Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)(C(C)(C)C)(C)C.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N(CCO)Cc1nc2c(c(=O)[nH]1)COCC2
Reaction time: 24 h
Yield: 22.2 %

Procedure:
To a solution of 2-((2-(tert-butyldimethylsilyloxy)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (10 mg, 0.029 mmol) in dichloromethane (0.1 mL) was added 3-phenylpropanoyl chloride (4.4 μL, 0.029 mmol) and then triethylamine (12 μL, 0.088 mmol) at 0° C. The mixture was stirred at 0° C. to ambient temperature for 24 h. Tetra-N-butylammonium fluoride (29 μL, 0.029 mmol, 1 M in THF) was added and the reaction was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo then purified via prep thin layer chromatography to provide the title compound (2.3 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.34 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 4.56 (s, 2H), 4.38 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.65-3.82 (m, 2H), 3.58 (t, J=4.5 Hz, 2H), 2.87-3.06 (m, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.67 (br. s., 2H). HRMS calculated for C19H23N3O4 358.1767. found (ESI, [M+H]+), 358.1767. Retention time=0.99 min.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].O1[CH2:41][CH2:40]OCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13]([N:7]2[CH2:41][CH2:40][CH2:4][CH2:5][CH2:6]2)=[N:14][CH:15]=1)=[O:9]
Reactant: C1COCCO1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N2CCCCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 191.4 %

Procedure:
To a solution of 0.5 g (0.96 mmol) 2-methylsulfonyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan 0.183 g (2.15 mmol) piperidin was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 20:1) to give 0.48 g (95%) 4-phenyl-2-piperidin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a waxy pale yellow solid, MS (ISP): 523.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[S:9][C:5]1[N:4]=[C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Sc2ncccn2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Sc3ncccn3)n2)sc2ccccc12
Yield: 5.2 %

Procedure:
2-Cyano-6-(2-pyrimidinyl)thiopyridine (1.30 g, 6.07 mmol) and methyl thiosalicylate (1.53 g, 9.10 mmol) were dissolved in toluene (100 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 5%) as pale yellow crystals.
Reaction SMILES: C(O[C:9]([CH2:11][N:12]([C@H](C)[C@@H](C1C=CC(OC2C=CC=CC=2)=CC=1)CCC1C=CC=CC=1)C([C@@H]1[C@@H](C([O-])=O)OC(C(OCC[Si](C)(C)C)=O)(C(OCC[Si](C)(C)C)=O)O1)=O)=O)C1C=CC=CC=1.C([O:69][C:70]([CH2:72][N:73]([C@H:96]([CH3:119])[C@@H:97]([C:106]1[CH:111]=[CH:110][C:109]([O:112][C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)=[CH:108][CH:107]=1)[CH2:98][CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[C:74]([C@@H:76]1[C@@H:80]([C:81]([O:83]C(C)(C)C)=[O:82])[O:79][C@:78]([C:93]([O-])=[O:94])([C:88]([O:90]CC)=[O:89])[O:77]1)=[O:75])=[O:71])(C)(C)C>>[C:70]([CH2:72][N:73]([C@H:96]([CH3:119])[C@@H:97]([C:106]1[CH:111]=[CH:110][C:109]([O:112][C:113]2[CH:114]=[CH:115][CH:116]=[CH:117][CH:118]=2)=[CH:108][CH:107]=1)[CH2:98][CH2:99][C:100]1[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=1)[C:74]([C@@H:76]1[C@@H:80]([C:81]([OH:83])=[O:82])[O:79][C@@:78]([C:93](=[O:94])[NH:12][CH2:11][CH3:9])([C:88]([OH:90])=[O:89])[O:77]1)=[O:75])([OH:69])=[O:71]
Reactant: CCOC(=O)[C@@]1(C(=O)[O-])O[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)N(CC(=O)OC(C)(C)C)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1
Reactant: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)OCc1ccccc1)C(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)[O-]
Product: CCNC(=O)[C@@]1(C(=O)O)O[C@H](C(=O)O)[C@@H](C(=O)N(CC(=O)O)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1

