Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(c(N3CCOCC3)c1)CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(cccc2N2CCOCC2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37]>>[CH3:39][S:36]([CH2:35][CH2:34][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)CCCl
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(C5CCNCC5)c4)nc23)cc1
Product: CS(=O)(=O)CCN1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
{3-[1-(2-Methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-piperidin-4-yl-phenyl)-amine and 1-chloro-2-methanesulfonyl-ethane (75.0 mg, 0.526 mmol) in a manner analogous to Example 183. Product isolated as a pale yellow solid (0.164 g, 65%). MP=217-219° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 8.27 (d, J=7.7 Hz, 2H), 8.09 (d, J=7.5 Hz, 2H), 7.68 (d, J=7.0 Hz, 1H), 7.63 (s, 1H), 7.36-7.27 (m, 2H), 7.04 (t, J=6.5 Hz, 1H), 6.90-6.85 (m, 2H), 3.24 (t, J=6.5 Hz, 2H), 3.12-3.05 (m, 8H), 2.94 (t, J=6.7 Hz, 2H), 2.62-2.52 (m, 1H), 2.25-2.16 (m, 2H), 1.98-1.90 (m, 2H), 1.85-1.72 (m, 2H). MS=554 (MH)+.
Reaction SMILES: [C:1]1([CH2:7][S:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23](=O)[CH3:24])[CH:20]=[CH:21][CH:22]=1.[K+].[Br-]>>[OH:15][C:13]1[CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[O:12][C:10](=[O:11])[C:9]=1[S:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(C)c1
Agent: [Br-]
Agent: [K+]
Product: Cc1cccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c1
Yield: 65 %

Procedure:
This compound was prepared by the condensation of the diethyl ester of [(phenylmethyl)thio]-propanedioic acid (1 g, 3.54 mmol) with the corresponding trimethylsilyl enol ether of 3'-methyl acetophenone (7.09 mmol, 1.46 g) as described in general procedure A. Isolated Yield: 65% m.p. 137-138° C. 1H NMR (400 MHz, DMSO-d6) δ11.9 (brs, 1 H), 7.6 (m, 2 H), 7.39 (t, 1 H), 7.35 (d, 1 H), 7.25 (d, 4 H), 7.2 (m, 1 H), 6.7 (s, 1 H), 4.0 (s, 2 H), 2.38 (s, 3 H); IR (KBr) 3030, 2585, 1617, 1536, 1402, 1100, 787, 696 cm-1; MS (CI) m/e 325 (65), 291 (2), 233 (4), 119 (9), 91 (100).
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].C(O)(=O)C>CO>[N:33]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:34][C:1]=1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccccc1N
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1nc2ccccc2[nH]1
Yield: 24.1 %

Procedure:
In 20 ml of methanol was dissolved 1.1 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 356 mg of o-phenylenediamine and 0.2 ml of a 50% aqueous solution of acetic acid were added thereto. The mixture was allowed to react at room temperature for 40 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was purifled by medium-pressure column chromatography on silica gel to obtain 330 mg of the titled compound as a colorless crystal.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.Br[C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>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(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:43]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH:31]([OH:40])[CH2:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[CH:41][CH:42]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: OC(CCc1cccnc1)COc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 120 °C

Procedure:
Prepared according to the method as described in Example 33a) from toluene (8 ml), aqueous sodium carbonate (2 M, 2.47 ml), 3-methoxybenzeneboronic acid (0.413 g), ethanol (2 ml), (±)-1-(3-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.79 g, Example 56a) and tetrakis(triphenylphosphine)palladium(0) (0.071 g) with heating at 120° C. for 4 hours. After work up the residue was purified by column chromatography over silica with ethyl acetate to give the title compound as a white solid after trituration with ether:hexane (0.27 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])C)[CH:7]=1.[H-].[Na+].ClC1O[C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:19][N:20]=1>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9]2[O:11][C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[CH:7]=1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (1.1 g, 6.7 mmol) in DMF (20 mL) was added to a suspension of NaH (402 mg, 10.05 mmol, 60% dispersion in mineral oil) in DMF (20 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 4-(2-Chloro-oxazol-5-yl)-benzonitrile (1.37 g, 6.7 mmol) in DMF (20 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (200 mL). The solid was collected by filtration, washed with water, and dried under vacuum to afford the title compound (1.45 g, 75%). m.p.=228° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>>[Br:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COC(=O)c1ccc(N)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 120 °C

