Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(Cl)cc12
Temperature: 120 °C
Reaction time: 6 h

Procedure:
0.771 g (24 mmol) of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 5.03 g (24 mmol) of 5-chloro-3-methoxycarbonyl-1H-indole in 120 cm3 of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere. After the reaction mixture has been stirred for 0.5 hour at a temperature in the region of 40° C., 3.94 g (24 mmol) of 4-chloroquinoline are added. After stirring for 6 hours at a temperature in the region of 120° C., the reaction mixture is cooled to a temperature in the region of 20° C. and then poured into 400 cm3 of water and extracted with 500 cm3 of ethyl acetate. The organic phase is washed three times with 250 cm3 of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica gel (eluent: dichloromethane). After the fractions containing the expected product have been concentrated to dryness under reduced pressure, 2.5 g of 5-chloro-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-indole are obtained in the form of a sticky beige-colored solid, which is used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([OH:22])=O.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([Cl:25])=[O:22]
Reactant: O=S(Cl)Cl
Reactant: CC1(C2CCCC2)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC1(C2CCCC2)Cc2cc(CC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
To a solution of (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetic acid (21.8 g., 0.0623 mole) in chloroform (150 ml) and dimethylformamide (1 drop) is added thionyl chloride (25 ml). The reaction mixture is heated at reflux for 3 hours, cooled and concentrated at reduced pressure. The crude (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetyl chloride, thus obtained, is dissolved in methylene chloride (75 ml) and added over 0.5 hour to a mixture of ether (100) ml) and methylene chloride (75 ml) which has been saturated with ammonia.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:54]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([C:63]3[CH:64]=[C:65]([CH:73]4[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]4)[N:66]4[C:71]=3[C:70]([NH2:72])=[N:69][CH:68]=[N:67]4)[CH:59]=[CH:60]2)=[N:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]([N:76]1[CH2:77][CH2:78][CH:73]([C:65]2[N:66]3[C:71]([C:70]([NH2:72])=[N:69][CH:68]=[N:67]3)=[C:63]([C:58]3[CH:59]=[CH:60][C:61]4[C:56]([CH:57]=3)=[N:55][N:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:62]=4)[CH:64]=2)[CH2:74][CH2:75]1)=[O:21])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (35.0 μL, 0.200 mmol, 2.0 eq.) was added to N-(tert-butoxycarbonyl)-L-proline (23.7 mg, 0.110 mmol, 1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.2 mg, 0.100 mmol, 1.0 eq), 1-hydroxybenzotriazole (13.5 mg, 0.100 mmol, 1.0 eq) and 1 mL of anhydrous DMF. The reaction was cooled to 0° C. and shaken for 30 minutes. Then to this mixture was added 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42.3 mg, 0.1 mmol, 1.0 eq.) in 1 mL of anhydrous DMF. The reaction was shaken for 5 minutes at 0° C. The reaction was slowly warmed to rt and shaken over night. The product was purified by acidic HPLC on a Sunfire column (5% to 90%, 12 min).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:22])=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Temperature: 25 °C
Yield: 114 %

