Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([CH:23]([C:25]1[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[CH:30]=O)[CH3:24])#[N:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([CH:23]([C:21]#[N:22])[CH3:24])[CH:26]=[CH:27][C:28]=2[O:33][CH3:34])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(C)C#N)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Yield: 103.8 %

Procedure:
To a stirred and ice-cooled solution of Compound 17 (160 mg, 0.60 mmol) and Compound 14 (120 mg, 0.60 mmol) in dry CH2Cl2 (5 ml) was added NaBH(OAc)3 (430 mg, 2.0 mmol) in one portion. The mixture was stirred at room temperature for 20 hours. The mixture was poured into NaHCO3 aq., and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give Compound 18 as a yellow oil (280 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:14])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3]
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: COCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 135.2 %

Procedure:
(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 97 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 42 mg, 0.20 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 5% methanol/ethyl acetate) to afford (R)-2-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (121 mg, 90%) as a colorless gum: [α]30589=−53.5° (c=0.17, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1900; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.75-2.30 (m, 8H, 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, OCH3), 3.19 (s, 3H, SO2CH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: C([CH:4]1[CH2:8][N:7]([NH2:9])[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[N:5]1)(=O)C.Cl>CO.C(O)(C)C>[C:15]1([N:14]2[C:10]([C:6]3[N:7]([NH2:9])[CH2:8][CH2:4][N:5]=3)=[CH:11][CH:12]=[N:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)C1CN(N)C(c2ccnn2-c2ccccc2)=N1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NN1CCN=C1c1ccnn1-c1ccccc1

Procedure:
Acetyl-2(1-phenyl-5-pyrazolyl)-amino-2-imidazoline (15.1 g.) was treated with HCl in methanol as described in Example II to give 12.5 g. product mp 206°-208° C. The hydrochloride, made with HCl in isopropyl alcohol had a mp of 232°-234° C.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:22][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a mixture of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.37 g, 20.11 mmol, PCT Appl. WO 2000/071129, U.S. pat. application 2003/0186982, the disclosure of which is herein incorporated by reference) and 2-fluoro-4-nitrophenol (3.48 g, 22.12 mmol) in anhydrous DMF (100 mL), stirred for 5 minutes under a nitrogen atmosphere, was added anhydrous potassium carbonate (6.11 g, 44.24 mmol). The mixture was heated at 60° C. for 15 h before 2-fluoro-4-nitrophenol (1.00 g, 6.37 mmol) was added and stirring continued at 60° C. for 4.5 h. The mixture was cooled to room temperature, diluted with dichloromethane, washed sequentially with water and 10% aqueous lithium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a tan solid. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with chloroform, afforded the title compound (4.19 g, 72%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.20-8.13 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H, J=2.6 Hz); 7.58-7.53 (m, 1H), 6.69 (d, 1H, J=2.4 Hz), 2.62 (s, 3H); HRMS(ESI), 289.0737 (M+H)+ calc, 289.0733 (M+H)+ found.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:17]2[N:13]([C:14]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:15]([CH3:22])[C:16]=2[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:5][O:8][C:9]1[C:17]2[N:13]([C:14]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:15]([CH3:22])[C:16]=2[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cccc(O)c12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cccc(OC)c12
Temperature: 60 °C

Procedure:
0.19 mL (2.02 mmol) of dimethyl sulfate is added to a mixture of 705 mg (1.84 mmol) of methyl [8-hydroxy-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate obtained in Example 2, in 10 mL of acetone with 330 mg (2.39 mmol) of potassium carbonate and the medium is heated at 60° C. for 6 hours.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[CH3:20][O:21][CH2:22]Cl.CCOC(C)=O>CN(C)C=O>[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]([CH2:20][O:21][CH3:22])[C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccc2[nH]c(=O)sc2c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCn1c(=O)sc2cc(C(C)=O)ccc21
Yield: 75.4 %

Procedure:
Add cesium carbonate (1.5 Eq; 310.5 mmoles; 101.1 g) to a solution of 6-acetyl-3H-1,3-benzothiazol-2-one (40.0 g, 207 mmoles) in dimethylformamide (690 mL). Add chloromethyl methyl ether (1.3 Eq, 269 mmoles, 20.4 mL) dropwise and stir at room temperature for 18 hr. Transfer to a separatory funnel, add EtOAc (1 L), wash with water (2×200 mL), and then brine (200 mL). Back extract with DCM (300 mL). Dry the combined organic layers over Na2SO4, filter and concentrate. Slurry the concentrate in 200 ml hexanes/EtOAc (75:25), and filter to give 6-acetyl-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one as a white solid (37.0 g, 156 mmoles, 75% yield). LCMS (low) rt=1.68 min., M+1=238.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCc1cccnc1
Reactant: O=S(Cl)Cl
Product: ClCCc1cccnc1

