Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)=[CH2:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cccc(C(=O)OCC)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc(CC)n1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Ethyl 6-vinylpicolinate (4.70 g, 26.5 mmol) was dissolved in 100 mL of ethanol. To this was added 20% Pd(OH)2 on carbon (1 g, 50% water) and the mixture was stirred under a hydrogen balloon for 2 hours. The mixture was purged with nitrogen, filtered through GF/F filter paper, and the filtrate concentrated under reduced pressure to give 4.5 g (95%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:43](P(=O)(OCC)OCC)[P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47].CN(C)C=O.[H-].[Na+]>O>[CH2:46]([O:45][P:44](/[CH:43]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:40]=[CH:39][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([N:28]4[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]4)[S:25][C:26]=3[CH3:27])=[C:18]([O:41][CH3:42])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:48][CH2:49][CH3:50])=[O:51])[CH3:47]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 1-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 25 mg) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]piperidine-4-carboxylate as a colorless oil (0.29 g, yield 78%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=O)[CH2:18][C:19]([C:21]1C=C[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)[CH:22]=1)=O)(C)(C)C.[C:36](O)([C:38](F)(F)F)=[O:37]>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[N:16]=[C:17]([C:18]3[CH:19]=[CH:21][CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[CH:24]=3)[CH2:38][C:36](=[O:37])[NH:7][C:8]=2[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M77) (0.36 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 81%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[C:10]2[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2][Cl:1])[C:10]([S:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:11]1
Reactant: Clc1cccc(CBr)c1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.7 g, 1.8 mmoles), 3-chloro-benzyl bromide (0.28 mL, 2.17 mmoles), and cesium carbonate (0.7 g, 2.17 mmoles) in DMF (5 mL) was stirred together in a round bottom flask at room temperature for 30 minutes. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (0.55 g, 1.1 mmoles).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].[NH2:11][C:12]1[C:13]([C:18](O)=O)=[N:14][CH:15]=[CH:16][N:17]=1>C(OCC)C>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:18]1[C:13]1[C:12]([NH2:11])=[N:17][CH:16]=[CH:15][N:14]=1)[CH3:2]
Reactant: Nc1nccnc1C(=O)O
Reactant: CCNc1ccncc1N
Solvent: CCOCC
Product: CCn1c(-c2nccnc2N)nc2cnccc21
Temperature: 195 °C
Yield: 5.5 %

Procedure:
To polyphosphoric acid, preheated to 130° C., was added in one portion an intimate mixture of the product of Example 1 Step 2 (206 mg, 1.5 mmol) and 3-aminopyrazine-2-carboxylic acid (230 mg, 1.65 mmol). The temperature was increased to 195° C. for 1 hour and then cooled back to 130° C. for a further 1 hour. The viscous oil was poured on to ice containing saturated sodium carbonate solution and diethyl ether (5 ml) and the aqueous solution was extracted with chloroform (×5). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude solid was purified by silica gel chromatography eluting with a gradient of dichloromethane to 0.880 ammonia:ethanol:dichloromethane (1:9:40), to afford the title compound, (20 mg, 6%); MS (ES+) m/e 241 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C@@H:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]1[OH:28]>O1CCCC1>[CH:8]1([C:11]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][C@H:16]2[OH:28])=[O:12])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)C2CC2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (4.85 mL, 34.8 mmol) and cyclopropanecarbonyl chloride (3.18 mL, 35.0 mmol) were added to a 0° C. solution of tert-butyl trans-4-amino-3-hydroxypiperidine-1-carboxylate (7.52 g, 34.8 mmol) in tetrahydrofuran (100 mL), and the reaction was allowed to warm to room temperature and stir for 18 hours. After concentration in vacuo, the crude product was diluted with ethyl acetate, insoluble material was removed by filtration, and the solids were washed with ethyl acetate (3×50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Gradient: 0% to 5% methanol in ethyl acetate) to afford the product as a solid. Yield: 1.30 g, 4.57 mmol, 13%. LCMS m/z 285.6 [M+H]+. 1H NMR (400 MHz, CDCl3), observed peaks: δ 5.79 (br d, J=5 Hz, 1H), 4.21-4.34 (br m, 1H), 4.03-4.21 (br m, 1H), 3.70-3.79 (m, 1H), 3.34-3.42 (m, 1H), 2.66-2.79 (br m, 1H), 2.59 (br dd, J=12, 11 Hz, 1H), 1.88-1.96 (m, 1H), 1.46 (s, 9H), 1.37-1.44 (m, 1H), 1.01-1.05 (m, 2H), 0.77-0.87 (m, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:35][CH:34]([NH2:36])[CH2:33]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[F:37][C:38]([F:53])([F:52])[C:39]1[CH:40]=[C:41]([CH:49]=[CH:50][CH:51]=1)[C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43]>>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:33][CH:34]([NH:36][C:46]([CH2:45][NH:44][C:42](=[O:43])[C:41]4[CH:49]=[CH:50][CH:51]=[C:39]([C:38]([F:53])([F:37])[F:52])[CH:40]=4)=[O:47])[CH2:35]3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(C2CCC(N3CC(N)C3)CC2)cc1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid from an EDCI coupling of 1-[4-(4-amino-phenyl)-cyclohexyl]-azetidin-3-ylamine TFA salt (as prepared in the previous step) and (3-trifluoromethyl-benzoylamino)-acetic acid using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:5]=1[F:11].[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]=1[F:11]
Reactant: COC(=O)c1cccc(Br)c1F
Reactant: O=C1CCCN1
Product: COC(=O)c1cccc(N2CCCC2=O)c1F
Yield: 26.9 %