Procedure:
The above identified compound was obtained by carrying out treatment in the same manner as in Example 25(2) except that instead of 2,2-bis{2-(trimethylsilyl)ethyl} (4S,5S)-4-[N-(benzyloxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,2,5-tricarboxylate, 5-tert-butyl 2-ethyl (2R*,4S,5S)-4-[N-(tert-butoxycarbonylmethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoyl]-1,3-dioxolane-2,2,5-tricarboxylate obtained in Example 20, was used, and carrying out the same reaction as in Example 21.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(COC1CCN(C(C)=O)CC1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
N-Acetyl-4-hydroxypiperidine (57.2 g.) in dry D.M.F. (250 ml.) was added dropwise to a stirred suspension of sodium hydride (23.2 g., 50% dispersion in mineral oil) in dry D.M.F. (200 ml.) under an atmosphere of nitrogen and with external cooling in an ice/water bath. The suspension was allowed to warm to room temperature then stirred for 5 hours. Bromoacetaldehyde diethylacetal (94.7 g.) was added slowly to the stirred reaction mixture with cooling then the mixture was stirred at room temperature for 18 hours. A further quantity of sodium hydride (23.2 g.) was added portionwise and stirring continued until effervescence had ceased. A further 100 ml. dry D.M.F. was added and the mixture cooled in an ice/water bath while a second batch of bromoacetaldehyde diethylacetal (94.7 g.) was slowly added. The mixture was stirred at room temperature for 3 hours then isopropopanol (150 ml.) added to destroy excess sodium hydride. The suspension was filtered, the filtrate concentrated under reduced pressure then the residue taken up in water and extracted with chloroform. The chloroform extract was dried (Na2SO4), the solvent evaporated in vacuo and the residue distilled to give N-acetyl-4-(2,2-diethoxyethoxy)piperidine (61.5 g.), b.p. 142°-145° C./3 mm., characterized by n.m.r.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:6]=[C:7]([N:8]([CH3:10])[CH3:9])[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: CN(C)c1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: C#C[Si](C)(C)C
Product: CN(C)c1cc(-c2ccc(Cl)cc2)cnc1C#C[Si](C)(C)C

Procedure:
The product was prepared analogously to Example 7.1c starting from [2-bromo-5-(4-chlorophenyl)pyridin-3-yl]dimethylamine and trimethylsilylacetylene. Yield: 0.50 g (quant. yield); C18H21ClN2Si (M=328.911); calc.: molpeak (M+H)+:329/331 (Cl); found: molpeak (M+H)+:329/331 (Cl); HPLC-MS: 7.41 minutes (method B).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10](SC2N=C(C)C=C(C)N=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([O:27][C:28]([CH2:30][CH2:31][CH2:32][CH2:33][C@@H:34]1[CH2:38][C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:36][NH:35]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:35]2[CH2:36][C@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:38][C@H:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[O:11])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
S-p-Nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (719 mg) was added to 770 mg of (2R,4R)-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine in 7 ml of tetrahydrofuran and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with brine, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(CNCCNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CCNC(=O)OC(C)(C)C)CC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of 18.80 g (47.54 mmol) of 3-(2-tert-butoxycarbonylamino-ethylamino)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester dissolved in 156 mL of anhydrous dichloromethane was added 8.02 mL (57.05 mmol) of triethylamine. The resulting mixture was cooled at 0° C. and 5.00 mL (52.29 mmol) of ethyl chloroformate dissolved in 30 mL of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 12 h. Saturated aqueous solution of ammonium chloride was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, sodium carbonate, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 led to afford 20.00 g (90%) of the desired compound as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[H-].[Na+].[O:25]1[CH2:29][CH2:28]OS1(=O)=O.O>CN(C)C=O>[OH:25][CH2:29][CH2:28][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: O=S1(=O)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g of tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate in 40 ml of N,N-dimethylformamide is added at 0° C. to the suspension of 0.26 g of sodium hydride dispersion (60%) in 40 ml of N,N-dimethylformamide. After 30 minutes, the reaction mixture is admixed with 0.83 g of [1,3,2]dioxathiolane 2,2-dioxide and stirred at room temperature over 18 hours. The reaction mixture is cooled to 0° C., admixed with water and concentrated by evaporation. The residue is stirred in a 1:10 mixture of 0.1 M H2SO4/dioxane at 50° C. over 60 hours, neutralized with saturated aqueous sodium hydrogencarbonate solution and concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.24.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nnc(N)nc1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nnc(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
To a stirred suspension of 1.2 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 25 ml of anhydrous acetonitrile was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring for 24 hours at ambient temperature, the resultant precipitate was filtered off to yield 2.5 g of the desired compound melting at 150°-151°. It showed infrared absorption peaks at 1700, 1680 and 1550 cm-1, consistent for N-[(5,6-dimethyl-1,2,4-triazin-3-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[NH:1]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:12]([CH3:13])=[O:14]
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 89 %

