Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]1.C(N(CC)CC)C>C(#N)C>[OH:21][CH2:20][C@@H:16]1[CH2:15][N:14]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6]2)=[O:4])[CH2:19][CH2:18][O:17]1
Reactant: OCC1CNCCO1
Reactant: O=C(CCl)N1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CN1CCO[C@H](CO)C1)N1CCc2ccccc21
Yield: 79 %

Procedure:
A microwave vial was charged with 1-(chloroacetyl)-indoline (compound 47; 390 mg, 2.00 mmol), hydroxymethylmorpholine (compound 54; 280 mg, 2.39 mmol), triethylamine (0.55 ml, 4.00 mmol) and acetonitrile (2 ml). The vial was sealed and irradiated for 30 min at 100° C. The crude mixture was purified by flash column chromatography (silica, DCM/MeOH 1:0 to 92:8). The product was obtained as a white solid (435 mg; yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][CH:6]([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC(C#N)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
First, 4.46 g of (3,4-dichlorobenzylidene)malononitrile was dissolved in 20 ml of tetrahydrofuran, and while stirring at room temperature, a suspension of 0.19 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloride acid was added and the mixture was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.15 g of (3,4-dichlorobenzyl)malononitrile (the intermediate (12)).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:9])[CH:3]=1
Reactant: NCC(=O)O
Reactant: Cc1cc(O)cc(=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cc(=O)n1CC(=O)O

Procedure:
178.7 g (1.4 mmol) of 4-hydroxy-6-methyl-2H-pyran-2-one are added, in portions at room temperature, to a solution of 106.4 g (1.4 mmol) of glycine in 1.4 l of a 1 N aqueous sodium hydroxide solution. The mixture is heated under reflux for 1 hour, the reaction medium is cooled and it is acidified with 500 ml of 3 N hydrochloric acid. The reaction medium is then concentrated to half the volume, the precipitate is filtered, it is washed with cold water and it is dried in an oven.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[OH:24])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[CH2:27]Br.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[O:24][CH2:27][C:26]([F:30])([F:29])[F:25])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3O)cccc2s1
Reactant: FC(F)(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A mixture of 211 mg (0.63 mmol) of 2-acetyl-4-(2-hydroxy-3-tert-butyl-5-methylphenyl)benzo[b]thiophene, 0.1 ml (132 mg, 0.81 mmol) of 1,1,1-trifluoro-2-bromoethane and 304 mg (0.94 mmol) of Cs2CO3 in 2.5 ml of dry DMF was heated at 60° C. in a pressure tube overnight. After cooling at room temperature, 10 mL of a 5/95 ethyl acetate/hexane solution was added and the remaining mixture was stirred for 5 minutes. The solution was filtrated through a silica plug (eluent: 5/95 ethyl acetate/hexane) and the solvents were removed under pressure. 188 mg (0.44 mmol, yield: 71%) of 2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thiophene was isolated as an oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 3.63 (m, 1H), 3.52 (m, 1H), 2.56 (s, 3H), 2.38 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O.O1CCOCC1>[C:35]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)n1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc), acetyl chloride (1.95 cc) in dioxane (50 cc) and sodium hydride (1.3 g as a 50% dispersion in vaseline oil). The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar), firstly with dichloromethane as eluant and then with ethyl acetate as eluant, then recrystallization from boiling acetonitrile (45 cc), 2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.3 g) is obtained, m.p. 163° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)CC)C.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>C1(C)C=CC=CC=1>[CH3:16][Si:17]([NH:7][C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([NH:8][Si:17]([CH3:20])([CH3:19])[CH3:16])[CH:2]=1)([CH3:20])[CH3:19]
Reactant: Nc1cccc(N)c1
Reactant: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Nc1cccc(N[Si](C)(C)C)c1
Yield: 95.8 %