Procedure:
3-Bromo-2-fluorobenzoic acid methyl ester (500 mg, 2.15 mmol) was treated with pyrrolidin-2-one (273 mg, 3.22 mmol) as described in D24 to afford the title ester (137 mg).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([CH2:33][C:32]([O:34][CH3:35])=[O:31])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Product: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Example 300, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene were reacted to give methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate. M/z 368.2, calc. 367.16
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:34](=[O:35])[CH2:33][CH2:32][C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[S:34](=[O:35])[CH2:33][CH2:32][C:11]=3[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Yield: 59.8 %

Procedure:
6.90 g ethyl 4-{4-[4-(3-chloro-phenylamino)-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperazin-1-yl}-benzoate and 70 ml of 1 molar sodium hydroxide solution are placed in 40 ml of methanol and 40 ml of tetrahydrofuran, then refluxed for 1.5 hours with stirring. The resulting solution is evaporated down, the residue is cooled and acidified slightly with 2 molar hydrochloric acid. The precipitate formed is suction filtered, washed and dried. The substance is stirred with ethyl acetate/methanol 9:1, suction filtered and dried. 3.90 g of the product are obtained as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20].[CH2:21]([O:23]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:22]>>[C:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20])(=[O:23])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2c(c1)CC(Cc1ccncc1Br)C2=O
Product: COc1ccc2c(c1)CC(Cc1ccncc1C(C)=O)C2=O

Procedure:
The title compound 113 is prepared according to the procedure reported in Example 36.5 with compound 106 (235 mg, 0.71 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.34 mL, 0.99 mmol) as reactants. White solid. (Yield 135 mg, 64%).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>O1CCOCC1.C(O)(C)C>[NH:17]1[CH2:16][CH2:15][CH:14]([O:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][C:9]=2[O:27][CH3:28])[N:6]=[CH:5][N:4]=[C:3]3[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[C:30]([Cl:29])[C:31]=2[F:37])[CH2:19][CH2:18]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Temperature: 100 °C

Procedure:
4.0M HCl in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100° C. for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a di-hydrochloride salt (2.38 g); 1H NMR Spectrum: (DMSO d6) 1.84-1.99 (m, 2H), 2.22-2.33 (m, 2H), 3.12-3.33 (m, 4H), 4.00 (s, 3H), 5.08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8.84-8.94 (m, 2H), 8.99-9.11 (m, 1H); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[CH2:17]([OH:19])[CH3:18]>C(Cl)(Cl)Cl>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:15])[O:19][CH2:17][CH3:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCO
Reactant: N#CCCCCc1csc(NC(=N)N)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)CCCCc1csc(NC(=N)N)n1
Reaction time: 2 h

