Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)[F:37])=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:37])[C:20]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-butyl 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)piperidine-4-carboxylate prepared according to methods similar to the one depicted in Example 1 was dissolved in DCM (5 mL). TFA (1 mL, 12.98 mmol) was added and the mixture was stirred at RT for 5 hr. The reaction mixture was concentrated to give 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid as a beige solid that was used in next step without further purification. MS (ES+) 418.1.
Reaction SMILES: [CH2:1]([S:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]=1)[CH2:2][CH3:3].[OH:31]O>C(O)(=O)C>[CH2:1]([S:4]([CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]=1)=[O:31])[CH2:2][CH3:3]
Reactant: OO
Reactant: CCCSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: CC(=O)O
Product: CCCS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 63 from 4'-[(2-n-propylthiomethyl-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid and hydrogen peroxide in glacial acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:41]=[CH:40][C:15]([CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.N1CCCCC1.[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:40][CH:41]=2)=[N:6][CH:7]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN(Cc2ccc(/C=C/COc3ccc(Br)cn3)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Brc1ccc(OC/C=C/c2ccc(CN3CCNCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 4-(4-{(E)-3-[(5-bromopyridin-2-yl)oxy]-prop-1-en-1-yl}benzyl)piperazine-1-carboxylate (0.604 g) in CH2Cl2 (10 mL) was added piperidine (0.196 mL). After stirring at room temperature for 1 hour, to the reaction mixture was added piperidine (0.784 mL) and stirred at room temperature for 4 hours. Then to the reaction mixture was added saturated aqueous NH4Cl and CH2Cl2. The organic layer was washed with saturated aqueous NH4Cl and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was washed with Et2O to afford 1-(4-{(E)-3-[(5-bromopyridin-2-yl)oxy]prop-1-en-1-yl}benzyl)piperazine as a white powder (0.282 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:29])([F:31])[F:30])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:24])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=639.99 (M+H+); retention time=0.69 minutes.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][C:19](=[O:41])[CH2:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[C@@H:24]([OH:28])[CH2:25][CH2:26][CH3:27])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:41])[CH2:20][C:21]([NH:22][C@@H:23]([CH2:29][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=2[CH3:39])[C@@H:24]([OH:28])[CH2:25][CH2:26][CH3:27])=[O:40])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
The compound [3-(2-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (45 mg, 0.08 mmol, see procedure 8b above) was dissolved in CH2Cl2 (1.5 mL) and treated with TFA (0.5 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in benzene and concentrated in vacuo; this procedure was repeated. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=495.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][N:23]1[CH2:24][CH2:25][C@@H:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]1=[O:27]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CN1CCC(Br)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H]2CCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (10.3 g, 40 mmol) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (8.54 g, 48 mmol) were dissolved in DMF and treated with potassium carbonate (12.1 g, 88 mmol) and stirred at room temperature for 16 hours and then at 50° C. for 3 hours. The DMF was evaporated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane to give the racemic product (8.7 g). The desired product was separated from its enantiomer by chiral HPLC using Merck 50 mm 20 μm Chiralpak AS—No ASV00SC JG001 and ASV000SC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL/min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in Ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted after its enantiomer. 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.51-2.63 (m, 1H), 2.94 (s, 3H), 3.31-3.54 (m, 2H), 3.89 (s, 3H), 4.87 (t, 1H), 5.08 (s, 2H), 6.90 (t, 1H), 7.27-7.46 (m, 7H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:29](=[O:33])[C:30]([NH2:32])=[O:31])=[C:9]([CH3:28])[N:10]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.CO.[Na]>[OH-].[Na+]>[NH2:32][C:30](=[O:31])[C:29]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:28])=[O:33]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Yield: 43.4 %

