Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([CH:7]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[C:4]1[N:5]=[N:6][N:2]([CH3:1])[N:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(C2CC(C(=O)O)CCN2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
1-Benzyl 4-ethyl 2-(2-methyl-2H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (0.92 g, 2.36 mmol) was dissolved in THF (10 mL) and water (10 mL) and LiOH (0.239 g, 9.98 mmol) was added. The mixture was stirred at room temperature for 1 h 10 min and then diluted with water and acidified with 2 M HCl. The aqueous phase was extracted 3 times with EtOAc, the combined organic phase dried over Na2SO4 and evaporated to yield 1-(benzyloxycarbonyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-4-carboxylic acid (828 mg, quant.). 1H NMR (400 MHz, cdcl3) δ 1.80-1.91 (m, 1H), 2.01-2.11 (m, 1H), 2.34 (dt, 1H), 2.63-2.79 (m, 2H), 3.55-3.65 (m, 1H), 4.01-4.09 (m, 1H), 4.24 (s, 3H), 5.13 (d, 2H), 5.60 (dd, 1H), 7.27-7.39 (m, 5H). MS m/z 346 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:26]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:26])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(S(C)(=O)=O)ccc3nc21
Temperature: 110 °C

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -5-(methylsulfonyl) anthranilic acid of example 37 (b) and POCl3 (50 ml) was heated at 110° C. for 16 hours. The reaction mixture was poured into ice-water, neutralized with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer was evaporated and the residue was purified by column chromatography on silica gel eluting with 50% ether/CH2Cl2 to afford 1.1 g of 1-ethyl-4-chloro-6-(methylsulfonyl)-1H-pyrazolo[3,4-b]quinoline, m.p. 158°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=O)=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.F[C:21]1C=CC(N)=CC=1.ClC(C(=O)C)C(=O)C.[S-]C#N.[K+]>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13](=[O:15])[CH3:21])=[C:11]([CH3:18])[N:10]=[C:9]2[SH:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)C(Cl)C(C)=O
Agent: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1

Procedure:
1-(1-(4-Fluorophenyl)-2-mercapto-4-methyl-1H-imidazol-5-yl)ethanone (60) was prepared in a similar manner as that described for the synthesis of compound 57 using 4-fluoroaniline (2 g, 18 mmol), 3-chloropentane-2,4-dione (2.7 g, 19.8 mmol), potassium thiocyanate (3.5 g, 36 mmol) and acetic acid (10 mL) in acetonitrile (100 mL).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[C:29]([C:35](O)=[O:36])=[CH:28]2>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:29]2[N:30]([CH3:34])[C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=3)=[O:36])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc3cc(F)ccc3n2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 5-Fluoro-1-methyl-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.99 min; [M+H]+=523.2.
Reaction SMILES: C([O-])(=O)C.[Y+3:5].C([O-])(=O)C.C([O-])(=O)C.[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])[CH3:15]>>[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15].[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15].[CH2:14]([CH:16]([CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([O-:19])=[O:18])[CH3:15].[Y+3:5]
Reactant: CCCCC(CC)C(=O)O
Agent: CC(=O)[O-]
Agent: [Y+3]
Product: CCCCC(CC)C(=O)[O-]

Procedure:
A yyttrium containing solution was prepared by mixing and reacting yttrium acetate with a stoichiometric excess of 2-ethylhexanoic acid to produce yttrium tri(2-ethylhexanoate) in 2-ethylhexanoic acid. The resulting solution contained 7.01 percent by weight yttrium, based on total weight.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36]2)=[O:45])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC2C=Nc3ccccc32)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-L-tryptophan (90 mg, 0.3 mmol). The final product was triturated with ether to yield 157 mg (81%) of the desired material.
Reaction SMILES: OC1C=CC(C(=O)C)=CC=1.OC1C=CC(C=C)=CC=1.[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](O)[CH3:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21].OS([O-])(=O)=O.[K+]>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccc(C(C)O)cc1
Agent: C=Cc1ccc(O)cc1
Agent: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)([O-])O
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
Synthesis of p-Hydroxystyrene p-Hydroxyacetophenone was converted to 1-(p-acetoxyphenyl)ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al (J. Org. Chem., 1958 23, 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0-5 degrees Centigrade for 2h. The mixture was then washed with ether, and the aqueous phase neutralised with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anhydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]([F:12])([F:11])[F:10])=[O:6].[H-].[Na+]>C1COCC1>[F:10][C:9]([F:12])([F:11])[CH2:8][N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6]
Reactant: O=C(NCCCl)NCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1CC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A 5° C. solution of 1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (0.91 g, 4.45 mmol) in THF (20 mL), under Ar, was treated with NaH (60% in mineral oil, 0.196 g, 4.89 mmol), warmed to RT and stirred for 5 h. The mixture was treated with satd. NH4Cl, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(2,2,2-trifluoroethyl)imidazolidin-2-one (730 mg, 98%). 1H NMR (400 MHz, DMSO-d6): δ 6.76 (s, 1 H), 3.81 (q, J=9.9 Hz, 2 H), 3.43 (m, 2 H), 3.28 (m, 2 H); MS (ESI) m/z: 169.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:36][C:24]1[CH:23]=[C:22]([NH:21][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH:12]=3)[N:17]=[CH:16][N:15]=2)[CH:27]=[CH:26][C:25]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Reactant: CN1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CN5CCN(C)CC5)cc34)cc2C)cn1
Yield: 51 %

