was added and hating continued for 4h. Then the mixture was evaporated in vacuo and the residue extracted with 100 ml of dichloromethane and 100 ml of water. The organic layer was washed twice with 100 ml of water dried over anhydrous sodium sulfate, treated with charcoal, filtered through a pad of celite, and evaporated. The residue was triturated with ether/petroleum ether (1:1) and filtered off and dried giving 0.50g (46%) of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo5-trimethylsilylethynyl-quinazoline.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:28]([N:24]1[C:23]([C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([CH:9]5[CH2:8][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:10]5)[CH:32]=[CH:31][C:14]=4[C:15]=3[N:16]=2)=[N:27][CH:26]=[N:25]1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)CO)C3)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester (147 mg, 0.31 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen was treated dropwise with a 1M solution of LiAlH4 in THF (0.47 mL, 0.47 mmol) and the mixture was stirred for 15 minutes then allowed to warm to RT. After 1.5 hours the mixture was cooled to 0° C. and quenched by cautious addition of water. EtOAc was added and the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was dissolved in DCM (20 mL) and treated with 4N HCl/dioxan (1 mL). The resulting solid was filtered off, washed with ether and dried to give 427 (142 mg, quant.). LCMS: RT=7.54 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 10.61 (1 H, s), 8.32 (1H, d, J=8.21 Hz), 8.07 (1 H, s), 7.22-7.16 (1 H, m), 7.06 (1 H, d, J=1.80 Hz), 5.81-5.72 (1 H, m), 4.55 (1 H, td, J=10.55, 4.79 Hz), 4.38-4.26 (3 H, m), 4.16-3.92 (3 H, m), 3.46-3.37 (5 H, m), 1.53-1.48 (6 H, m), 1.27-1.14 (6 H, m)
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.[F:10][C:11]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[OH:38])[CH2:31][CH2:30]3)[C:23]2=[O:39])=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1.O>[CH:6]1([NH:9][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([N:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[OH:38])[CH2:31][CH2:30]4)[C:23]3=[O:39])[C:19]([CH3:21])=[CH:20][C:11]=2[F:10])[CH2:8][CH2:7]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C

Procedure:
Isopropylmagnesium chloride (5.19 mL of a 2.0 M solution in THF) was added over 20 min of a solution of cyclopropylamine (1.830 mL) and methyl 2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate (Example 318f, 1.063 g) in THF (20 mL) stirring at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2 M HCl were cautiously added and the volatiles removed in vacuo. The residue was basified with saturated aqueous sodium bicarbonate solution and extracted into DCM. The organics were combined, dried (MgSO4) and evaporated to give the subtitle compound (1.189 g).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:54][O:55][NH:56][CH3:57]>CN(C=O)C>[CH3:54][O:55][N:56]([CH3:57])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (10 g, 42.0 mmol) was dissolved in DMF (200 mL) and Hunig's Base (20.54 mL, 118 mmol). Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP, 27.9 g, 63.0 mmol) and N-methoxy-N-methylamine hydrochloride (4.51 g, 46.2 mmol) were added to the reaction flask, and the resulting reaction mixture was stirred at 25° C. overnight. Crude reaction mixture was concentrated and purified on a silica gel column (340 g cartridge 0-10% EtOAc/Hexanes gradient) to afford N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide. 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 3H), 3.57 (s, 3H), 5.95 (t, J=52.9, 2.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=7.7 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:16][O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:17][C:18]([C:20]1[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=1)=[O:19])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
The mixture of 5-methoxy-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (80) (458 mg, 1.2 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (81) as a pale brown solid (448 mg, 100%).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=N.Cl.CC[O:45]C(C)=O.O>CO>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:20])=[O:21])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=[O:45]
Reactant: CCOC(C)=O
Reactant: COC(=N)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1

Procedure:
To 0.586 g of 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt, product of example 41 c), in methanol (10 ml) were added 6 N HCl (3 ml) and the mixture was refluxed for 1 h until the reaction was complete according to TLC analysis (eluent: CH2CL2/EtOAc: 4/1). The mixture was poured into water and the product extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 4/1). Combination of the purified fractions and evacuation in vacuo afforded 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as an off-white solid. ISN mass spectrum, m/e 564.2 (M−1 calculated for C27H27N5O7S: 564).
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]1([NH:27][CH2:28][C:29]([NH2:31])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][C:29]([NH2:31])=[O:30])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: NC(=O)CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (370 mg, 1 mmol), 2-phenylamino-acetamide (200 mg, 1.33 mmol) and K2CO3 (300 mg, 2.2 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. The mixture was poured into water (30 ml), extracted with ethyl acetate (10 mL×3). The organic phase was separated, dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 60 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetamide. MS: [M+H]+=439.8.