Procedure:
In a flask 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.11 g, 8.74 mmol) was dissolved in dioxane (120 mL) and H2O (30 mL) and the mixture cooled at 0° C. Sufamic acid (5.09 g, 52.4 mmol) was added, followed by a solution of sodium chlorite (1.28 g, 11.4 mmol) and potassium dihydrogen phosphate (14.3 g, 104.9 mmol) in H2O (75 mL) via an addition funnel over 15 min. The mixture was allowed to warm to room temperature over 2 h. The resulting yellow solid was filtered off, washed with H2O and hexane and dried. The filtrate was then extracted with EtOAc, and the combined organics washed with brine, dried over MgSO4 and concentrated to give additional product. In total 3.71 g of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:23]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]([NH2:22])=[O:23])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OO
Reactant: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cnc(C(N)=O)nc2)cc1OC1CCCC1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of the compound of Example 14 (1.3 g) in ethanol (8 ml) was added hydrogen peroxide (40 vols, 15 ml) and 6M aqueous NaOH (6 ml). After 15 min, the reaction mixture was diluted with water (75 ml) and the white solid filtered off. Recrystallisation from acetonitrile furnished the title compound (200 g) as small white plates (mp 235-238° C.). Found C, 65.06; H, 6.09; N, 13.44. C17H19N3O3 requires C, 65.16; H, 6.1 1; N, 13.41%.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)N.[BrH:14].N([O-])=O.[Na+]>O>[Br:14][C:4]1[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1cc(F)cc(F)c1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(F)c(C(F)(F)F)c(Br)c1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A suspension of 3,5-difluoro-2-(trifluoromethyl)aniline (24, 1.0 g, 5.07 mmol) in a 48% aqueous HBr (8 mL) and H2O (8 mL) was stirred at −5° C. for 5 min. To the suspension, NaNO2 (350 mg, 5.07 mmol) was added in a 10 mL aqueous solution dropwise maintaining −5° C. The resulting mixture was stirred at −5° C. for 1 h then CuBr (1.09 g, 7.63 mmol) was added portion-wise and the resulting suspension was allowed to slowly warm to ambient temperature. After 4 hours, the resulting solution was extracted with hexanes (3×75 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, pure hexanes) to afford 1-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (25) as a light yellow liquid (1.01 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.34-7.28 (m, 1H), 6.99-6.85 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Mg]Br.CCOCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])([CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C)(O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (170 mg, 0.687 mmol) in THF (5 mL) at 0° C. was added 3.0M methylmagnesium bromide in ether (688 mL, 2.1 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water (2 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and the solvent was removed in vacuo to give an oil that was subjected to flash chromatography (silica gel, hexanes/ethyl acetate, 7:3) to afford 120 mg (66%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methylquinoline: 1H NMR (400 MHz, DMSO-d6) 7.54 (d, J=7.7, 1H), 7.50 (dd, J=7.7, 1.5, 1H), 7.14 (ddd, J=7.3, 7.3, 1.7, 1H), 7.04 (ddd, J=7.9, 7.9, 1.0, 1H), 5.14 (s, 1H), 3.69 (m, 2H), 1.87 (t, J=6.5, 2H), 1.46 (s, 9H), 1.37 (s, 3H).
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[C-:18]#[N:19]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[C:12]1([CH2:11][N:8]2[CH2:9][CH2:10][C@H:6]([C:18]#[N:19])[CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 60 °C
Yield: 109.3 %

Procedure:
(3R)-1-(phenylmethyl)-3-pyrrolidinyl methanesulfonate (12.9 g, 50.6 mmol) and tertrabytulamonium cyanide (25 g, 93.3 mmol) was mixed in DCM (20 mL) and refluxed at 60° C. for 6 h. The resulting solution was cooled down to room temperature and diluted with saturated sodium bicarbonate solution in water. The aqueous phase was extracted several times with toluene. The organic fractions was combined, washed with brine and concentrated to provide the title compound as an oil (10.3 g, quantit.) which was used without further purification: LC/MS (ES) m/e 187 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[C:6]1([S:12]([O:14][Na])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[C:6]1([S:12]([CH2:2][C:3]([NH2:5])=[O:4])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(O[Na])c1ccccc1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of α-bromoacetamide IV in anhydrous DMF, is added PhSO2Na at 0° C. The reaction mixture is stirred for 1 hour at room temperature and is then poured into water. The organic layer is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica gel column chromatography to give α-phenylsulfonylacetamide III.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]3[C:34]4[C:39]([CH:40]=[CH:41][C:26]2=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:21][CH:20]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]3[C:34]4[C:39]([CH:40]=[CH:41][C:26]2=3)=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:21][CH:20]=1)=[O:9])([CH3:2])[CH3:3]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C)Oc1ccccc1C(=O)O
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 75.1 %

Procedure:
2-Isopropoxybenzoic acid (36 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol), the title compound (36 mg, yield 75%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: S(O[CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:26]([CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2COS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of methyl 4-(2-mesyloxymethyl-5-chlorophenoxymethyl)-benzoate (628 mg; prepared in Reference Example 48.) in DMF (5.0 ml), sodium azide (530 mg) was added in a stream of argon. The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate. The impurity was filtered with celite. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=10:1) to give the title compound (404 mg) having the following physical data.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:20]([O:18][C:15]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Yield: 69 %

