Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10][C:9]=1[CH:19](Br)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]2[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:19]([C:9]3[O:10][C:11](=[O:18])[C:12]4[C:17]([C:8]=3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH3:20])[N:23]=[CH:24][C:25]=12
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1Cc1ccccc1)n1ncc2c(N)ncnc21
Yield: 35.4 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 4-benzyl-3-(1-bromoethyl)-1H-isochromen-1-one (intermediate C13, 22 mg, 0.064 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (12.99 mg, 0.096 mmol), and K2CO3 (13.29 mg, 0.096 mmol) in DMF (1 ml) at 55° C. for 2 hrs to give the title compound (9 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=412.1, tR (minutes, Method F)=2.18
Reaction SMILES: [S:1]1(=O)(=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10]>O>[CH2:8]([NH:11][CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1)[CH2:9][NH:10][CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: O=S1(=O)CC=CC1
Reactant: NCCN
Solvent: O
Product: C(CNC1CCSC1)NC1CCSC1
Yield: 63 %

Procedure:
A mixture of 2,5-dihydrothiophene 1,1-dioxide (236.4 parts, 2.0 moles); ethylenediamine (480.8 parts, 8 moles); and water (600 ml.) was heated at 70°-80° C. for 4 hours. The water and unreacted ethylenediamine were distilled under reduced pressure. Benzene (750 ml.) was added to the residue and the residual water was removed by azeotropic distillation. After removing the benzene, a reddish colored viscous oil in the amount of 375 g. (63 percent yield) that solidified on cooling was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[C:21]([C:28]3[NH:36][C:35]4[CH2:34][CH2:33][NH:32][C:31](=[O:37])[C:30]=4[CH:29]=3)[CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C>[O:37]=[C:31]1[C:30]2[CH:29]=[C:28]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[N:19]=[C:18]([O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH:27]=[CH:26]4)[NH:36][C:35]=2[CH2:34][CH2:33][NH:32]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Similar to the method described in Example 103, tert-butyl 4-hydroxypiperidine-1-carboxylate (Aldrich; 357 mg, 1.77 mmol) was added to a suspension of NaH (70.9 mg, 1.77 mmol) in DMF (2.0 mL) and the resulting light yellow solution was stirred at RT for 10 min. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 66 mg, 0.22 mmol) was added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 2.5 h. The mixture was cooled to RT and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (40 mL) and brine (40 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH in DCM) gave tert-butyl 4-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate as an orange oil. m/z (ESI, +ve ion) 463.3 (M+H)+.
Reaction SMILES: C[Si](I)(C)C.C[O:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15].O>C(#N)C>[OH:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 83.6 %

Procedure:
Trimethylsilyl iodide (11.1 mL, 76.3 mmol) was added to a solution of 3-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[4-(methylsulfonyl)phenoxy]benzamide (7.00 g, 15.3 mmol) in dry acetonitrile (100 mL) under argon for 21 h. Water (40 mL) was added to quench the reaction and the acetonitrile was removed in vacuo. The residue was diluted with ethyl acetate-(200 mL) and 1M aqueous hydrochloric acid. The organic layer was separated and further washed with 10% w/v aqueous sodium thiosulfate pentahydrate to remove residual iodine. The organic layer Was separated, dried (MgSO4), filtered and evaporated and purified by column chromatography, eluting with 3% to 5% methanol in DCM, to give the title compound as a white foam (5.70 g, 84%). Recrystallisation from hot ethanol (125 mg/mL) afforded the title compound as colourless needles (87% recovery). Mpt 126-132° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[C:29](Cl)[N:28]=2)[CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.[NH:44]1[CH2:54][CH2:53][CH:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:45]1.C(N(C(C)C)CC)(C)C>C(O)(CC)C.ClCCl>[CH2:51]([O:50][C:48]([CH:47]1[CH2:53][CH2:54][N:44]([C:29]2[N:28]=[C:27]([N:22]3[CH2:21][C@@H:20]([N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:42])([F:43])[F:1])[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=4)[C:8]4[N:9]=[CH:10][C:11]([C:14]5[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=5)=[CH:12][N:13]=4)[CH2:24][C@H:23]3[CH2:25][CH3:26])[C:32]([Cl:33])=[CH:31][N:30]=2)[CH2:45][CH2:46]1)=[O:49])[CH3:52]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(Cl)ncc1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cnn(C)c5)cn4)C[C@H]3CC)n2)CC1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzyl-[(3S,5R)-1-(2,5-dichloro-pyrimidin-4-yl)-5-ethyl-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (50.6 mg, 0.0784 mmol), ethyl isonipecotate (31 μL, 0.196 mmol) and diisopropyl-ethylamine (21 μL, 0.118 mmol) in sec-butanol (2 mL) is stirred at 120° C. for 10 hour. After addition of ethyl isonipecotate (12 μL, 0.0784 mmol) and diisopropyl-ethylamine (27 μL, 0.157 mmol), the mixture is stirred for additional 8 hours. The mixture is diluted with dichloromethane and washed with waterm 1N HCl aq, and the brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:2 to 5% MeOH in AcOEt) to give (1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester, 34.7 mg). The obtained solid is dissolved in MeOH (2.5 mL), 1N NaOH aq (225 μL, 0.225 mmol) and water (0.3 mL), and the resulting mixture was stirred at room temperature for 18 hour. 1N HCl (225 μL, 0.225 mmol) and then MeOH were added to the mixture and the solvent was removed by evaporation. The residue was dissolved in dichloromethane and then filtered. The filtrate was evaporated to give 1-[5-chloro-4-((2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-pyrimidin-2-yl]-piperidine-4-carboxylic acid (29.2 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(NC2CCCCC2)c(Br)c1
Yield: 98.1 %