Procedure:
In a 300 mL sealed tube was placed 3,5-dibromo-1-methylpyridin-2(1H)-one (4.0 g, 15.0 mmol), methyl 6-aminonicotinate (2.3 g, 15.0 mmol), cesium carbonate (10.7 g, 33 mmol), and Xantphos (740 mg, 8.5 mol %). The flask was evacuated and filled with nitrogen 3×. Dioxane (100 ml) was added and the mixture degassed for 25 min with bubbling nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (690 mg, 5 mol %) was then added, the vessel sealed and the reaction heated to 120° C. overnight. The reaction was cooled and diluted with Ethyl acetate (500 mL) and saturated aqueous NaHCO3 (150 mL), the layers were separated and extracted ethyl acetate 2×. The organics were washed with brine 3×, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography: ISCO 80 g silica, ethyl acetate/hexanes, to give 186a.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:17])[CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)cc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(OCc2ccccc2)c1

Procedure:
Preparation takes place in analogy to Example 11 from 2.8 g (12.3 mmol) of 3-(benzyloxy)-5-hydroxybenzaldehyde (Example 3J), 1.67 g (24.5 mmol) of imidazole and 3.57 g (13.5 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:19][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(O)c1ccc(CC(C)C)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC(Br)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.3 %

Procedure:
To a solution of 1-(4-isobutylphenyl)hexan-1-ol (9.15 g) and carbon tetrabromide (25.9 g) in tetrahydrofuran (250 ml) was added triphenylphosphine (20.5 g). The mixture was stirred at room temperature for 6 hours. After the white solid was filtered off, the filtrate was evaporated. n-Hexane (300 ml) was added to the residue and the precipitate was filtered off. The filtrate was evaporated and the residual oil was distilled under reduced pressure to give 1-(1-bromohexyl)-4-isobutylbenzene (3.52 g) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:58]2[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=2)[CH2:56][CH3:57])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:58]2[CH:63]=[CH:62][C:61]([C:1]#[N:2])=[CH:60][CH:59]=2)[CH2:56][CH3:57])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: CCNC(=O)c1cn(C(CC)c2ccc(Br)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(CC)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Example 35 is prepared as described for Example 15, substituting preparation 15b with preparation 35a. ESI mass spectrum: [M+H]+=468; Retention time HPLC: 0.51 min (Z011_S03).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2C=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[Cl:18])=[CH:5][N:4]=1.O.N>C(COC)OC>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[C:15]([NH2:16])=[C:14]([Cl:18])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc3c(Cl)ncnc32)cn1
Agent: N
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Nc2ncnc(Cl)c2N)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
A mixture of 25 g of 5-(6-chloro-9H-9-purinyl)-2-pyridyl methyl ether, 250 mL conc. ammonia water and 500 mL dimethoxyethane was stirred at 70° C. for 4 hours, and the resulting suspension was filtered, to give 21.2 g of the title compound as white crystals (91% y.). (4) 8-Bromo-9-(6-methoxy-3-pyridyl)-9H-6-purineamine
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.[OH-].[Na+].O>C(O)C>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cnc2c3ccccc3ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2c3ccccc3ccn2c1=O

Procedure:
A mixture of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (2.78 g., 0.010 mole), 1.0 N NaOH (15.0 ml.), H2O (40 ml.) and ethanol (30 ml.) was refluxed for 15 minutes. The mixture was filtered and the cooled filtrate acidified with 15.0 ml. of 1.0 N HCl to precipitate crude acid (2.36 g.), m.p. 193°-223°. Two recrystallizations from 2-methoxyethanol gave peach needles, m.p. 252°-253.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].Br.[C:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:23])[CH3:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:33][CH:32]=1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CNC(=O)c1ccc(OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17.4 g (0.05 mol) of glycyl-L-tyrosine ethyl ester·HBr, 9 g (0.05 mol) of p-acetoxybenzoic acid and 5.1 g (0.05 mol) of triethylamine were dissolved in 250 ml of dichloromethane, and after the solution was cooled to 0° C., 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added to the solution, and the solution was stirred overnight. The reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the mixture under reduced pressure to obtain p-acetoxybenzoylglycyl-L-tyrosine ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[S-:10][C:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][S:10][C:11]#[N:12]
Reactant: ClCc1cccc(Cl)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: N#CSCc1cccc(Cl)c1

Procedure:
The mixture of 250 g of m-chlorobenzyl chloride, 16.6 g of potassium thiocyanate and 150 ml of 95% aqueous ethanol is refluxed for 3 hours and evaporated. The residue is taken up in methylene chloride and water, the organic solution separated; washed with water dried and evaporated to yield the m-chlorobenzyl-thiocyanate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][C@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[C:17]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl>CO>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:31][CH2:32][C@H:33]4[CH2:37][CH2:36][CH2:35][O:34]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC[C@H]4CCCO4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydrofuran-2-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (75 mg, 0.15 mmol) was dissolved in methanol (2 mL). Hydrochloric acid (4.51 μL, 0.15 mmol) was added and the reaction mixture was stirred at 75° C. for 30 minutes. The solvent was evaporated under reduced pressure and the crude (R)-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (56.0 mg, 93%) was used as such in the subsequent step. MS (ES+) m/z 406.3 (M+H)+
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:4]=1>C1COCC1.C(O)(=O)C.O=[Pt]=O>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14][CH2:13]3)[CH:4]=1
Reactant: CNc1cc(Oc2ccc3ncccc3c2)ncn1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1cc(Oc2ccc3c(c2)CCCN3)ncn1

