Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[O:29]([C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[N:44][C:36]=3[O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccnc3Oc3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS m/e: 577.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:4][CH2:5][C:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[O:14][CH2:13][CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: C=CCCC(=O)COC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCC1(COC(C)=O)OCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 15.6 g. (0.1 mole) of 1-acetoxy-5-hexen-2-one, 18.6 g. (0.3 mole) of ethylene glycol in 250 ml. of benzene containing 1.56 g. of p-toluene sulfonic acid monohydrate is heated to reflux using a Dean-Stark water separator. After 2 hours, the reaction mixture is shaken well with 250 ml. of cold water. The aqueous layer is washed with 3×25 ml. of ether. The combined organic layers are dried over anhydrous magnesium sulfate. Evaporation of the solvent gives 2-acetoxymethyl-2-(3-buten-1-yl)-1,3-dioxolane in 90% yield as a light brown oil. ##STR41##
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>[Pd].CO>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[CH3:1])=[CH:13][CH:12]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.8 %

Procedure:
A 250-mL flask was purged with nitrogen and charged with 115a (1.5 g, 4.6 mmol), 10% palladium on carbon (50% wet, 200 mg), and methanol (70 mL). It was evacuated, charged with hydrogen gas, and stirred at room temperature for 10 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 115b (1.1 g, 81%) as a brown solid. MS-ESI: [M+H]+ 293
Reaction SMILES: COC[O:4][C:5]1[CH:43]=[CH:42][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.Cl.O>CO>[OH:4][C:5]1[CH:43]=[CH:42][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCSCCN2CCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCN1CCCCC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[9-(2-piperidinoethylthio)nonyl]-2,3-dihydro-4H-benzopyran (174 mg, 0.28 mmol) and methanol solution of 5N--HCl (1 ml) were dissolved in methanol (10 ml) and then stirred for 5 hours at 40° C. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with flash column chromatography (dichloromethane:ethanol=9:1) to obtain 139 mg (yield: 93%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])C(O)=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C[N:19](C)[CH:20]=[O:21].C(Cl)(=O)[O:24][CH2:25][CH3:26].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(N(CC)CC)C>[CH2:25]([O:24][C:20]([NH:19][C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1)([CH3:16])[CH3:17])=[O:21])[C:26]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: CN(C)C=O
Reactant: CC(=O)NCc1ccc(C(C)(C)C(=O)O)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCc1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-acetylaminomethylphenyl)-2-methylpropionic acid (14 g) in a mixed solvent of acetone (40 ml) and dimethylformamide (30 ml) was added triethylamine (8.75 ml) under ice-cooling and a solution of ethyl chlorocarbonate (6.76 g) in acetone (20 ml) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min. To this solution was added dropwise a solution of sodium azide (4.26 g) in water (28 ml) under ice-cooling over 10 min, and the mixture was stirred for 30 min. The reaction mixture was poured into ice water (500 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained oil was dissolved in toluene (100 ml) and heated at 80° C. for 2 hr. To this solution was added benzyl alcohol (6.77 ml) and the mixture was stirred at 80° C. for 42 hr. To the reaction mixture was added isopropyl alcohol to allow crystallization to give the title compound (14.62 g) as white crystals, m.p.=132-135° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]2[NH:9][C:8]=1[CH:25]=O)=[O:6])[CH3:3].Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:11]2[CH:22]=[CH:23][N:24]=[C:10]2[NH:9][C:8]=1[CH:25]=[N:28][OH:29])=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(C=O)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C1=C(C=NO)Nc2nccn2C1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-ethoxycarbonyl-7-formyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine hydrochloride in a mixture of 20 ml of ethanol and 20 ml of dimethylformamide are added 0.88 g of hydroxylamine hydrochloride and 1.22 g of sodium carbonate and the mixture is stirred at 50° C. for 1.5 hours. The solvent is distilled off under reduced pressure and water is added to the residue, then precipitated crystals are collected by filtration. The crystals are recrystallized from a mixture of chloroform and methanol to give 2.0 g of 6-ethoxycarbonyl-7-hydroxyiminomethyl-5-(3-nitrophenyl)-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 229°-230° C. with decomposition.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:30]=[O:31])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=3[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:30]([CH:1]2[CH2:3][CH2:2]2)[OH:31])=[CH:9][CH:8]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.2 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.33 mL, 0.33 mmol) was added to a stirred solution of 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (111 mg, 0.299 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give [9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (155 mg).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[C:21]([O:20][CH3:19])[CH:22]=[N:23][CH:24]=3)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cncc(C(=O)O)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: COc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCC3)c2)c1