Procedure:
2 g of 2-guanidino-4-(4-cyanobutyl)thiazole was suspended in a mixture of 15 ml of ethanol and 25 ml of chloroform, and hydrogen chloride gas was passed through the solution under stirring at -5° to 5° C. for 2 hours. The resulting solution was allowed to stand at 5° C. for 4 days and the solvent was distilled away under reduced pressure. The residue was suspended in ethanol, and the suspension was poured into ice water containing 15 g of potasium carbonate. The precipitated crystals were collected by filtration washed with water and ether to provide 2.1 g of ethyl 5-(2-guanidinothiazol-4-yl)pentanoimidate having a melting point of 138°-139° C. ##STR64##
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:30])[C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[O:14])=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:30][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[C:13]([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[CH:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[O:14])(=[O:3])[CH3:2]
Reactant: C#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)cc2)cc1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCOc1ccc(CCNC(=O)C(OC(C)=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetylchloride (0.7 g, 8.9 mmol) is slowly added to a cooled (0° C.) mixture of 2-(4-chloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (3.0 g, 8.0 mmol) and pyridine (0.7 g, 8.9 mmol) in 30 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room temperature and subsequently poured on ice and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over sodium sulfate and the solvent is evaporated, the residue is purified by chromatography on silica gel to give 2-acetoxy-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 2.13 (s, 3H, CH3CO2), 2.52 (t, 1H, C≡CH), 2.80 (t, 2H, CH2CH2), 3.57 (t, 2H, CH2CH2), 3.87 (s, 3H, OCH3), 4.79 (d, 2H, OCH2C≡C), 6.03 (s, 1H, CHOH), 6.65–7.34 (m, 8H, CH arom., NH).
Reaction SMILES: [Li].[CH3:2][Si:3]([CH3:6])([CH3:5])Cl.[N:7]1[CH:12]=[C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:14]2[CH3:15])[CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH3:15][N:14]1[CH2:16][CH2:17][CH2:18][CH:13]1[C:11]1[CH:10]([Si:3]([CH3:6])([CH3:5])[CH3:2])[CH:9]=[CH:8][N:7]([Si:3]([CH3:6])([CH3:5])[CH3:2])[CH:12]=1
Reactant: CN1CCC[C@H]1c1cccnc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CN1CCCC1C1=CN([Si](C)(C)C)C=CC1[Si](C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a suspension of lithium powder (0.42 g, 60 mmol) in freshly distilled THF (20 mmol) cooled at −10° C. was added freshly distilled trimethylchlorosilane (7.6 mL, 60 mmol). A solution of (S)-nicotine (3.2 mL, 20 mmol) in THF (20 mL) was injected dropwise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The precipitate formed was decanted over 2 h and the liquid portion was canulated into a 2 neck flask mounted with a distillation apparatus under Ar. After removal of the THF by distillation at atmospheric pressure, the product was distilled under vacuum (1.5 mm Hg, bp=130–135° C.) to give 71% (4.36 g) of 3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine i as a yellow oil (95% pure by NMR). 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 1 H), 5.78–5.72 (m, 1 H), 4.37–4.29 (m, 1 H), 3.06–2.93 (m, 1 H), 2.4–1.4 (m, 10 H), 0.08 (s, 9 H), −0.05 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 127.49, 126.41, 121.14, 102.08, 101.00, 66.67, 57.21, 41.05, 32.52, 26.41, 21.84, −0.83, −0.90, −2.43, −2.64. HRMS Calcd for C16H32N2Si2: 309.2182 [M+H]+. Found: 309.2166 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Cl)c(Cl)c1
Temperature: 4 °C
Yield: 52.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4-dichlorobenzoic acid (15.3 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (17.6 g; m.p. 228° C.) is dissolved in boiling ethanol (900 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with isopropyl ether (2×30 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4-dichlorobenzamide (9.2 g), m.p. 230° C., is obtained.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3][C:2]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14].[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(Cl)Cl>O>[Si:20]([O:14][CH2:13][C@@H:12]([NH:11][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:1]=1)[CH3:15])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1ncc2c(n1)CNCC2
Yield: 66.2 %

Procedure:
A solution of (S)-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (138, 0.215 g, 1.03 mmol), TBDMS-Cl (0.171 g, 1.14 mmol) and TEA (0.216 ml, 1.55 mmol) and DCM (5 mL) were stirred for 18 h, poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 0.220 g (66.1%) of (S)—N-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (152).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1.O>C(Cl)Cl>[C:24]([O:23][C:21](=[O:22])[C:20]1[CH:28]=[CH:29][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reaction time: 4 h
Yield: 87.1 %

Procedure:
Trifluoromethanesulfonic anhydride (1.04 ml, 6.2 mmol) was added to a cooled (5° C.) solution of tert-butyl 4-hydroxybenzoate (1 g, 5.1 mmol) in a mixture of DCM (25 ml) and TEA (1.1 ml, 7.8 mmol). After 4 h at 5° C., water was added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (eluent: cyclohexane/iPr2O 95/5) to yield the above-titled compound as a colorless oil (1.45 g). 1H NMR (CDCl3): 8.09 (2H, d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 1.60 (9H, s).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.ClC(OC)=O.CCN(CC)CC>CO>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1ccc(NC(=O)Nc2c(F)ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (790 mg, 1.71 mmol, 1.0 equiv) in MeOH (5 mL) was added by syringe HCl (4.0 M in dioxane, 4.5 mL, 17 mmol, 10 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in DCM (20 mL) and methyl chloroformate (158 μL, 2.05 mmol, 1.2 equiv) and Et3N (716 μL, 5.13 mmol, 3.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 1.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by preparative thin layer chromatography (10% MeOH/DCM) to provide methyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (275 mg, 38%). LCMS m/z (APCI)=420.2 (M+H).