Procedure:
m-Phenylenediamine (10.8 g; 0.1 mole) and triethylamine (20.2 g; 0.2 mole) in dry toluene (100 ml) were stirred and treated with trimethylchlorosilane (21.7 g; 0.2 mole) which was added dropwise over 1 hour. Stirring was continued for a further hour, and the mixture was then heated under reflux for 1 hour. After cooling and filtering the product, the solvent was evaporated to leave 24.2 g of m-bis(trimethylsilylamino)benzene, which is hereinafter referred to as Silamine II. This product has a theoretical amino-hydrogen equivalent weight of 63, i.e., its theoretical amino-hydrogen content is 15.87 equivalents/kg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C:18](=[O:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(B(CC)CC)C.N#N.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: COC(=O)CC(O)CC(=O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCB(CC)CC
Agent: N#N
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
The compound (1g) (1.0 g, 1.96 mmol) was dissolved in dry THF (5 mL) under N2 and then treated with triethylborane (1 M in THF, 2.9 mL, 2.9 mmol). After aging for 5 minutes, the reaction mixture was cooled to -98° C. (MeOH-liq. N2 bath). Sodium borohydride (85 mg, 2.25 mmol) was added followed by MeOH (2 mL) over 5 minutes. After stirring for an additional 0.5 hours, the reaction mixture was allowed to warm to -60° C. and then was quenched by the careful addition of 30% H2O2 (4 mL) in H2O (10 mL). The mixture was stirred vigourously at ambient temperature for 0.5 hours and then distributed between 1 N HCl (50 mL) and EtOAc (100 mL). The organic layer was washed with H2O (2×50 mL), dried, filtered and evaporated to provide the compound (1h) as a pale yellow gum. 1H NMR shows an 11:1 ratio of erythro vs threo; NMR 0.12 (6 H, s), 0.93 (9 H, s), 1.42-1.61 (2 H, m), 2.32 (6 H, s), 2.34-2.46 (2 H, m), 3.70 (3 H, s), 4.05-4.15 (H, m), 4.3-4.4 (H, m), 4.7-4.85 (2 H, m), 5.29 (H, dd, J=7 and 16 Hz), 6.43 (H, d, J=16 Hz), and 6.50 (H, d, J=16 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[S:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Yield: 75.1 %

Procedure:
1-[4-Hydroxy-5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl]ethanone (0.179 mmol, 48.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.179 mmol, 37.9 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (62.6 mg, yield 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccc(C(F)(F)F)c1
Yield: 28.8 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.302 g (1.4 mmol) of 3-(trifluoromethyl)benzoyl chloride in 9 ml and 0.145 g (1.4 mmol) of triethylamine for 1.5 hour at room temperature. The product is recrystallized from ethyl acetate-hexane to give 0.14 g of crystals, m.p. 190°-191° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCCc2ccc3c(c2)C(C)(C)CCN3C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1CCC(C)(C)c2cc(CCNc3ccc(C(=O)O)cc3)ccc21
Temperature: 40 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
Ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethylamino]-benzoate (Compound 11, 71 mg, 0.18 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 2.3 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 18 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by recrystallization in ethanol gave the title compound (60 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18](C3C=CC=CN=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:26]1([NH:32][C:33](=[O:50])[NH:34]CCN2CCN(C(OC(C)(C)C)=O)CC2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:34][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:50])[CH2:14][CH2:13]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNC(=O)Nc2ccccc2)CC1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(CCNC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(2-(3-phenylureido)ethyl)piperazine-1-carboxylate (1.1 eq, 0.43 mmol, 150 mg), TFA (1 mL) and CH2Cl2 (2 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (103 mg, 0.29 mmol) in iPrOH (2 mL) and DIPEA (0.5 mL). Filtration and washing as previously described gave the product (190 mg, 95% for two steps) as a bright yellow solid; 1H-NMR (500 MHz, DMSO-d6) 2.45-2.65 (2 m, 4H, piperazine N(CH2)2), 3.08-3.17 (2 m, 6H, piperazine N(CH2)2 & CH2), 3.60-3.63 (m, 2H, CH2), 6.10 (br s, 1H, NH), 6.89 (t, J=6.9 Hz, 1H, phenyl H-4), 7.02 (br s, 2H, NH2), 7.21 (t, br, J=7.4 Hz, 2H, phenyl H-3 & H-5), 7.38 (d, J=7.5 Hz, 2H, phenyl H-2 & H-6), 8.17 (s, 1H, pyridine H-6), 8.66 (s, br, 1H, NH);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[CH:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15])[CH:11]=O>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15])=[CH:11][N:1]=[C:2]2[CH:7]=1
Reactant: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Reactant: Cc1ccnc(N)c1
Product: Cc1ccn2c(CC(C)(C)[N+](=O)[O-])cnc2c1
Yield: 63.4 %