Procedure:
5-Aminomethylindole (5.3 g, 0.036 mol) was mixed with acetic anhydride (13 ml) and kept at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was stirred with toluene. The precipitated solid was collected by filtration to yield 6.1 g (89%) of 5-acetaminomethylindole.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]=[O:18])[C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:37]([CH2:39]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:38]>CO>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])=[C:19]([F:30])[C:12]3[N:13]=[CH:14][N:15]([CH2:16][C:17]4[O:18][CH:39]=[N:37][CH:38]=4)[C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2CC=O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Cl)ccc1Nc1c(C(=O)NOCC2CC2)cc2c(ncn2Cc2cnco2)c1F
Yield: 50.9 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3-(2-oxo-ethyl)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide (0.020 g, 0.046 mmol) is dissolved in methanol (2 mL). Potassium carbonate (0.013 g, 0.093 mmol) and 1-isocyanomethanesulfonyl-4-methyl-benzene (0.010 g, 0.051 mmol) are added. The reaction mixture is stirred at reflux for 16 hours under N2, then concentrated under reduced pressure. The residue is dissolved in ethyl acetate and poured into a separatory funnel and washed with water and brine. The combined aqueous layers are reextracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (Na2SO4,) and concentrated under reduced pressure. The resulting solid was purified by flash column chromatography (eluting with 15:1 methylene chloride:methanol) to yield 0.011 g (50%) of the desired product. MS APCI (+) m/z 470, 472 (M+, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 10.51 (br s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 6.92 (dd, 1H), 6.31 (d, 1H), 6.11 (br s, 1H), 5.45 (s, 2H), 3.62 (d, 2H), 2.40 (s, 3H), 0.87 (m, 1H), 0.49 (m, 2H), 0.20 (m, 2H). 19F NMR (376 MHz, CDCl3) −134.54 (s).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8].Cl>O1CCCC1.O>[CH3:14][O:13][C:11]1[C:10]([CH3:15])=[CH:9][C:6]([CH:7]([OH:8])[CH3:1])=[C:5]([CH3:4])[CH:12]=1
Reactant: COc1cc(C)c(C=O)cc1C
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(C)O)cc1C
Yield: 74 %

Procedure:
Methyl magnesium bromide (2.4 mL, 1.2 eq) was dropwise added at −78° C. to a solution of 2,5-dimethyl-4-methoxybenzaldehyde (1.0 g, 6.0 mmol) in 30 mL of tetrahydrofuran (THF) with stirring and the reaction mixture was allowed to react at that temperature while being stirred. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (20 mL) and extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified through silica gel chromatography to yield 1-(4-methoxy-2,5-dimethylphenyl)ethanol as a white oil (0.87 g, yield 74%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=3)[CH:22]=2)[CH2:17][CH:16]1[C:41](=[O:53])[NH:42][C:43]1([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:14])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:51]([O:50][C:48]([C:43]1([NH:42][C:41]([CH:16]2[CH2:17][CH:18]([O:20][C:21]3[C:30]4[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=4)[CH:22]=3)[CH2:19][CH:15]2[C:13]([OH:14])=[O:12])=[O:53])[CH2:45][CH:44]1[CH:46]=[CH2:47])=[O:49])[CH3:52]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h
Yield: 79.7 %

Procedure:
TFA (24 mL) was added at room temperature to a solution of 2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)-4-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yloxy]cyclopentanecarboxylic acid tert-butyl ester (98, 1.1 g, 1.75 mmol) and triethylsilane (510 mg, 2.5 eq) in CH2Cl2 (24 mL). After 2 h, the reaction mixture was concentrated under reduced pressure, and then co-evaporated with toluene. The residue was re-dissolved in AcOEt and successively washed with a solution of NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated, to give 800 mg (80%) of the title compound 99 (800 mg, 80%): m/z=574 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:33])[CH2:31]C>>[C:30]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:33])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CCC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3)cc1

Procedure:
Compound dr was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with propionyl chloride. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: BrC1C=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:22]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[Br:35])[CH:26]1[CH2:36][C:37]([O:39]C)=O)(=[O:24])[CH3:23].C([O-])(O)=O.[Na+]>O.CO>[Br:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]1[C:22](=[O:24])[CH2:23][NH:6][C:37](=[O:39])[CH:36]=[C:26]12
Reactant: COC(=O)CC1NCCc2c(Br)cccc21
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (1280 mL) was cooled to −15° C. and conc. Sulfuric acid (147 mL, 2759 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (90 g, 276 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (540 g) in water (1.35 L). The slightly basic aqueous solution was extracted with AcOEt (3×500 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (76 g) which was used without further purification. UPLC-MS: MS 284.1/286.1 (M+H+); UPLC rt 0.50 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using General Procedure II-C, the title compound was prepared from 3,5-difluorophenylacetyl chloride (General Procedure II-B) and L-alanine (Aldrich).