Procedure:
To a refluxed suspension of K2CO3 (32.8 g, 238 mmol) in methanol (180 mL) and CHCl3 (350 mL) was then added a mixture of methyl 2,5-dihydroxybenzoate (10.0 g, 59.5 mmol) and bromomethylbenzene (7.10 mL, 59.5 mmol) in methanol/CHCl3 (50 mL/25 mL) drop wise over 30 minutes. The resulting mixture was stirred at reflux for another 4 hours. After cooling down and filtration, the filter cake was washed with CHCl3 (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was redissolved in CHCl3 (200 mL), washed with HCl (1N) (100 mL×2). The organic was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (8:1) to give methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 69.0%) as a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]3=[N:13][C:14]([NH:16][C:17]([C@@H:19]4[CH2:24][O:23][CH2:22][CH2:21][NH:20]4)=[O:18])=[CH:15][N:10]3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:40](O)=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:26]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40](=[O:41])[N:20]1[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]1[C:17](=[O:18])[NH:16][C:14]1[N:13]=[C:11]2[N:10]([CH:15]=1)[CH:9]=[C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:12]2)([CH3:28])([CH3:25])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(Nc1cn2cc(-c3ccccc3)sc2n1)[C@@H]1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCOC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
Compound 16 (0.063 mmol), Boc-D-α-phenylglycine (0.126 mmol), and BOP (0.126) were added to dichloromethane (1.9 mL). Triethylamine (3.15 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was diluted in dichloromethane, washed sequentially with saturated solution of NaHCO3, water, and brine. The organic layers were gathered, dried, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC to give compound A22 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.41 (s, 2H), 1.44 (s, 7H), 1.83-2.09 (m, 1H), 2.64-3.90 (m, 4H), 4.33-4.68 (m, 1H), 5.19-6.09 (m, 2H), 7.29-7.45 (m, 9H), 7.50-7.582 (m, 2H), 7.60-7.64 (m, 1H); MS (ESI, EI+) m/z=562.29 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([O:11][C:12]2[CH:17]=[C:16](I)[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[CH:21]([CH3:23])[CH3:22])=[CH:6][N:5]=1)[CH3:2].[C:24]([Cu])#[N:25].O>CN(C=O)C>[NH2:10][C:8]1[C:7]([O:11][C:12]2[C:13]([CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:17]=2)[C:24]#[N:25])=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: N#C[Cu]
Reactant: CCNc1ncc(Oc2cc(I)c(OC)cc2C(C)C)c(N)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution of N2-Ethyl-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1.65 g, 4.12 mmol) in anhydrous DMF (10 ml) was added CuCN, and the reaction mixture was heated to 120° C. for 3 hrs. The reaction mixture was poured into water (200 ml) and the insoluble portion was collected by filtration. The solid was triturated with 10% MeOH/methylene chloride/0.1% NH4OH solution (100 ml) and filtered again. The filtrate was concentrated and flash chromatographed on silica (3% MeOH in methylene chloride with 0.1% NH4OH) to give 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.87 g, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([C:40]([OH:42])=[O:41])[CH:48]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3cccc(C(=O)O)c3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 3-carboxyphenylboronic acid replacing phenylboronic acid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[O:4]=[CH:5][C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1.C(O)C.Cl>O>[OH:4][CH:5]([C:6]1[CH:14]=[CH:13][C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(O)C#N)ccc1O
Temperature: 0 °C

Procedure:
Sodium cyanide (10.2 g) is dissolved in water (40 ml) and cooled to 0° C. A second solution comprising vanillin (15.5 g) and ethanol (30 ml) is added at 0° C. Now, concentrated hydrochloric acid (28.5 g 32%) is added to the mixture at 0 to +5° C. within 30 to 45 minutes and the dropping funnel is rinsed with water (10 ml). After confirming that the conversion has proceeded to a satisfactory level by HPLC, the mixture is worked up by extracting repeatedly with t-butyl methyl ether (3×50 ml). The collected organic phases are washed twice with 10% aqueous bisulfite (50 ml) and once with water (40 ml). Finally, the product solution is dried and the solvent is evaporated in vacuum to yield the crude product as a yellow oil, which crystallized on standing (mp 80-81° C.). If the already pure product needs further purification, it can be crystallized from ether/hexane (m.p82-83° C.).
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:7]1([CH2:2][C:3]([CH2:5][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH2:4])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: c1nc[nH]n1
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cn1cncn1)Cn1cncn1
Yield: 60.5 %

Procedure:
A mixture of 25 g (0.2 mol) of 3-chloro-2-chloromethyl-propene, 27.6 g (0.4 mol) of 1,2,4-triazole and 27.6 g (0.2 mol) of potassium carbonate in 200 ml of acetone is heated under reflux for 15 hours. After cooling, the mixture is filtered and the filtrate is concentrated in vacuo. The oily residue is chromatographed (silica gel 60, Merck, chloroform). 23 g (63% of theory) of 3-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-yl-methyl)-propene of melting point 52° C. are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.[F:59]C1C=C(N)C=CC=1F>>[F:59][C:5]1[CH:4]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]4)[CH:21]=[CH:20][C:19]=3[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=2)[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Reactant: Nc1ccc(F)c(F)c1
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(F)c(F)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-difluoro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 149.6 (dd), 147.5, 145.7, 144.7 (dd), 142.3, 142.2, 138.4 (dd), 135.3, 135.2, 134.4, 132.1, 127.0, 120.7, 120.5, 118.4, 117.9 (d), 117.7, 116.0 (dd), 111.4, 108.5 (d), 60.2, 29.2, 22.0, 18.9