Procedure:
The procedure of Example 62 was repeated except for using 0.07 g of the compound obtained in Example 67 and 0.05 ml of 1-methylpiperazine instead of the compound obtained in Example 61 to obtain the title compound (0.04 g, 51%).
Reaction SMILES: ClC1S[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[N:6]=1.C(OCC)(=O)[CH2:20][C:21](C)=[O:22].C([O-])(=O)C.[Na+].FC(F)(F)C(F)(F)C#N>O.CO>[C:21]([C:4](=[C:5]([NH2:6])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:22])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: N#CC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 37 %

Procedure:
Preparation of Ethyl 2-Chloro-4-Pentafluoroethyl-5-Thiazolecarboxylate To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil; dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo -4-pentafluoroethyl-5-thiazole-carboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoro-ethyl-5-thiazolecarboxylate, nD25 =1 4460.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][N:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([Cl:19])[NH:13]1.ClC1N=NN=C(Cl)C=1Cl.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[Cl:11][N:12]1[N:13]=[C:14]([Cl:19])[CH:15]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:17]1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClC1=CC(Cl)=NN(Cl)N1
Agent: Clc1nnnc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Para-nitroaniline (13.8 g) was dissolved into acetone (150 ml) at room temperature. 2,4,6-Trichlorotriazine (18.4 g) was dissolved into acetone (100 ml). Then the trichlorotriazine solution was dropwisely added to the p-nitroaniline solution as the p-nitroaniline solution was cooled with iced water. After the reaction was carried out for 2 hours at 0° C., an aqueous sodium bicarbonate solution (8.4 g of sodium bicarbonate being dissolved in 100 ml of water) was dropwisely added to the solution over 30 minutes. Then, the cooling was stopped by removing the ice bath and the solution was stirred until the temperature of the solution became room temperature. The reaction product was filtered off, washed with water and vacuum dried to obtain 23 g of 2,4-dichloro-6-p-nitroanilinotriazine. The chemical structure of the reaction product was confirmed by NMR and the melting point.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3]/[CH:4]=[CH:5]/[C:6]([N:8]([C@@H:10]([CH3:44])[C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][C:19]1[C:20]([NH:40][CH2:41][CH2:42][CH3:43])=[N:21][C:22]([NH:25][C:26]2[CH:34]=[C:33]3[C:29]([CH:30]=[N:31][N:32]3C(OCC)=O)=[CH:28][CH:27]=2)=[N:23][CH:24]=1)=[O:12])[CH3:9])=[O:7].O1CCCC1.[OH-].[Li+].O>C(OCC)(=O)C>[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([NH:25][C:22]3[N:21]=[C:20]([NH:40][CH2:41][CH2:42][CH3:43])[C:19]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])/[CH:5]=[CH:4]/[CH2:3][N:2]([CH3:1])[CH3:45])[CH3:44])=[CH:24][N:23]=3)[CH:34]=2)[CH:30]=[N:31]1
Reactant: CCCNc1nc(Nc2ccc3cnn(C(=O)OCC)c3c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2ccc3cn[nH]c3c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To (S,E)-ethyl 6-((5-(5-(2-(4-(dimethylamino)-N-methyl-2-butenamido)propaneamido)-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)-1H-indazole-1-carboxylate (21-23, 17.3 mg), tetrahydrofuran (1.0 mL) and 1.0 mol/L aqueous lithium hydroxide (1.0 mL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 100 to 90% ethyl acetate in methanol) to obtain (S,E)-N-(1-((5-(2 -((1H-indazol-6-yl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (21-53, 9.8 mg) as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[S:5][CH:6]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:29]2[CH:30]=[N:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)[CH:3]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1cncc(B(O)O)c1
Reactant: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1cc(-c2cncc(S(C)(=O)=O)c2)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide (example 14, step 2) was reacted with 5-(methylsulfonyl)-3-pyridineboronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[4-(5-methanesulfonyl-pyridin-3-yl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 557.1 ([M+OAc]−)
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:18][CH3:19])=[C:6]([C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[NH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1c(-c2c[nH]c(C(=O)O)c2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1c[nH]c(C(=O)O)c1
Yield: 23.2 %

