Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[O-]CC.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:3]1([C:1]#[N:2])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: N#CC1c2ccccc2Cc2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1(C#N)c2ccccc2Cc2ccccc21
Yield: 70.2 %

Procedure:
9-Cyano-9,10-dihydroanthracene [2] (1.25 g, 6.09 mmol) was added to sodium ethoxide prepared from Na (0.196 g, 8.53 mmol) and EtOH (10 mL) and heated at reflux (1 hr). The solution was then cooled in an ice bath and ethyl bromoacetate (1.42 g, 8.53 mmol) was added drop wise via a syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 1.245 g (70%) of the product as a colorless oil, which crystallized on prolonged standing: mp 69-70° C. (EtOAc-pet. ether). 1H NMR (CDCl3)d: 1.10-1.15 (t, J=7.5 Hz, CH3), 2.85 (s, 2H, CH2), 3.97-4.14 (m, 4H, CH2), 7.33-7.89 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58, 127.70, 128.93, 134.21, 135.10, 167.96
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-(4-fluorophenoxy)benzaldehyde (10 g, 46.3 mmol) in methanol (50 mL) was added NaBH4 (1.750 g, 46.3 mmol) portionwise, after addition the mixture was stirred at room temperature overnight. After removing the solvent, the residue was diluted with DCM (50 mL), the suspension was filtered though a pad of Celite, the filtrate was concentrated to afford the title compound (7 g, 30.5 mmol, 65.9% yield) as a gray solid. LCMS: rt=1.49 min, [M+H+]=219
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[N:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: C=CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCN1CCN(CCCOc2cc3ncnc(Oc4cnc5[nH]ccc5c4)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (288 mg, 0.76 mmol), 5-hydroxy-7-azaindole (113 mg, 0.84 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (116 mg, 0.84 mmol) in DMA (8 ml) was stirred at 85° C. for 3 hours and allowed to cool to ambient temperature. The mixture was filtered, the filtrate evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (100/8/1). The volatiles were removed under vacuum to give a white solid which was triturated with diethyl ether, filtered and dried to give 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (280 mg, 77%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][CH:16]=[CH:17][C:11]=2[N:10]([CH3:18])[C:9]1=[O:19])(=[O:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:11]=2[N:10]([CH3:18])[C:9]1=[O:19])(=[O:3])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)OCCCn1c(=O)c2[nH]ccc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCCn1c(=O)c2c(ccn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 60.3 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (52 mg, 0.2 mmol) in DMF (3 mL) was added 1-chloro-4-(chloromethyl)benzene (64 mg, 0.4 mmol) and K2CO3 (82 mg, 0.6 mmol). The reaction was heated at 85° C. for 2 h, cooled to RT then diluted with EA (30 mL) and water (20 mL). The organic layer was washed with aq. 1N LiCl solution (3×10 mL), dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (47 mg, 59% yield) as a solid. LCMS: MH+ 390 and TR=1.399 min. Used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=2)[C:13]=1[F:29])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]([CH:9]1[CH2:11][CH2:10]1)[C:12]1[C:13]([F:29])=[C:14]([C:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:27])[CH:21]=2)=[O:28])[C:15]([Cl:18])=[CH:16][CH:17]=1
Reactant: Cc1cc(C(=O)c2c(Cl)ccc([C@H](NC(=O)OC(C)(C)C)C3CC3)c2F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C(=O)c2c(Cl)ccc([C@H](N)C3CC3)c2F)ccc1N
Reaction time: 18 h
Yield: 102.7 %

Procedure:
Step 3 To a solution of {(R)-[3-(4-amino-3-methyl-benzoyl)-4-chloro-2-fluoro-phenyl]-cyclopropyl-methyl}-carbamic acid tert-butyl ester (570 mg, 1.32 mmol) in DCM (6 mL) was added 4M HCl in dioxane (1.65 mL, 6.58 mmol, 5 eq) and the reaction stirred for 18 hours. The resulting mixture was partitioned between DCM (50 mL) and water (20 mL) and basified with NaOH. Not all of the compound dissolved and so the aqueous phase was extracted with 4:1 CHCl3:IPA (2×30 mL). The combined organics were washed with brine (20 mL) and then dried (MgSO4), filtered and concentrated to give [3-((R)-amino-cyclopropyl-methyl)-6-chloro-2-fluoro-phenyl]-(4-amino-3-methyl-phenyl)-methanone (451 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][CH3:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.23 mmol) in 1.0 mL tetrahydrofuran was added methyl chloroformate (35 ul, 0.46 mmol) and DIEA (39 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate/water. The organic layer was collected, dried over sodium sulfate, and concentrated under high vacuum to yield methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate. The crude product was taken to next step without further purification. LCMS (M+1=276)
