Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][O:13][C@H:14]1[O:33][C@H:32]([CH2:34][O:35][C@H:36]2[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]2[OH:38])[C@@H:30]([OH:31])[C@H:17]([O:18][C@H:19]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:20]2[OH:21])[C@@H:15]1[OH:16])=[O:9])[C:3]([OH:5])=[O:4].[O:47]=[C:48]([NH:62][CH2:63][CH2:64][O:65][C@@H:66]1[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]1[OH:68])[CH2:49][CH2:50][CH2:51][C:52](ON1C(=O)CCC1=O)=[O:53].C(OC(=O)CCCCC(O)=O)C1C=CC=CC=1>CN(C=O)C>[C@H:19]1([O:18][C@H:17]2[C@H:30]([OH:31])[C@@H:32]([CH2:34][O:35][C@H:36]3[O:44][C@H:43]([CH2:45][OH:46])[C@@H:41]([OH:42])[C@H:39]([OH:40])[C@@H:37]3[OH:38])[O:33][C@H:14]([O:13][CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@H:2]([NH:1][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][C:48](=[O:47])[NH:62][CH2:63][CH2:64][O:65][C@@H:66]3[O:74][C@@H:73]([CH3:75])[C@@H:71]([OH:72])[C@@H:69]([OH:70])[C@@H:67]3[OH:68])[C:3]([OH:5])=[O:4])[C@H:15]2[OH:16])[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]([OH:23])[C@@H:20]1[OH:21]
Reactant: N[C@@H](CCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O)C(=O)O
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: O=C(O)CCCCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-5-[(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)amino]-5-oxopentanoic acid (350 mg, 4.75 mmol) in DMF (5 mL) at 0° C. was added 2,5-dioxopyrrolidin-1-yl 5-oxo-5-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentanoate (216 mg, 0.517 mmol, prepared according to Example 4, ML-4, Step A, substituting 5-(benzyloxy)-5-oxopentanoic acid for 6-(benzyloxy)-6-oxohexanoic acid and TEA (0.2 mL, 1.435 mmol). After stirring at 0° C. for 2 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 silica gel (150 g), eluting with 5-40% AcCN in H2O to give the title compound. UPLC Method B: calculated for C38H65N3O26 979.39, observed m/e: 980.31 [M+1]; Rt=0.92 min.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C@:13]2([CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]2)[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:11](=[O:27])[N:10]=1.F[C@H]1CCCC[C@@H]1NC1[C@]2(CCN[C@@H](C)C2)N([C:47]2[CH:52]=[CH:51][CH:50]=[C:49](F)C=2)C(=O)N=1.C([O-])([O-])=O.[K+].[K+].BrCC1CCC1>CN(C=O)C.O>[CH:50]1([CH2:49][N:16]2[CH2:17][CH2:18][C@@:13]3([N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[C:11](=[O:27])[N:10]=[C:9]3[NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[F:1])[CH2:14][C@@H:15]2[CH3:19])[CH2:51][CH2:52][CH2:47]1
Reactant: C[C@H]1C[C@]2(CCN1)C(N[C@H]1CCCC[C@@H]1F)=NC(=O)N2c1cccc(F)c1
Reactant: C[C@H]1C[C@]2(CCN1)C(N[C@@H]1CCCC[C@H]1F)=NC(=O)N2c1cccc(F)c1
Agent: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C[C@]2(CCN1CC1CCC1)C(N[C@@H]1CCCC[C@H]1F)=NC(=O)N2c1cccc(F)c1
Temperature: 60 °C

