Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH:15]([OH:29])[C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[CH:27][C:25](=O)[NH:24][C:22]2=[O:23])[CH2:18][CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31]>O>[C:7]([CH:15]([OH:29])[C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[CH:27][C:25](=[S:31])[NH:24][C:22]2=[O:23])[CH2:18][CH2:17]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(c1ccccc1)C(O)[C@@H]1CC[C@H](n2ccc(=O)[nH]c2=O)O1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)C(O)[C@@H]1CC[C@H](n2ccc(=S)[nH]c2=O)O1
Yield: 157.8 %

Procedure:
Into 50 ml of pyridine were dissolved 3.16 g of 5'-benzoyl-2',3'-dideoxy-uridine and 0.22 g of distilled water. Then, after added 2.67 g of phosphorus pentasulfide at room temperature under stirring, the mixture was refluxed for 3 hours. After the completion of reaction, the solids deposited by allowing to cool were collected by filtration, which were washed with small amount of pyridine. The pyridine filtrate obtained was concentrated to dryness and the residue was extracted with chloroform to separate 3.15 g of 5'-benzoyl-2',3'-dideoxy-4-thio-uridine(yield: 95%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](Br)[CH:9]=2)[NH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH:3]=[C:2]2[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: Cc1c[nH]c2ccc(Br)cc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 90 %

Procedure:
3-(3-Methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXXI (656 mg, 90% yield) was prepared from 3-methyl-5-bromoindole using the procedure described above for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (see Example 14).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10](=[O:17])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(O[NH2:33])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:33][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]1=[O:17]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(-c2ccccc2)c2c1CCCC2
Product: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
4-Phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. MS (APCI+) M/Z 242 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O>>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]1=[O:15]
Reactant: CN1CCCC1=O
Reactant: O=C1Cc2ccccc2N1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCC1=C1C(=O)Nc2ccccc21
Reaction time: 0.25 h

Procedure:
Under nitrogen, N-methyl-2-pyrrolidone (3 ml) was cooled in an ice-water bath. Phosphorus oxychloride (0.91 ml, 0.01 mole) was added dropwise. After stirring 15 minutes, the bath was removed and 2(1H,3H)-indolone (oxindole, 1.3 g, 0.01 mole) in 3 ml. additional N-methyl-2-pyrrolidone (3 ml) was added dropwise. The temperature rose to 40° C. The reaction mixture was then heated at 80° for 16 hours, cooled and partitioned between ethyl acetate and water. The aqueous layer was washed with fresh ethyl acetate, basified to pH 9 with 6N NaOH and clarified by filtration. The filtrate was extracted with ethyl acetate. The extract was evaporated to dryness and the resulting title product triturated with ethyl acetate, 0.24 g, m.p. 268°-271° C. (dec). See Ind. J. Chem. 12: 940-942 (1974).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N+:8]([O-:31])=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccco2)c2cc(Cl)ccc2N(CCCl)C(CCl)C1
Yield: 69.9 %

Procedure:
A solution of 17.8 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 250 ml of methylene chloride is heated under reflux with 10.4 g of 3-chloroperbenzoic acid for 2 hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked up in the customary manner, and the reaction product is isolated and then purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and crystallised from methanol. 13 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine-4-oxide are obtained. Melting point: 158° to 159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].C(N(C(C)C)CC)(C)C.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH2:53]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:53][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 42.1 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (300 mg, 0.54 mmol) in CH2Cl2 (30 mL) were added diisopropyl ethyl amine (0.2 mL, 1.14 mmol), N,N-dimethyl-ethylenediamine (0.3 mL, 2.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (131 mg, 42%). LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) δ 2.19 (s, 6H), 2.35 (s, 3H), 2.42 (m, br, 2H), 3.24 (m, br, 2H), 4.16 (s, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.83 (s, 1H), 7.99 (d, 1H).
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:14])[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=O)C.C1COCC1.O.[OH-].[Li+]>O>[Cl:14][C:13]1[C:8]2[C@H:7]([CH3:15])[CH2:6][CH:5]([OH:4])[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC(O)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (11.86 g, 52.33 mmol) in 2:1 THF:H2O (270 mL) was cooled to 0° C. and treated with lithium hydroxide hydrate (3.95 g, 94.2 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was concentrated and diluted with water and acidified with 6N HCl to a pH of 6. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried MgSO4, filtered, and concentrated. The crude residue was chromatographed (Biotage 65) eluting with 30-50% EtOAc/hexane to give (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09 g, 63%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([O:22]CC)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:14]1([N:10]2[C:8]3[N:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]=3[C:12]([CH3:13])=[N:11]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(C2CCCCC2)c2nc(C3CC3)cc(C(=O)O)c12