Procedure:
2-Amino-4-methylpyridine (2.2 g, 20.3 mmol) and 2-bromo-4-methyl-4-nitropentanal (20.3 mmol) are reacted as described in Amine 7 to give 3.0 g of 7-methyl-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([O:24]C)=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[N:12]=1)=[O:10].C1COCC1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[N:12]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)c2nn(C)c3ccccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)Nc2ccc(CC(=O)O)cc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To methyl (3-chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.08 g, 3.02 mmol) were added THF (30 ml) and 0.25N NaOH (18.1 ml, 4.53 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured in 1N HCl (5.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (3-chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetic acid (0.99 g, 95%) as a brown solid.
Reaction SMILES: I[C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[CH:34][C:35]=2[O:37][CH3:38])[C:30](B(O)O)=[CH:29]1)=O)(C)(C)C.C(=O)([O-])O.[Na+].C1CCCCC1.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36](=[C:35]([O:37][CH3:38])[CH:34]=1)[NH:28][CH:29]=[C:30]2[C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: COc1cc(OC)c2c(c1)c(B(O)O)cn2C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3cccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: COc1cc(OC)c2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Yield: 8 %

Procedure:
But using 2.9 g of 2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 2.34 g of 1-tert-butyloxycarbonyl-5,7-dimethoxy-1H-indole-3 boronic acid and 19 ml of a saturated aqueous solution of sodium hydrogen carbonate in 63 ml of dimethylformamide, and 0.42 g of tetrakis(triphenylphosphine)palladium is added. After flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)], 0.26 g of 2-(5,7-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:16][C:10]2[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=2[CH:8]=1.P(Cl)(Cl)(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH:26][C:14]1[C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Oc1ncnc2[nH]c(-c3ccccn3)cc12
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Nc2ncnc3[nH]c(-c4ccccn4)cc23)cc1Cl

Procedure:
Under a protective gas, 20 mg (0.09 mmol) of 6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (see Step 1.2) are heated at boiling with 1 ml of phosphorus oxychloride for 30 min. The reaction mixture is concentrated to dryness by evaporation and made into a suspension in 1 ml of n-butanol. 16.4 mg (0.108 mmol) of 3-chloro-4-fluoro-aniline are added and the suspension is boiled under reflux for 2 hours. The dark-brown suspension is then concentrated by evaporation and the residue is dissolved in methanol. Silica gel is added and drying is carried out. The powder is applied to a silica gel column and elution is carried out with ethyl acetate, yielding the title compound; 1H-NMR (400 MHz, DMSO-d6): 12.5 (sb, HN), 9.64 (s, HN), 8.64 (d, J=5, 1H), 8.38 (s, 1H), 8.35 (dd, J1 =7, J2 =3, 1H), 7.92 (m, 2H), 7.83 (m, 1H), 7.53 (s, 1H), 7.41 (t, J=9, 1H), 7.33 (m, 1H); HPLC: tRet (Grad20)=10.4 min; MS: (M)+ =339.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:14]1[CH2:15][CH2:16][N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[C:13]1=[O:17])[CH3:24]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate (2.00 g, 7.83 mmol), ethyl bromoacetate (1.30 mL, 11.75 mmol) and potassium carbonate (1.62 g, 11.75 mmol) in N,N-dimethylformamide (20 mL) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, and then partitioned between ethyl acetate (75 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (75 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford the title compound as a colorless solid (2.03 g, 76%): 1H NMR (300 MHz, CDCl3) δ 4.33-4.13 (m, 6H), 4.09 (s, 2H), 3.76-3.69 (m, 2H), 2.62 (s, 3H), 1.37-1.26 (m, 6H); MS (ES+) m/z 342.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH:37]1[CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35][CH2:36]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(N)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.25-8.23 (d, J=1.4, 1H), 8.11-8.08 (m, 1H), 7.96 (m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.32-7.29 (m, 1H), 7.28 (s, 1H), 3.47-3.40 (m, 2H), 3.18-3.08 (m, 1H), 2.57-2.43 (m, 2H), 1.91-1.84 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(Cl)Cl.O>[CH2:33]([NH:35][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)N1CCC(C2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.10 g, 0.21 mmol, Preparation #K.1) and TEA (0.065 g, 0.64 mmol, Sd Fine Chem) in DCM (10 mL) was added ethyl isocyanate (0.018 g, 0.25 mmol, Lancaster). The reaction mixture was slowly warmed to RT and stirred for about 2 h. The reaction mixture was diluted with water (20 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 1% methanol in DCM. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-(ethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 60 mg (56%): LC/MS (Table 1, Method c) Rt=1.83 min; MS m/z: 499.2 (M+H)+.