Procedure:
To a solution containing 55 mg (0.15 mmol) of (5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one and (5R,7S)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one in DMF (1.5 mL) was added powdered K2CO3 (81 mg, 0.58 mmol) and bromomethylcyclobutane (22 mg (0.15 mmol). The solution was heated to 60° C. overnight. The reaction was diluted with water (1.5 mL) and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated then chromatographed using 100% EtOAc to give the desired product which was further purified on a Waters automated system affixed with a Chiralpak AD 5 cm×50 cm cartridge eluting at 80 mL/min with isocratic 20% ethyl alcohol in hexanes with no modifier. The second peak was the product. The salt could be formed as described for the examples in Table 5.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5](C)[CH2:6][NH:7][C:8](=[O:41])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11](C)[CH:10]=1)C.[Li+].[OH-:45].Cl>C1COCC1>[CH:18]1([CH2:17][CH:16]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[O:15][C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][CH:5]([OH:45])[C:4]([OH:3])=[O:43])=[O:41])=[CH:10][CH:11]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(C)CNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(C)c1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC(O)C(=O)O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
To a mixture of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-3-methyl-benzoylamino}-2-methyl-propionic acid ethyl ester (0.0571 g, 0.0978 mmol) in THF (1.0 mL) is added LiOH (1N aqueous, 1.0 mL) and stirred at RT for 4 d. The reaction mixture is acidified with 1N HCl (1.0 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are dried over Na2SO4, filtered, and conc. to provide (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-2-hydroxy-propionic acid (0.0474 g, 87%) as a white foam. MS (ES): 554.3 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9]C(C(F)(F)F)=[CH:11][N:12]=2)=[CH:4][N:3]=1.[OH-:17].[Na+].[CH2:19]([OH:21])[CH3:20]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[NH:9][C:20]([C:19]([OH:17])=[O:21])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCO
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)nc2)[nH]1
Agent: [Na+]
Product: O=C(O)c1cnc(-c2ccc(Br)nc2)[nH]1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In ethanol (10 mL) was dissolved 2-bromo-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]-pyridine (500 mg), 2N aqueous sodium hydroxide solution was added to the solution, and the mixture was stirred at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, and 1N aqueous citric acid solution was added thereto. The precipitated solid substance was collected by filtration, washed with water, and then, with ether, and dried to obtain 2-(6-bromopyridin-3-yl)-1H-imidazol-5-carboxylic acid (722 mg).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[N:11][N:10]=[N:9]1.Cl[CH:14]([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:14]([N:9]2[N:10]=[N:11][CH:12]=[N:8]2)[CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:29][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CCc2ccc(F)cc2)n2ncnn2)cc1
Temperature: 25 °C

Procedure:
NaH (0.45 g of 55% suspension in mineral oil) is added to anhydrous DMF under nitrogen atmosphere. Tetrazole (1.1 g) is added and the mixture is gently heated for 20 minutes. The mixture is cooled to room temperature and 1-chloro-1-(4-cyanophenyl)-3-(4-fluorophenyl)propane (1.53 g) is added. The reaction mixture is then heated for 6 hours. Water is added and the products are extracted into ethyl acetate. After drying and solvent evaporation the products are purified by flash chromatography. Elution, starting with pure methylene chloride with increasing methanol content, affords first 2-[1-(4-cyano-phenyl)-3-(4-fluorophenyl)propyl]tetrazole which 1H NMR spectra is as follows:
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: COc1cccc(CCl)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CC#N)c1F