Yield: 55.9 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.33 mmol) and 5-methoxy-nicotinic acid (50.49 mg, 0.33 mmol) as starting materials. The title compound (73 mg, 48.2%) was isolated as off white solid; MS (ESI): 396 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[CH:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].CCN(CC)CC.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([C:15]([NH:17][CH:18]([CH2:26][C:27]#[C:28][C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: C#CCC(NC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(C(=O)NC(CC#CC(=O)N(C)C)C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound from Step A of Example 49 (0.389 g, 1 mmol) was dissolved in dry DMF (5 mL) with dichlorobis(diphenylphosphine)palladium (II) (0.02 eq), CuI (0.02 eq), Et3N (0.4 eq, 3 mL), and N,N-dimethylcarbamyl chloride (1.0 eq, 92 μL). The reaction mixture was stirred overnight at room temperature and then at 70° C. for 1 hour. The mixture was filtered through a pad of Celite and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/hexanes, 2:3) to afford the title compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:21][C:22]=1[F:23].[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:50][CH2:51][O:52][CH3:53])=[C:35]([C:37](=[N:43][S@:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=1.C(O)(=O)C>C1COCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([O:50][CH2:51][O:52][CH3:53])=[C:35]([C@@:37]([C:18]2[CH:19]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:21]=[C:22]([F:23])[C:17]=2[Cl:16])([NH:43][S@:44]([C:46]([CH3:49])([CH3:47])[CH3:48])=[O:45])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:36]=1
Reactant: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)c1cc(Br)ccc1OCOC
Reactant: Fc1nc(N2CCOCC2)ccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)[C@](N[S@@](=O)C(C)(C)C)(c1cc(Br)ccc1OCOC)c1cc(N2CCOCC2)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 67.1 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (45 mL) was cooled to −78° C. and treated with n-BuLi (1.6M in hexanes) (6.77 mL, 10.83 mmol) under nitrogen atmosphere. The solution was warmed to 0° C. and stirred at that temperature for 25 minutes. The solution was cooled back down to −78° C. and treated with a solution of 4-(5-chloro-6-fluoropyridin-2-yl)morpholine (2.165 g, 9.99 mmol) in THF (11.25 mL) under nitrogen atmosphere. The solution was allowed to stir at that temperature for 40 minutes and then added drop wise via cannula to a solution of (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate (3.5 g, 8.33 mmol) in THF (11.25 mL) also cooled to −78° C. under nitrogen atmosphere. The reaction mixture was allowed to stir at −78° C. for additional 2 hours and then quenched with acetic acid (0.715 mL, 12.49 mmol). The reaction mixture was allowed to warm to RT overnight. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (10-60% EtOAc/hexane) to afford 3.56 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(3-chloro-2-fluoro-6-morpholinopyridin-4-yl)-2-((S)-1,1-dimethylethylsulfinamido)acetate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([OH:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2cccc(O)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-hydroxybenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give example 67. ESI-MS m/e 343.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH3:22][I:23]>C(Cl)Cl>[I-:23].[Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N+:11]1[CH:15]=[CH:14][N:13]([CH3:22])[CH:12]=1
Reactant: COc1ccc(OCCCCCCn2ccnc2)c(Cl)c1
Reactant: CI
Solvent: ClCCl
Product: COc1ccc(OCCCCCC[n+]2ccn(C)c2)c(Cl)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Stir at room temperature for about 2.5 hours, 300 mg. of the compound prepared in Example 1, 5 ml. methylene chloride and 0.066 ml. methyl iodide. Elute on a coarse silica column with methylene chloride, then 5% methanol/methylene chloride and finally 10% methanol/methylene chloride, to isolate the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH3:22])[C:15](=[O:21])OC(C)(C)C)[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si]([O:27]S(C(F)(F)F)(=O)=O)(C)(C)C.[NH4+].[Cl-].CCN(C(C)C)C(C)C.C1C([N+]([O-])=O)=CC=C([Cl-][C:56]([O-])=[O:57])C=1.[Cl:59][C:60]1[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:61]=1[CH2:62][NH2:63]>C(Cl)Cl.C1COCC1>[CH3:56][O:57][C:13](=[O:27])[CH2:12][CH2:11][CH:10]([N:14]([CH3:22])[C:15]([NH:63][CH2:62][C:61]1[CH:64]=[CH:65][CH:66]=[C:67]([F:68])[C:60]=1[Cl:59])=[O:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: NCc1cccc(F)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(CO[Si](C)(C)C(C)(C)C)N(C)C(=O)NCc1cccc(F)c1Cl