Procedure:
The title compound was prepared in the same manner as described for intermediate 52 using ethyl 6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (820 mg, 2.5 mmol) and sodium hydroxide (7.51 mL, 7.51 mmol). The final product was collected as a solid, 0.660 g (88%). LCMS E-S (M+H)=300.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.11 (m, 4 H), 1.16-1.31 (m, 1 H), 1.36-1.55 (m, 2 H), 1.70 (d, J=12.38 Hz, 1 H), 1.80-1.98 (m, 6 H), 2.32 (m, J=7.80, 7.80, 5.05, 4.86 Hz, 1 H), 2.55 (s, 3 H), 4.60-4.73 (m, 1 H), 7.40 (s, 1 H), 13.71 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH3:12])[N:3]=1.Cl[C:14]1N=C(Cl)C(C#N)=C(NC)[N:15]=1.CN>>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH3:14])[N:3]=[C:4]([NH:11][CH3:12])[N:5]=1
Reactant: CNc1nc(Cl)nc(Cl)c1C#N
Reactant: CNc1nc(Cl)c(C#N)c(Cl)n1
Agent: CN
Product: CNc1nc(Cl)c(C#N)c(NC)n1

Procedure:
The crude reaction product of Example IX, approximately 19% 4,6-dichloro-2-methylamino-5-pyrimidinecarbonitrile and 72% 2,4-dichloro-6-methylamino-5-pyrimidinecarbonitrile, was treated with aqueous 40% methylamine in the manner of Example V, to give 4-chloro-2,6-bis(methylamino)-5-pyrimidinecarbonitrile; mp, 281°-284° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N>O>[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12]([N:9]2[CH2:10][CH2:11][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)=[O:13])[CH2:15][CH2:16]1)(=[O:26])[CH3:25]
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: O
Product: CC(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21

Procedure:
0.25 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline and 1.05 ml of acetic anhydride are placed in a 10 ml round-bottomed flask. The reaction medium is brought to reflux for two hours and then a solution of ammonia in water is added at 0° C. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.284 g of 1-acetyl-4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[OH:11][C:4]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:16][CH:17]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:1]
Reactant: C[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
) CH3MgCl, 22% (w/w)/THF (0.003 mol) was added dropwise to a cooled (0° C.) solution of (±)-N-(4-benzoylphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.003 mol) in THF (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. More CH3MgCl, 22% w/w/THF (0.003 mol) was added and the mixture was stirred for 30 minutes at 0° C. Extra CH3MgCl, 22% (w/w)/THF (0.003 mol) was added and the reaction mixture was stirred for 30 minutes at 0° C. The mixture was allowed to warm to RT for 30 minutes, then cooled again to 0° C. Water was added. This mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The crude oil was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 0.5 g(50%) of (±)4,5-dihydro-N-[4-(1-hydroxy-1-phenylethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 51).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C)s1
Product: Cc1ccc(C(=O)C=CN(C)C)s1

Procedure:
A mixture of 56.08 g of 2-acetyl-5-methylthiophene and 250 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16 hours. The mixture was cooled in an ice bath and filtered giving 66.82 g of the desired compound, mp 118°-121° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CN(C=O)C>[C:11]1(=[O:21])[N:15]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ccccc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 40 °C
Yield: 85.6 %

Procedure:
A solution of 2-bromoacetophenone (30.0 g, 151 mmol) in DMF (120 ml) was treated with potassium phthalimide (30.8 g, 166 mmol) portionwise at ambient temperature, and then heated to 40° C. for 3.5 hr. The cooled mixture was poured into water (600 ml) and extracted with chloroform (300 ml then 100 ml). The combined organic phases were washed with sodium hydroxide (200 ml, 0.2 N), water (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The resulting cream solid was suspended in ether (100 ml), recovered by filtration, washed with ether (100 ml) and dried in vacuo to yield pure 2-phthalimido-acetophenone as a white solid (34.3 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1COCC1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:30]3[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(-c3cccnc3F)c3ccccc32)cc1