Procedure:
24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride is stirred in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 90° C. The reaction mixture is poured into water and extracted four times with methyl tert-butyl ether. The combined organic phases are washed with brine, dried, the desiccant is suctioned off, and the solvent is spun off. First, only a portion of the residue (21.43 g) is incorporated in crude form into the next stage.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:10]=1
Reactant: Cc1cccnc1CCl
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Product: COCOc1cc(SCc2ncccc2C)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-(chloromethyl)-3-methylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]12([C:28]([Cl:30])=[O:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)CC)C>C(Cl)Cl>[ClH:30].[ClH:30].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:28]([C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:29])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCNC(=O)C23CC4CC(CC(C4)C2)C3)CC1
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred solution of [4-(2-methoxyphenyl)piperazino]ethylamine (2.53 g, 0.01 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (3 g, 0.02 mol) and triethylamine (2 g, 0.02 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was subjected to preparative HPLC. In repeated preparations, the residue was dissolved in ethyl acetate (10 mL) and subjected to flash chromatography using a 9 inch column of silica gel and ethyl acetate as the eluent. The title compound (TLC Rf =0.65 in 30% methanol/ethyl acetate system) was separated and converted to the dihydrochloride three-quarters hydrate salt with ethanolic HCl (1.6 g), m.p. 206°-212° C.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:6]1([CH:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: ClCCl
Product: O=C(O)C(Nc1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
α-Bromophenylacetic acid (5.01 g, 23.2 mmol) was dissolved in aniline (25 ml, 274 mmol), and the mixture was reacted in a closed vessel under microwave irradiation at 120° C. for 5 minutes (UPLC-MS monitoring: complete conversion). Dichloromethane (DCM) (100 ml) was added to the reaction mixture, and the resulting solid was filtered; 2M Na2CO3 (50 ml) was added to the solution, and the aqueous layer was washed with DCM (3×100 ml). The aqueous layer was acidified with 12N HCl (36 ml) and the title compound was recovered as racemic mixture by filtration (5.1 g, 97% yield).
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12].[CH2:13]([O:15][CH:16]([O:19]CC)[CH:17]=[CH2:18])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][CH2:18][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:11][CH3:12])[CH3:14]
Reactant: C=CC(OCC)OCC
Reactant: CCc1cc(C#N)cc(C)c1Br
Product: CCOC(=O)CCc1c(C)cc(C#N)cc1CC

Procedure:
The title compound is prepared from 4-bromo-3-ethyl-5-methyl-benzonitrile and commercially available acrolein diethyl acetal following literature procedures (G. Battistuzzi, S. Cacchi, G. Fabrizi, R. Bernini, Synlett 8 (2003) 1133-1136); LC-MS: tR=0.91 min; 1H NMR (CDCl3): δ 1.2 (m, 6H), 2.38 (s, 3H), 2.44 (m, 2H), 2.70 (q, J=7.5 Hz, 2H), 3.03 (m, 2H), 4.18 (q, J=7.3 Hz, 2H), 7.30 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6]O.Cl.[CH3:9][NH2:10].[C:11](=[O:14])([O-])[O-].[Na+].[Na+]>C=O>[CH3:9][NH:10][CH2:6][C:2]1[O:1][C:5]([CH2:11][OH:14])=[CH:4][CH:3]=1
Reactant: CN
Reactant: OCc1ccco1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: CNCc1ccc(CO)o1
Reaction time: 3 h

Procedure:
A mixture of 2-furanmethanol (49 g), methylamine hydrochloride (51.5 g) and 36% formaldehyde solution (50 ml) was stirred at 0°-3° for 3 hr and allowed to stand for 16 hr. Excess sodium carbonate was added and the slurry extracted with ethyl acetate. After removal of solvent the residue was distilled to give 5-(methylamino)methyl-2-furanmethanol (36.2 g) b.p. 111°-113° (0.2 mm).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:38]1([S:35]([C:31]2[CH:30]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O
Temperature: 25 °C
Reaction time: 113 h

Procedure:
N-{5-[(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (33.2 mg) was added to a solution of 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v.) (50 mg) in DMF (5 ml). The reaction mixture was treated with N,N-diisopropylethylamine (29.3 μl) and stirred at room temperature for 113 h. The reaction mixture was partitioned between EtOAc and water and the organic extracts were washed with ammonium chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column DCM) to afford the title compound. LCMS RT=2.73 min 610(M+H)+
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:3]=1.O1C=C[CH:30]=[C:29]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:22][C:17]3=[N:16][CH:15]=1)[CH:3]=[C:2]2[CH:29]=[CH2:30]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: COCCOc1ccn2c(-c3cc(I)c4cccc(OC)c4n3)cnc2c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: C=Cc1cc(-c2cnc3cc(OCCOC)ccn23)nc2c(OC)cccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-iodo-8-methoxy-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline (898 mg, 1.89 mmol) in NMP (10 mL) was added Pd2dba3 (87 mg, 0.09 mmol), trifuran-2-ylphosphine (88 mg, 0.37 mmol) and tributyl(vinyl)stannane (659 mg, 2.1 mmol). The reaction flask was purged with N2 and the reaction was stirred at 80° C. for 2 hours. The crude mixture was diluted with EtOAc (30 mL) then washed with H2O, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc/Hexane 8:1) affording the desired product (80%).
Reaction SMILES: F[C@@H]1[C@@H](NC2C3C(=CC=C(C)C=3)N=C(N3CC4C=CC=CC=4S(=O)CC3)N=2)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([N:52]1[CH2:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[S:55](=[O:63])[CH2:54][CH2:53]1)[NH:46][C:45]2=O.[NH:65]1[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])[CH2:66]1>>[CH3:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([N:52]1[CH2:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[S:55](=[O:63])[CH2:54][CH2:53]1)[N:46]=[C:45]2[N:65]1[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:77])[O:72][C:73]([CH3:75])([CH3:74])[CH3:76])[CH2:66]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)[nH]c(=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H]3F)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N3CCC(NC(=O)OC(C)(C)C)C3)c2c1