Procedure:
A mixture of Example 86a (0.136 g, 0.5 mmol) and cyclohexanamine (0.198 g, 2.0 mmol) in dioxane (2 mL) was heated under microwave conditions (140° C., 1 hour). The solvent was removed, and the residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give 0.164 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC1CCCC(C(=O)O)C1
Reaction time: 192 h
Yield: 57.2 %

Procedure:
A mixture of 3-aminobenzoic acid (66.12 g, 0.48 mol) and 10% palladium-on-carbon (13.2 g) in 30% aqueous ethanol (1200 mL) was placed in a 4 L stainless steel high-pressure reactor and reduced at 50° C. and 500 psi of hydrogen for 30 h. The mixture was filtered through Celite and the filter cake was washed with ethanol. The solvent was evaporated, boiling ethanol (1 L) was added and the mixture was allowed to stand for 8 days at room temperature. The mixture was filtered and the product was washed with ethanol and then dried in a vacuum oven at 50° C., to give 3-aminocyclohexanecarboxylic acid (39.30 g, 57%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with m-anisidine to yield 2-[(3-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([OH:21])[CH:20]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:19]2[CH:20]=[C:15]([C:13](=[O:14])[CH3:12])[CH:16]=[CH:17][CH:18]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 3-hydroxyacetophenone (5.5 g, 42.2 mmol), and K2CO3 (11.7 g, 84.6 mmol) in DMF (50 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified by flash chromatography eluting with (hexanes/ethyl acetate 70:30) to give the title compound (8.6 g, 70%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:42][CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C(O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(CNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
906 mg (4.73 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) are added to a solution of 1.24 g (3.64 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzoic acid (prepared in accordance with WO 2008/017361), 382 mg (3.64 mmol) of aminoacetaldehyde dimethyl acetal and 557 mg (3.64 mmol) of 1-hydroxybenzotriazole hydrate (HOBt) in 14 ml of DMF, and the mixture is stirred overnight at room temperature. Water is added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-N-(2,2-dimethoxyethyl)benzamide as colourless crystals; ESI 430.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30](OC)=[O:31])=[C:14]([NH2:34])[N:13]=1)[CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C1COCC1>[CH2:7]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])=[C:14]([NH2:34])[N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1nc(N)c2ncn(CCOc3ccccc3C(=O)OC)c2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOc1nc(N)c2ncn(CCOc3ccccc3CO)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a suspension of lithium aluminum hydride (74 mg, 1.9 mmol) in THF (10 ml) was added a solution of 2-butoxy-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine (500 mg, 1.4 mmol) obtained by Reference Example 5 in THF (2 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 1N Aqueous sodium hydroxide solution was added thereto, followed by filtration through celite pad, and the filtrate was concentrated under reduced pressure to give 500 mg (1.4 mmol) of the titled compound as a white solid. Yield: 99%.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH3:5][C:6]1[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C=O.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:14]1[C:15]2[C:6]([CH3:5])=[CH:7][CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(C(=O)O)c2c1NCCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)c2c1N(C)CCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
24 mmol of sodium cyanoborohydride w&e added to 5 mmol of 8-methyl-1,2,3,4-tetrahydroquinoline-5-carboxylic acid and 50 mmol of paraformaldehyde in 30 ml of glacial acetic acid, the temperature of the reaction mixture being kept below 30° C. using an ice bath. The reaction mixture was stirred at room temperature for 15 hours, poured onto ice and adjusted to pH 4 with aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate and concentrated.
Reaction SMILES: C([Si](CC)(CC)[O:4][CH2:5][CH2:6][C:7]#[C:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])C.Cl.CCCCCC.O>CO>[CH2:14]([Si:9]([CH2:10][CH3:11])([CH2:12][CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:4])[CH3:15]
Reactant: CC[Si](C#CCCO[Si](CC)(CC)CC)(CC)CC
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: CC[Si](C#CCCO)(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Triethyl(4-(triethylsilyl)but-3-inyloxy)silane (32.99 g, 110.66 mmole) was dissolved in MeOH (336 ml), 2N HCl (62 ml) was added, and the mixture was stirred for 4 hours at RT. Hexane (250 ml) and H2O (200 ml) were then added to the solution and the aqueous phase was extracted with hexane (3×100 ml). The combined organic phases were washed with H2O (100 ml) and then with saturated NaCl-Solution (50 ml) and dried over MgSO4. After filtering off the drying agent the solvents were removed on a rotary evaporator. Column chromatography of the residue (hexane/ether=4:1, then ether) yielded 4-(triethylsilyl)but-3-in-1-ol (19.6 g, 96%) as a colourless oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH2:27][OH:28])[CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[C:15]([CH:27]=[O:28])[CH:14]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)c(F)cc1C=O
Reaction time: 3 h
Yield: 26 %