Procedure:
4-(3-Nitro-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57g (633 mg, 2.41 mmol) was dissolved in 15 mL of ethyl acetate followed by addition of 127 mg of palladium on carbon and ammonium formate (609 mg, 9.66 mmol). Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4-(3-amino-2-methoxy-phenyl)-1H-pyrrole-2-carboxylic acid 57h (130 mg, yield 23.2%) as a grey solid.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2]1
Reactant: O=C1CCc2ccccc21
Reactant: C1CCNC1
Product: C1=C(N2CCCC2)c2ccccc2C1

Procedure:
According to a modification of the procedure of Noland et al (Noland, W. E.; Kaneswaran, V. J. Org. Chem. 1981, 46, 1940-1944.), 1-indanone (25.0 g, 0.189 mol) and 50 mL of pyrrolidine which had been dried over 3A sieves were added to a 500 mL, 3-neck flask equipped with an overhead stirrer, Dean-Stark apparatus and condenser which was maintained under a dry N2 atmosphere. Benzene (200 mL dried over 4A sieves) was added and the solution was brought to reflux for 30 hours. At the end of this period 1H NMR analysis of a reaction aliquot indicated a 93:7 mole percent ratio of desired product to starting material. The bulk of the solvent was removed in vacuo and the crude dark product was distilled (6″ Vigreaux column) to give pure enamine as a light yellow oil (24.3 g, 0.132 mol) in 70 percent yield. This compound was both air and water sensitive and was transferred to the dry box upon distillation. Capillary GC analysis indicated a hexane solution of distillate to be of 99 area percent purity: bp=125-127° C. @ 2.0 mm, bp. lit=118-120° C. @ 1 mm;
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 88.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-2, step-3 using ethyl 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoate (1.00 g, 3.31 mmol) and NaOH (530 mg, 13.26 mmol) in THF:MeOH:H2O (3:2:1; 12 mL) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 14.10 (s, 1H), 8.32 (br t, 1H), 7.38-7.29 (m, 2H), 4.25 (d, J=5.1 Hz, 2H), 2.40 (m, 1H), 1.00 (d, J=6.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[CH:4][CH:3]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].CO>CC(O)C>[CH:27]1([NH:30][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: Cc1cc(Nc2nc(C(NC3CC3)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 140 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (100 mg, 0.28 mmol) in 2-propanol (3 mL) were added cyclopropylamine (0.1 mL) and 3A (8-12 mesh) molecular sieves, and the mixture was heated at 140° C. in a Biotage microwave reactor. Additional cyclopropylamine (0.15 mL) was added and the mixture in a sealed vial was heated conventionally at 90° C. for 4 d. Then a suspension of sodium borohydride (140 mg) in 2-propanol was added dropwise and the mixture was stirred at rt for 1 h. Then MeOH (0.1 mL), sodium borohydride (100 mg), and more MeOH (2 mL) were added, and the mixture was filtered and the filtrate was concentrated. To the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg) and the mixture was stirred for 1 h at rt. AcOH (0.4 mL) was then added and the mixture was concentrated. DMSO (3 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) followed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) to afford 2-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (5.5 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ 0.34 (m, 4 H) 1.24 (m, 1H) 2.03 (m, 1H) 2.26 (s, 3H) 4.91 (s, 1H) 6.41 (m, 1H) 7.11 (t, 2H) 7.4-7.6 (m, 3H) 7.76 (m, 2H) 8.56 (d, 1H) 10.38 (bs, 1H) 12.15 (bs, 1H); LC-MS (ESI) m/z 389 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1COCC1.O>[Cl:13][C:14]1[C:19]([C:23]([O:24][CH2:25][CH3:26])=[O:27])=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1
Reactant: CCOC(=O)Cl
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Under an argon atmosphere, to a solution of diisopropylamine (15.7 mL, 112 mmol) in THF (70 mL) was added dropwise butyllithium (1.6M hexane solution, 70 mL, 112 mmol) at −78° C. The mixture was stirred at 0° C. for 30 min and cooled to −78° C. A solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (14.12 g, 72.4 mmol) in THF (20 mL) was added dropwise thereto, and the mixture was stirred at −78° C. for 1 hr. A solution of ethyl chlorocarbonate (13.9 mL, 145 mmol) in THF (20 ml) was added dropwise thereto, and the mixture was stirred at −78° C. for 30 min, and then at 0° C. for 30 min. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=100:0→90:10) to give the title compound (13.28 g, 69%) as a colorless solid.