Procedure:
Using the procedure described in Example 2, Part E, 956 mg (2.1 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester was hydrolyzed in 10 mL of 1N NaOH and 20 mL of MeOH to give 403 mg (41% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:26])[CH:10]=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:22]([N:21]([CH2:24][CH3:25])[C:19]1[CH:18]=[CH:17][C:16]([NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:15]([C:11]2[CH:10]=[C:9]([C:8](=[O:27])[NH:7][CH2:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:20]=1)[CH3:23]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
A mixture of 80 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(diethylamino)phenyl)isonicotinamide, 64 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 83 mg of HATU, and 190 μL of diisopropylethylamine in 0.5 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 17.6 mg of product. 1H NMR (400 MHz, CD3OD, ppm): δ 9.54 (t, J=5.9 Hz, 1H), 8.98 (dd, J=5.2, 0.6 Hz, 1H), 8.88 (d, J=9.0 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.20 (s, 1H), 8.16-8.10 (m, 1H), 7.90 (dd, J=5.2, 1.5 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.75-7.63 (m, 4H), 7.63-7.50 (m, 2H), 4.74-4.67 (m, 2H), 4.21-4.03 (m, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.90-3.69 (m, 4H), 3.76 (q, J=7.2 Hz, 4H), 3.54 (t, J=5.9 Hz, 2H), 3.34-3.18 (m, 2H), 3.10 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI, m/z) 717.24 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[C:17](#[N:20])[CH:18]=[CH2:19]>>[CH:14]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:18][C:17]#[N:20])[CH2:7][CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CCNCC1
Reactant: C=CC#N
Product: CC(C)[Si](C(C)C)(C(C)C)N1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 194.0 g (0.8 mol) of 1-triisopropylsilylpiperazine (Synthesis Example 2) and heated at 70° C. Once the internal temperature became steady, 46.7 g (0.88 mol) of acrylonitrile was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 224.8 g of a fraction having a boiling point of 179-180° C./0.4 kPa was collected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19]>>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:19]1[CH2:18][O:20][CH2:21][CH3:22]
Reactant: CCOCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 6 %

Procedure:
Using the general method of Example 91, 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (46.2 g. 0.20 mol) was reacted with ethoxyacetic acid (62.5 g, 0.6 mol) to provide 53.6 g of crude product as a greyish solid. A small amount was recrystallized from toluene to provide 3.6 g of a colorless solid, m.p. 117-120° C. Analysis: Calculated: %C 68.2; %H, 7.1; %N, 14.0; Found: %C, 68.5; %H, 7.1; %N, 14.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[CH3:19][S-:20].[Na+]>CN(C)C=O>[CH3:19][S:20][CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 96.6 %