Procedure:
Pyridiniumchlorochromate (9.36 g, 43.4 mmol) was added to the solution of the crude N-(4,5-difluoro-2-(hydroxymethyl) phenyl) pivalamide in CH2Cl2 (150 mL) at rt. The yellow solution turned into dark brown in 10 min, and the mixture was continued stirring for 3 hr, and then passed through a thin silica gel pad with CH2Cl2 (2×50 mL). The combined organic solution was concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜60% EtOAc/hexanes (1300 mL) to afford the expected product as a brown solid (1.91 g, 26% yield after three step); 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 7.42-7.48 (m, 1 H), 8.75 (dd, J=13.35, 7.30 Hz, 1 H), 9.77-9.80 (m, 1 H), 11.40 (s, 1 H); Mass spec. 242.08 (MH+), Calc. for C12H13F2NO2 241.09
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)Oc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(=O)Oc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 80.5 %

Procedure:
Using general procedure A, 1-Boc-4-piperidone (2.52 g, 12.66 mmol) and acetic acid 4-amino-phenyl ester (Bargota, Rakesh S.; et al., Bioorg. Med. Chem. Lett., 13, 10, 2003, 1623-1626) (2.95 g, 19.52 mmol) afforded 4-(4-acetoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.41 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8]1([N:14]=[C:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([NH:14][C:15]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccncc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)NC1CCCCC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and cyclohexyl isocyanate (146.3 mg, 1.17 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:43])[C@H:26]([CH2:41][SH:42])[NH:27][S:28]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([S:42][CH2:41][C@H:26]([NH:27][S:28]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:43])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NS(=O)(=O)c1cccc2ccccc12
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Product: CCOC(=O)CCCn1ccc2c(SC[C@H](NS(=O)(=O)c3cccc4ccccc34)C(=O)OC(C)(C)C)nc(C)nc21

Procedure:
Preparation in analogy to example 6c from 282 mg of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) and 440 mg of N-(naphthalene-1-sulfonyl)-(R)-cysteine-tert-butyl ester. Yield: 110 mg.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:29]=[CH:28][C:8]([O:9][CH:10]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[O:12])=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH3:30]O>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[O:12])=[CH:28][CH:29]=1)([O:4][CH3:30])=[O:3]
Reactant: CC(C)(C)C(=O)C(Oc1ccc(C(=O)O)cc1)C(=O)Nc1ccc(Cl)cc1Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(OC(C(=O)Nc2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
HCl gas was bubbled into a suspension of N-[2-[4-carboxyphenoxy]-4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (12.0 g, 28.3 mmol, available from Eastman Kodak, Rochester, N.Y.) in absolute methanol (175 mL) for 30 minutes. The mixture was heated to reflux for 2 hrs during which complete solution was obtained. Upon cooling to room temperature, white crystals of the product began to form. The reaction mixture was cooled in an ice bath, and the solids were collected by filtration, washed with fresh methanol and air-dried to provide N-[2-[4-carbomethoxyphenoxy]-4,4-dimethyl-3-oxopentanoyl]-2,4-dichloroaniline (8.4 g, 68% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:13]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:19][S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:13]3[C:12]([NH:11][CH2:10][CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:30])[CH3:29])=[CH:3][CH:4]=4)=[N:17][CH:16]=[N:15][C:14]=3[S:18][CH:19]=2)=[CH:26][CH:25]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCCNc2ncnc3scc(-c4ccc(F)cc4)c23)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of N-[3-(4-aminophenyl)propyl]-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine (0.014 g, 0.037 mmol) and acetic anhydride (0.01 mL) in methylene chloride (2.0 mL) was heated to 60° C. for 6 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was then dissolved in ethyl acetate (30 mL) and the organic layer was washed with sodium bicarbonate (2×25 mL). Concentration, followed by followed by silica gel column chromatography purification (using 3% methanol in 1:1 ethyl acetate/hexane and ammonia (0.03%) as eluent) afforded N-[4-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propyl)phenyl]acetamide in 90% yield.