Procedure:
Reflux a mixture of 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (1.33 g, 3.01 mmol, 1 equiv), 2-fluoropyridine-3-boronic acid (Frontier Scientific®; 0.47 g, 3.3 mmol, 1.1 equiv), sodium carbonate (2M in H2O; 3.0 mL, 6.0 mmol, 2.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (62 mg, 0.080 mmol, 0.025 equiv) in THF (15 mL) under N2 for 2 h (reaction mixture turned very dark when heated). Rotary evaporate the reaction mixture. Dissolve the resultant residue in Et2O (15 mL) and wash with H2O (5 mL). Back-extract the aqueous layer is with Et2O (5 mL). Dry the combined organic layers with (anhydr Na2SO4), and rotary evaporate (40° C.) giving the crude 4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid methyl ester as a brown foam. Dissolve this material in THF (10 mL) and add 5M aq NaOH (2 mL). After 18 h, add H2O (25 mL) and Et2O (25 mL). Separate the aqueous layer and extract the organic layer with H2O (25 mL). Combine the aqueous layers and wash with Et2O (25 mL). Acidify this aqueous layer with 1M aq HCl (8 mL) to pH 5 causing much precipitation. Extract this mixture with CHCl3 (1×50 mL, 2×25 mL). Dry the combined organic layers (anhydr Na2SO4) and rotary evaporate (40° C.) yielding 673 mg (56.3%) of 4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid as a brown powder. MS (m/e): 396.94 (M+1); 394.99 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH2:30]([O:37][C:38](=[O:48])[CH2:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:41]([N:40]([CH2:39][C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:48])[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: O=C(CNCc1ccccc1)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a solution of (2R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (5.14 g) in dichloromethane (50 ml) was added triethylamine (8.49 ml), N-benzylglycine benzyl ester hydrochloride (5.08 g), and 2-chloro-1-methylpyridinium iodide (4.89 g) under ice-bath cooling. After being stirred at room temperature 90 minutes, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 ml) and water (50 ml) were added to the residue with stirring, adjusted pH 1 with diluted hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100 g) using a mixed solvent of toluene and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give N-benzyl-N-(benzyloxycarbonylmethyl)-(2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propionamide (8.57 g) as a syrup.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C@:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C@:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)[C@@](C)(F)C(=O)O
Product: CCOC(=O)[C@@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (S)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Light yellow oil (>98%). MS: m/e=505(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[C:41]([CH3:43])[O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[C:41]([CH3:43])[O:40][N:39]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)C)cn4COCC[Si](C)(C)C)c3ccc(Cl)cc32)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was allowed to stir for 30 min. 3-(Bromomethyl)-5-methylisoxazole (31.9 mg, 181 μmol) was added and the mixture was warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20%-50% ethyl acetate in hexanes 15 min) to give 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 153 μmol, 93.0%) as a yellow powder. MS (M+Na)+=602; 1H NMR (CDCl3) δ: 9.23-9.32 (m, 1H), 8.48 (s, 2H), 8.18-8.30 (m, 1H), 7.54-7.61 (m, 1H), 7.27 (m, 2H), 5.70-5.76 (m, 2H), 5.65-5.69 (m, 2H), 4.38-4.56 (m, 1H), 3.52-3.65 (m, 2H), 2.31-2.41 (m, 3H), 1.35-1.47 (m, 6H), 0.89-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24]>[N+](C1C=CC=CC=1)([O-])=O>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:20]2[CH:21]=[C:16]([F:15])[C:17]([O:23][CH3:24])=[CH:18][C:19]=2[F:22])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1cc(F)ccc1F
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(F)c(C(=O)c2ccc(Br)cc2)cc1F
Temperature: 25 °C

Procedure:
75 ml of nitrobenzene are cooled in an ice bath and treated in succession with 17.3 g of aluminium chloride and 4-bromobenzoyl chloride in 25 ml of nitrobenzene at a maximum 6° C. The mixture is stirred for 10 min., whereupon 15.7 g of 2,5-difluoroanisole are added in such a manner that the temperature does not exceed 6° C. The solution is left to warm to room temperature overnight, then poured on to ice-water and extracted with methylene chloride. The organic phase is washed with water and 10% sodium chloride solution, dried over sodium sulphate and concentrated. After crystallization from cyclohexane there are obtained 28.4 g of (4-bromo-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone.
Reaction SMILES: [CH3:1]C(OC(N(C)C)N(C)C)(C)C.[CH3:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([CH3:23])[C:15]=1[Br:24]>CN(C=O)C.[Zn]>[Br:24][C:15]1[C:16]([CH3:23])=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:1][NH:20]2
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1Br
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]ccc2c1Br
Temperature: 122.5 °C
Yield: 29 %

Procedure:
Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol) is added at room temperature to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml). The reaction mixture is heated at 120-125° C. under N2 for 5 hours or until starting material is mostly consumed according to TLC. The reaction mixture is allowed to cool to room temperature, poured into water (300 ml), and extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material is carried on to the next step without purification. The crude mixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0° C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions. After complete addition, the reaction mixture is heated at 110° C. for 4 h. Zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml×3). The combined extracts are dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica get (EtOAc/Hexane 1:20) to obtain 4-bromo-5-methylindole (5.3 g) (21) as a light purple oil.