Procedure:
A suspension of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (28 g, 99 mmol) and sodium thiomethoxide (8.3 g, 119 mmol) in N,N-dimethylformamide (DMF, 200 mL) was heated to 80° C. and maintained at that temperature until analysis by thin layer chromatography (TLC) indicated that the starting material had been consumed. The reaction mixture was allowed to cool to ambient temperature and was then quenched with water (200 mL). The reaction mixture was extracted with diethyl ether (2×200 mL). The combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to provide 22.5 g of tert-butyl 2-[2-(methylthio)ethoxy]ethylcarbamate as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C1COCC1>CCOC(C)=O>[C:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
Ethyl bromoacetate (1.70 g, 10.2 mmol), tris-(1-naphthylene)phosphine (379 mg, 0.93 mmol) and tribasic potassium phosphate (10.8 g, 51 mmol) were placed in a flask. The flask was evacuated and back-filled with argon. A solution of 4-acetylphenylboronic acid (2.0 g, 12.2 mmol) in anhyd THF (40 mL) was added to the flask. The reaction was stirred at rt for 16 h. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was pre-adsorbed on to SiO2 and the product isolated via SiO2 chromatography to yield 616 mg (29%) of ethyl 4-acetyl-phenylacetate. MS 207.1 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:16]2[N:17](C(=O)C)[C:18](=[O:25])[C:19]([CH:22]([CH3:24])[CH3:23])([CH3:21])[N:20]=2)[N:7]=1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:16]2[NH:17][C:18](=[O:25])[C:19]([CH:22]([CH3:23])[CH3:24])([CH3:21])[N:20]=2)[N:7]=1
Reactant: COC(=O)c1ccc(COC(C)=O)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CO)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 16.7 g of methyl 6-acetoxymethyl-2-(1-acetyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate in 125 mL methanol containing 0.7 g of sodium methoxide is stirred at room temperature for 16 hours. The solution is adjusted to pH 5 with acetic acid and concentrated in vacuo. The residue is chromatographed on silica gel using ether-methanol as eluant to give the desired product as a solid. Recrystallization from methylene chloride-hexane gives analytically pure material, mp 115°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[C:25]([Si:29]([O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([N:39]=[C:40]=[O:41])[CH2:35][CH2:34]1)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC>ClCCCl>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:40](=[O:41])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH2:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2cccc(Cl)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)N(c2cccc(Cl)c2)c2c3ccccc3nn2-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine (example 19.1) was reacted with trans-tert-butyl-(4-isocyanato-cyclohexyloxy)-dimethyl-silane (Dermatakis, Apostolos; Kabat, Marek Michal; Luk, Kin-Chun; Rossman, Pamela Loreen; So, Sung-Sau. PCT Int. Appl. (2004), WO 2004041822 A1) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 6 days under reflux conditions to give the title compound as brown solid. MS: m/e=611.2 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=O)C.[CH2:38]([NH2:40])[CH3:39]>CO>[CH2:38]([NH:40][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=[O:3])[CH3:39]
Reactant: CCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.64 (s, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3 Hz, J=9.3 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.17-7.19 (m, 3H), 7.11 (dd, 1H, J=2.0 Hz, J=8.0 Hz), 6.99 (br. S, 1H), 3.44 (dq, 2H, J=5.8 Hz, J=7.3 Hz), 2.86-3.05 (m, 10H), 2.11-2.19 (m, 2H), 1.21 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H28N6O3: 496.22, Found: 497.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[Cl:1])=[O:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: O=C(Cl)CCl
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1

Procedure:
2-Chloro-4-sulphamoylaniline (50 g) and α-chloroacetyl chloride (24 ml) were refluxed together for 45 min. and the product worked up as in Example 2(a) to yield 59.5 g, m.p. 162°-164°
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCCC1C=CC(=O)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(F)c(F)c2)CC1

Procedure:
A solution of 7.1 g of 3,4-difluorobromobenzene in 25 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(3,4-difluorophenyl)-4-hydroxy-l-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[Cu][C:11]#[N:12].C(N)CN>CN1C(=O)CCC1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[CH:3][C:4]=1[F:9]
Reactant: N#C[Cu]
Reactant: Nc1ccc(Br)cc1F
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1

Procedure:
In NMP, compound [O], commercially available 4-bromo-2-fluoroaniline is cyanated with copper (I) cyanide and the resulting copper complex is decomposed with ethylene diamine (EDA) to yield compound [P], 4-amino-3-fluorobenzonitrile. Compound [P] is reacted with nitrosyl hydrogen sulfate (HSO4 --ONO2), prepared by mixing sodium nitrite and concentrated sulfuric acid in glacial acetic acid, and converted into the corresponding diazonium salt. The diazonium salt is brominated with copper (I) bromide in hydrobromic acid to yield compound [Q], 4-bromo-3-fluorobenzonitrile. Compound [Q] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [R], 4-bromo-3-fluorobenzimidate hydrogen chloride. In ethanol, compound [R] is reacted with gaseous ammonia to yield compound [S], 4-bromo-3-fluorobenzamidine hydrogen chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:31]=[CH:30][C:17]2[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[NH:20][C:16]=2[CH:15]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:31]=[CH:30][C:17]3[NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)=[N:20][C:16]=3[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1cccc(Nc2nc3ccc(N)cc3[nH]2)c1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: COc1cccc(Nc2nc3cc(NC(=O)c4ccc(N(C)C)cc4)ccc3[nH]2)c1

Procedure:
Compound 429 was prepared from 4-dimethylaminobenzoate and 5-amino-2-(3-methoxyphenylamino)benzimidazole by standard conditions. [M+H]+ calcd for C23H23N5O2: 402.19; found: 401.96.