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:39][CH2:40][CH3:41])=[C:33]([NH:35][C:36]([NH2:38])=[S:37])[CH:34]=1>>[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:39][CH2:40][CH3:41])=[C:33]([NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[N:16]=[CH:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:3])=[S:37])[CH:34]=1
Reactant: CCCc1ccc(C)cc1NC(N)=S
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CCCc1ccc(C)cc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(5-methyl-2-propylphenyl)thiourea (CA38) isolated as a white solid (0.107 g, 34%): 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.09 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.95 (m, 2H), 7.61 (dd, J=8.6, 1.3 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.07-6.97 (m, 2H), 3.46 (q, J=6.5 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.48-2.39 (m, 2H), 2.26 (s, 3H), 1.54-1.42 (m, 2H), 0.84 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:15]1([CH:21]2[CH2:22][CH2:23][N:24]([CH2:5][CH2:6][C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:25][CH2:26]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(#Cc1ccccc1)CCN1CCC(c2ccccc2)CC1
Yield: 48.3 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (200 mg, 0.870 mmol), 4-phenylpiperidine (120 mg, 0.744 mmol) and K2CO3 (308 mg, 2.23 mmol) in 10 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product (104 mg, 41%): mp 65-66° C.; 1H NMR (CDCl3) 1.81 (m, 4 H), 2.26 (m, 2 H), 2.65 (m, 1 H), 2.69 (m, 2 H), 2.76 (m, 2 H), 3.13 (d, J=11 Hz, 2 H), 7.13-7.36 (m, 10 H).
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10]OS(C)(=O)=O)[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:10][CH2:9][C:4]2([CH:1]([CH3:2])[CH3:3])[O:5][CH2:6][CH2:7][O:8]2)[CH3:24])=[CH:19][CH:18]=1
Reactant: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1(CCN[C@@H](C)c2ccc(Br)cc2)OCCO1
Yield: 38 %

Procedure:
To a solution of methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (12 g, 50 mmol) and (S)-1-(4-bromophenyl)ethanamine (19.9 g, 100 mmol) in CH3CN (250 mL) was added K2CO3 (8 g, 58 mmol), and the mixture was refluxed for 10 h. The solution was filtered, and the filtrate was concentrated to afford the crude product, which was purified by column chromatography to give [(S)-1-(4-bromophenyl)-ethyl]-[2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl]-amine (6.5 g, 38%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=1[NH2:16]>O>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]2[C:15]=1[N:16]=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=[C:5]2[OH:7]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cc(F)ccc1Cl
Solvent: O
Product: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of ethyl 4,4,4-trifluoroacetoacetate (commercially available, 4 mL, 27.3 mmol, 1.05 eq.) in polyphosphoric acid (22 mL) was heated to 100° C. 2-chloro-5-fluoroaniline (3.78 g, 26.0 mmol, 1 eq.) was added slowly to the stirred hot solution. The resulting reaction mixture was further heated to 150° C. and then stirred at that temperature overnight (approximately 18 hours). The reaction was cooled to room temperature and water was added carefully. The resulting light brown precipitate was collected by vacuum filtration, washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 3.54 g (51% yield) of the desired product as an off-white solid; MP=141-142; MS (ES) m/z (relative intensity): 266 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][CH:19]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:30]([C:25]2[N:26]=[C:27]([CH3:29])[O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:31])[CH:13]=[N:12]1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)o1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)oc2-c2ccc(Cl)cc2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.99 min; [M+H]+=401.13.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]Br.O>N1C=CC=CC=1>[Br:9][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(O)c(Br)n1
Reaction time: 1.5 h

Procedure:
To a solution of 5-hydroxy-2-methylpyridine (Commercial, Aldrich, 44.5 g) in pyridine (400 ml) is added dropwise over 30 min at room temperature a solution of bromine (71.64 g) in pyridine (550 ml). The reaction mixture was stirred for an additional 1.5 h. The reaction mixture was poured into water (4 liters), stirred for a few minutes and extracted with diethyl ether (4×300 ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:31][C@H:32]1[O:61][C@H:60]([CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@H:51]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:42]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:33]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10](O[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:71].O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([NH:8][C@@:9]([OH:71])([CH2:31][C@H:32]1[O:61][C@H:60]([CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@H:51]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C@H:42]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:33]1[O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](C[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@](O)(C[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To 12 (2.51 g, 2.56 mmol, 1 eq) dissolved in THF (11 mL) at room temperature was added tetrabutylammonium fluoride trihydrate (2.02 g, 6.41 mmol, 2.5 eq). The mixture was stirred at room temperature for 16 h and diluted with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over MgSO4 and concentrated. Purification by flash chromatography on silica gel (petroleum ether/EtOAc 65:35) afforded 13 as white solid (1.6 g, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy) propylthio)propanoate (14) in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen. The residue was then diluted in MTBE and washed once with 1M citric acid (adjusted to pH3). The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo to afford (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15) as a waxy solid that was used without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[SH:30]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:26]3[NH:25][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncc[nH]1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 34.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea (149 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1H-imidazole-2-thiol (200 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A mixture of methyl 4-(4-(trifluoromethoxy)phenylamino)quinazoline-7-carboxylate (156 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) was dissolved in THF (4 ml) and H2O (1 mL). The mixture was stirred at 60° C. for 3 h. Acidified with acetic acid resulted brown solid which was collected by filtration. It was then dried in vacuo and used for the next step without any further purification (120 mg, 80% Yield). 1H NMR 400 MHz (DMSO-d6) δ 12.25 (s, 1H), 10.12 (s, 1H), 8.68 (s, 1H), 8.65 (d, 1H, J=1.6 Hz), 8.20-8.11 (m, 2H), 8.02 (d, 2H, J=8.8 Hz), 7.42 (d, 2H, J=8.8 Hz. MS m/z 350.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(OC3CCOCC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 24.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g, 4.5 mmole), tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (1.4 g, 5.4 mmole) and K2CO3 (1.3 g, 9 mmole) in DMF (10 mL) was heated at 85° C. for 20 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by ISCO (silica gel, elute: 10% ethyl acetate in hexane) to give the title compound (335 mg, 24% yield) as a solid. MS (ESI) m/z: Calc. 304.2 (M+). Found: 305.3 (M++1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al]([C:21]#[N:22])(CC)CC>C1COCC1>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[C:21]#[N:22]
Reactant: CC[Al](C#N)CC
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: N#CC(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(phenylmethyl)-4-piperidinecarbaldehyde (2.35 g, 11.6 mmol)[prepared according to Alfaro-Lopez, J.; et al. J. Med. Chem. 1999, 42, 5359] in THF (160 mL) at 0° C. was added dropwise Et2AlCN (25 mL, 1M solution in toluene). After 1 h, the solution was partitioned between NaHCO3(sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated yielding the title compound as a yellow oil which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([C:14]1[C:13](=[O:20])[N:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:11]([CH3:10])[C:15]=1[CH3:16])=[O:18]
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a suspension of 4-amino-3-fluorophenol (1.0 g, 7.87 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.19 g, 9.44 mmol) in CH2Cl2 (20 mL) were added EDCI (3.02 g, 15.7 mmol) and HOAT (0.21 g, 1.57 mmol). The reaction mixture was refluxed for 20 hours, and then cooled to rt. Water (10 mL) was added and the mixture stirred at rt overnight, then filtered and the filter cake was washed with water (5 mL), followed by purifying by a silica gel column chromatography (CH2Cl2/MeOH (v/v)=70/1) to give the title compound as a beige white solid (1.25 g, 46.6%).