Procedure:
A mixture of 3-(2-hydroxyethyl)pyridine (1.2 g., 9.8 m.moles ) and thionyl chloride (10 ml.) was refluxed for 3 hours and then excess of the thionyl chloride was removed by evaporation. To the residue was added a 5% aqueous solution of Na2CO3 (20 ml.) and the mixture was extracted with chloroform (2×30 ml.). The extracts were combined, dried with anhydrous Na2SO4 and concentrated to dryness to yield 3-(2-chloroethyl)-pyridine, 1.3 g. (98%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[NH:1][CH2:2][CH:3]([CH2:4][O:5][CH3:6])[O:7]2)=[CH:11][CH:10]=1
Reactant: COCC(O)CN
Reactant: O=Cc1ccc(Cl)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCC1CNC(c2ccc(Cl)cc2)O1
Temperature: 25 °C

Procedure:
Twelve and six tenths (12.6) grams of 1-amino-3-methoxy-2-propanol and 16.9 grams of p-chlorobenzaldehyde were combined in 150 milliliters of benzene and heated to reflux under a modified Dean-Stark apparatus until about 2.5 milliliters of water were azeotropically removed. An additional 50 milliliters of benzene was distilled over and the mixture was cooled to room temperature and the volume was adjusted to 109.2 milliliters, so that 4 milliliters=1 gram of intermediate. Aliquots of this solution were used in subsequent reactions.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].N12CCCN=C1CCCCC2.[Cl-].[Na+]>ClCCl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1)[CH3:14]
Reactant: O=Cc1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a mixture of 1H-pyrazole-4-carbaldehyde (5.5 g) and ethyl bromoacetate (19.0 g) in dichloromethane (150 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10 ml) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and the reaction was stopped by addition of a saturated aqueous sodium chloride solution. The products were extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as the eluent to afford the title compound as a colourless oil (8.09 g, yield: 78%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=[O:13])[C:10](O)=[O:11]>Cl>[NH:8]1[C:10](=[O:11])[C:9](=[O:13])[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cccnc1N
Agent: Cl
Product: O=c1[nH]c2cccnc2[nH]c1=O
Yield: 90.1 %

Procedure:
To a suspension of 2,3-diaminopyridine (20 g, 0.136 mol) in 4N aqueous HCl (200 ml) is added oxalic acid (20.7 g, 0.164 mol) and the reaction mixture is refluxed for 20 h. The reaction mixture is cooled and the solid precipitated is filtered, washed with water and dried under vacuum to afford 20 g (89%) of the title compound as a solid. HPLC (max plot) 98%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:18][NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])[C:12]=2[OH:38])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:18][NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:21])[C:12]=2[OH:38])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(=NNC(=O)c2ccc(C(=O)O)cc2)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To methyl 4-({2-[[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl](phenyl)methylene]hydrazino}carbonyl)benzoate (0.196 mmol, 100 mg), methanol (4 mL) was added, and 1 M aqueous sodium hydroxide (0.981 mmol, 0.981 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1 hour of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (0.981 mmol, 0.981 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (93 mg, yield 95%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:6]1[C:7]([NH:27][C@@H:28]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)=[N:8][C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][C:20]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:25][CH2:26]3)=[CH:13][CH:12]=2)=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cnc(C(N)=O)c(Nc3ccc(N4CCC5(CC4)OCCO5)cc3)n2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nc(Nc3ccc(N4CCC5(CC4)OCCO5)cc3)c(C(N)=O)nc2Br)C1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (10 g), chloroform (200 mL) was added N-bromosuccinimide (3.46 g) under ice-cooling, followed by stirring for 1 hour. To the reactant was added silica gel, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-400:10:1) to obtain tert-butyl (3R)-3-[(3-bromo-5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (6.17 g) as a yellow amorphous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.O.[CH3:26][N:27](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.[C-]#N.[Zn+2].[C-]#N>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[C:26]#[N:27])=[O:9])=[CH:11][CH:12]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(C#N)c2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (284 mg, 0.246 mmol) to a solution of (5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone (1.0 g, 2.46 mmol) and zinc cyanide (578 mg, 4.92 mmol) in dimethylformamide (25 mL) and stir. Purge solution with nitrogen and heat to 80° C. After 18 hours, add water (100 mL) and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue with flash chromatography eluting with 12.5% ethyl acetate:hexanes to yield the title product as a white solid (550 mg, 63%): 1H NMR (DMSO-d6) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H), 7.53 (d, 2H), 7.83 (d, 2H), 8.61 (t, 1H), 9.09 (d, 1H), 9.26 (d, 1H).
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9]1)C1C=CC=CC=1>O1CCCC1.[Pd]>[Si:20]([O:19][CH2:18][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][CH2:9]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CNc2ccccc2C1
Yield: 40 %