Temperature: 24 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (91.0 g, 242.6 mmol) in DCM (750 mL) was added TMSOTf (87.8 mL, 485.2 mmol) at 0° C. The mixture was stirred for 1 h, and then poured into saturated aq. NH4Cl (1 L) and CH2Cl2 (1 L) (Note: water (700 mL) was added to dissolve salts). The organic layer was then washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was re-dissolved in THF (300 mL) and DIEA (84.5 mL, 485.2 mmol). To this THF solution was added a pre-stirred solution of 4-nitrophenylchloroformate (56.3 g, 279.0 mmol), 2-chloro-3-fluorobenzylamine (46.5 g, 291.1 mmol), and DIEA (50.7 mL, 291.1 mmol) in THF (1.1 L) at 0° C. The reaction mixture was stirred for 2 h allowing the reaction to gradually warm to 24° C. at which point the LCMS analysis revealed reaction completion. The mixture was concentrated under reduced pressure and purified on silica gel column using a mixture of hexanes and EtOAc to give 5-(tert-butyl-dimethyl-silanyloxy)-4-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentanoic acid methyl ester (73.1 g, 65% over two steps). LRMS (M+H+) m/z 461.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCNCC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NC1CCNCC1)c1ccccc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
Benzaldehyde (21.2 g; 0.2 mol) was added, dropwise, to a solution of 4-aminopiperidine (20 g; 0.2 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature. After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 31 g N-(phenylmethylene)piperidine-4-amine was thus obtained, and was used in the subsequent reactions without further purification.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added N,N-dimethylglycine (122 mg), diisopropylethylamine (582 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. This gave 2-(3-{2-[1-(N,N-dimethylglycyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (310 mg, 55%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][Br:7].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[Na+].Cl>O>[CH2:12]([O:11][C:9](=[O:10])[N:4]([CH2:5][CH2:6][Br:7])[CH2:3][CH2:2][Br:1])[CH3:13]
Reactant: BrCCNCCBr
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N(CCBr)CCBr
Yield: 30.7 %

Procedure:
To a stirred solution of bis-(2-bromo-ethyl)-amine (1 g, 3.21 mmol) in water (10 mL) at 0° C. was added ethyl chloroformate (0.293 mL, 3.08 mmol) and then NaOH (4.01 mL, 8.02 mmol), and stirred for 10 min at 0° C. The reaction mixture was acidified by 2 N HCl to pH 5, and extracted three times with 20 mL of ethyl acetate, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (gradient of 85:15 to 70:30 heptane/ethyl acetate in 30 min) to give the title compound (287 mg, 0.947 mmol, 29.5% yield). MS calculated for C7H14Br2NO2 304.0. found (ESI) m/z 304.2 (M+H)+, retention time 0.56 min.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(c2ccccc2)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A suspension of 4-methylbenzophenone (1, 3.6 g, 10.0 mmol), TiCl4 (1.9 g, 10.0 mmol), and Zn dust (1.3 g, 20.0 mmol) in dry THF (100 mL) was refluxed for 20 h. Afterward, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the crude product was purified on a silica-gel column using DCM as eluent. Compound 2 was isolated as white solid in 94% yield. 1H NMR (300 MHz, CDCl3), δ (TMS, ppm): 7.11-7.00 (m, 10H), 6.91 (d, 8H), 2.26 (d, 6H). 13C NMR (75 MHz, CDCl3), δ (TMS, ppm): 144.8, 141.6, 141.1, 136.6, 132.0, 131.9, 129.0, 128.2, 126.9, 21.9. m/z (FAB) 360.2 [M+]; calc. 360.2.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.O.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH:11]([C:3]1[C:2]([C:20]2[CH:21]=[C:16]([NH2:15])[CH:17]=[CH:18][CH:19]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a 20 ml microwave reaction vial was added 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (690 mg, 2.41 mmol), 3-aminophenylboronic acid monohydrate (411 mg, 2.65 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (197 mg, 0.24 mmol), acetonitrile (8 ml), and 1 M aqueous Na2CO3 solution (5 ml). The mixture was placed in a microwave reactor for 2 hours at 140° C. The reaction mixture was concentrated in vacuo, and the crude material partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 30% ethyl acetate in hexanes) to give 205 mg (34%) of 3-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine. 1H-NMR (250 MHz, DMSO-d6) δ 8.40 (d, J=7.0 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.25-7.18 (m, 1H), 7.03-6.97 (m, 1H), 6.81 (d, J=7.3 Hz, 1H), 6.71 (s, 1H), 6.67-6.62 (m, 2H), 3.65 (broad s, 2H), 3.35 (sept, J=6.9 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H). LC/MS 252.3 m/z (M+H+). Compound 1100.