Procedure:
In the presence of 1 g of PtO2 (Engelhard 7018), a solution of 2.63 g (10.4 mM) 6-methylamino-4-(quinolin-6-yloxy)-pyrimidine in 175 ml of THF/acetic acid 4:1 is hydrogenated. The catalyst is filtered off and the filtrate concentrated in vacuo. The residue is diluted with EtOAc and sat. Na2CO3 solution and extracted 3× with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and partially concentrated in vacuo. The crystallized title compound can be filtered off and washed with EtOAc and DIPE: TLC(EtOAc): Rf=0.18; MS: [M+1]+=257. More product can be isolated from the filtrate by column chromatography (SiO2; EtOAc).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13].[N-:21]=[N+]=[N-].[Na+]>CS(C)=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:3]([CH2:2][NH2:21])=[CH:12]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CN

Procedure:
Prepared according to Procedure D using 3-(chloromethyl)-8-methyl-2-o-tolyl-quinoline (667 mg, 2.4 mmol) in DMSO (10 mL) was added NaN3 (500 mg, 3 eq). After purification, (8-methyl-2-o-tolylquinolin-3-yl)methanamine was obtained as pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:20][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Cc1cc(CCC(C)=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In 50 ml of acetone was dissolved 2.17 grams of 4-(7-hydroxy-2-fluorenyl)-butan-2-one, then 1.43 grams of potassium carbonate (anhydrous) was added, and heated to reflux for 2 hours after addition of an excess of methyl iodide. The mixture was stirred at room temperature for overnight and acetone was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with magnesium sulfate, and ethyl acetate was removed therefrom by evaporation in vacuo. The residue was subjected to a silica gel column chromatography, eluted with a 4:1 mixture of n-hexane and ethyl acetate, and the resulting crystals were recrystallized from methanol to give 1.15 grams of 4-(7-methoxy-2-flourenyl)-butan-2-one, white crystals, m.p. 100°-101° C.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:10]2=[O:23])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][C:10](=[O:23])[N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:3][CH:4]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(I)nc3)c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(C#C[Si](C)(C)C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
According to Scheme 33 Step 2: A mixture of 1-((6-iodopyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.48 mmol, 200 mg), PdCl2(PPh3)2 (33 μmol, 23 mg), CuI (24 μmol, 4.5 mg), iPr2EtN (0.99 mmol, 1.72 μl), trimethylsilylacetylene (1.43 mmol, 203 μL) and DMF (3 mL, previously deoxygenated) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2/MeOH(NH3)sat. 3% yielding 5-(4-methoxyphenyl)-1-((6-(2-(trimethylsilyl)ethynyl)pyridin-3-yl)methyl)pyridin-2(1H)-one (174 mg, 93%).
Reaction SMILES: O.[O:2]1CCCC1.[CH3:7][C:8]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:9][C:10](=[O:13])[CH2:11][CH3:12].[BH4-].[Na+]>[OH-].[Na+]>[OH:2][C:21]([CH3:22])([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:24])[CH2:16][CH:15]=[CH:14][C:8]([CH3:7])=[CH:9][C:10](=[O:13])[CH2:11][CH3:12]
Reactant: C1CCOC1
Reactant: CCC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Reaction time: 0.33 h

Procedure:
To a mixture of 1.9 g. of mercuric acetate, 6 ml. of water and 20 ml. of tetrahydrofuran is added 1.49 g. of 5,9,13-trimethyltetradeca-4,6,12-trien-3-one slowly. After addition is complete, the reaction mixture is stirred for about 20 minutes. The mixture is cooled to about 0° and 6 ml. of aqueous sodium hydroxide (3 molar) is added followed by 0.49 g. of sodium borohydride in aqueous sodium hydroxide (about 3 molar). The mixture is stirred for about 30 minutes. The mixture is then decanted, concentrated, diluted with water and then extracted with ether. The ethereal extract is washed with water, dried over magnesium sulfate and the product chromatographed on silica to yield 13-hydroxy-5,9,13-trimethyltetradeca-4,6-dien-3-one.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-geranyloxybenzoic acid(2.47 g) was dissolved in chloroform(50 ml) and triethylamine(2.49 ml), and then diphenylphosphinic chloride(1.72 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(aminomethyl)pyridine(0.97 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 3.10 g of the aimed compound.