Procedure:
25.2 g of 1-benzyl-3(R,S)-(tert-butyldimethylsilyloxymethyl)-1,2,3,4-tetrahydroquinoline in 250 ml of tetrahydrofuran are hydrogenated in the presence of 2.0 g of 10% palladium-on-charcoal under customary reaction conditions. Purification of the crude product over 500 g of silica gel with a 1:1 mixture of methylene chloride and hexane as the solvent gives 7.6 g of the title compound: Rf (1:1 mixture of methylene chloride and hexane)=0.19.
Reaction SMILES: [NH3:1].C(O)C.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:25]=O)=[C:10]([NH:12][C:13](=O)[CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])[CH:11]=1>>[Br:5][C:6]1[CH:11]=[C:10]2[C:9]([CH:25]=[N:1][C:13]([CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:12]2)=[CH:8][CH:7]=1
Reactant: N
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1cc(Br)ccc1C=O
Solvent: CCO
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc2ccc(Br)cc2n1
Temperature: 150 °C
Yield: 94 %

Procedure:
A solution of ammonia in ethanol (2 M, 14 mL, 28 mmol) was added to N-(5-bromo-2-formyl-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-propionamide (0.5 g, 1.36 mmol). The mixture was heated in a microwave reactor at 150° C. for 2 h. A second solution of ammonia in ethanol (2 M, 14 mL, 28 mmol) was added to N-(5-bromo-2-formyl-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-propionamide (1.0 g, 2.72 mmol). The mixture was heated in a microwave reactor at 150° C. for 2 h. The two resultant solutions were combined and evaporated and the residue purified by silica gel chromatography using iso-hexanes/dichloromethane 1:1 to 1:3 to 0:1 to yield the title compound (1.34 g, 94%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.08 (s, 6H), 0.91 (s, 9H), 1.64 (d, J=6.7 Hz, 3H), 5.22 (q, J=6.5 Hz, 1H), 7.71-7.83 (m, 2H), 8.26 (s, 1H), 9.40 (s, 1H). LCMS (m/z) 367.0, 369.0 [M+H], Tr=4.00 min.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: O=C(O)C=Cc1ccco1
Reactant: CCOC(=O)c1ccccc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1ccco1
Yield: 30.2 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (1.272 g, 4.34 mmol) was suspended in dry methylene chloride (5 ml). To the suspension a solution of 3-(2-furyl)acrylic acid (500 mg, 3.62 mmol), triethylamine (1.2 ml, 8.69 mmol), and ethyl 2-aminobenzoate (0.53 ml, 3.62 mmol) in dry methylene chloride (5 ml) was added. The mixture was heated under reflux for 40 hours. Then, the reaction mixture was diluted with methylene chloride, and washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a viscous oil, which, on washing with n-hexane gave white solids of the title compound (312 mg, yield: 30.2%), which was recrystallized from methanol. m.p., 85°-86° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[NH:8][C:9]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15]CC)=[O:14])=[O:10].[OH-].[Na+]>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[NH:8][C:9]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:10]
Reactant: CCOC(=O)C(NC(=O)NN1CC(=O)NC1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CN(NC(=O)NC(C(=O)O)c2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29.4 g. of α-[[[(2,4-dioxo-1-imidazolidinyl)amino]-carbonyl]amino]benzeneacetic acid, ethyl ester are added to 138 ml. of 2N sodium hydroxide solution with stirring. The substance goes quickly into solution upon slight heating. The mixture is stirred for 2 hours at room temperature, filtered and the clean filtrate is acidified to pH 1 with concentrated hydrochloric acid. Upon rubbing, α-[[[(2,4-dioxo-1-imidazolidinyl)amino]carbonyl]amino]benzene acetic acid crystallizes out. The mixture is let stand in the refrigerator overnight and then filtered under suction, yield 21.9 g., m.p. 139°-143°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:22]#[N:23])=[N:9]2)=[CH:4][CH:3]=1.[CH:24](O)=[O:25]>>[CH:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:22]#[N:23])=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: O=CO
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(N)cc2)s1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(NC=O)cc2)s1

Procedure:
A mixture of 1-(4-aminophenyl)-5-[5-(methylsulfonyl)-2-thienyl]pyrazole-3-carbonitrile (1.1 g) and formic acid (5 ml) was refluxed for 30 minutes. The mixture was concentrated and the residue was triturated in water to give crystals of 1-[4-(formylamino)phenyl]-5-[5-(methylsulfonyl)-2-thienyl]pyrazole-3-carbonitrile (1.1 g).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][CH:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: FC1CCNC1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]