Procedure:
The title compound was prepared in analogy to benzyl (3S,4S)-3-fluoro-4-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}pyrrolidine-1-carboxylate in Example 92 by using 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one and tert-butyl (pyrrolidin-3-yl)carbamate.
Reaction SMILES: [CH3:1][C:2]1([C:10](Cl)=[O:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:3]1.C1(C(Cl)=[O:20])CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([C:39]2([CH3:47])[CH2:43][CH2:42][CH:41]([CH:44]([CH3:46])[CH3:45])[CH2:40]2)=[O:38])=[CH:32][C:31]=1OC(C1(C)CCC(C(C)C)C1)=O)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH3:1][C:2]1([C:10]([O:11][C:34]2[CH:35]=[C:30]([CH:31]=[CH:32][C:33]=2[O:36][C:37]([C:39]2([CH3:47])[CH2:43][CH2:42][CH:41]([CH:44]([CH3:45])[CH3:46])[CH2:40]2)=[O:38])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)C1CCC(C)(C(=O)Cl)C1
Reactant: CC(C)C1CCC(C)(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)c(OC(=O)C3(C)CCC(C(C)C)C3)c2)C1
Product: CC(C)C1CCC(C)(C(=O)Oc2ccc(C(O)CNC(C)(C)C)cc2OC(=O)C2(C)CCC(C(C)C)C2)C1

Procedure:
When 1-methyl-3-isopropylcyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 2,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N)C(C)C>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Solvent: CC(C)CN
Product: CC(C)CNCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using isobutylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:1]1([NH:5][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Cyclobutylamine (370 mg) was added to an ice-cold suspension of tert-butyl bromoacetate (1.0 g) and potassium carbonate (700 mg) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, which was then extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure to afford tert-butyl N-cyclobutylglycinate (949 mg) as the residue.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:21]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: CCCCC(CC)CNCC(CC)CCCC
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)C(Cl)c1ccccc1
Yield: 96 %

Procedure:
Step A is conducted starting from 2,2′-diethylhexylamine and α-chlorophenylacetyl chloride and leads to 2-chloro-N,N-bis(2-ethylhexyl)-2-phenyl-acetamide (Yield: 96%) for which the characterisations by 1H and 13C NMR are given below:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.C[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1.Cl.[CH:20]1C=CC=CC=1>>[CH3:18][C:15]1[CH:16]=[C:17]([CH3:20])[CH:12]=[CH:13][C:14]=1[C:7]([C:3]1[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=1)=[O:8]
Reactant: c1ccccc1
Reactant: Cc1ccc(C)cc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Product: Cc1cccc(C(=O)c2ccc(C)cc2C)c1

Procedure:
A mixture of 15.46 g (0.1 mole) of m-toluoyl chloride, 24.6 ml (0.2 mole) of p-xylene, and 2 g of MoS2 was stirred and refluxed. After 24 hours no more HCl evolved. The mixture was diluted with 100 ml of benzene, filtered from 2 g of MoS2, and distilled to obtain 12.5 g boiling at 245°-250° C./200 of 2,4,3'-trimethylbenzophenone, 82.6 mole % yield.