Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9](OS(C)(=O)=O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Si](OC1CCC([N:33]2[CH2:37][C:36]([B:38]3[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]3)=[CH:35][NH:34]2)C1)(C(C)(C)C)(C)C>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([N:33]2[CH2:37][C:36]([B:38]3[O:39][C:40]([CH3:46])([CH3:45])[C:41]([CH3:44])([CH3:43])[O:42]3)=[CH:35][NH:34]2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CNN(C3CCC(O[Si](C)(C)C(C)(C)C)C3)C2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(OS(C)(=O)=O)C1
Product: CC1(C)OB(C2=CNN(C3CCCC(O[Si](C)(C)C(C)(C)C)C3)C2)OC1(C)C
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield from methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl ester by a procedure analogous to Intermediate 28, Step C. The crude compound was purified by column chromatography (25% ethyl acetate:hexanes and then DCM) to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.76 (s, 1H), 7.27 (s, 1H), 4.45-4.63 (m, 1H), 4.23 (br. s, 1H), 2.05-2.09 (m, 2H), 1.5-1.9 (m, 6H), 1.45 (s, 9H), 1.31 (s, 12H), 0.05 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CCO.[OH-].[Na+]>COC(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH:9]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCO
Product: O=C(C=Cc1cccc(Cl)c1)c1cc(Br)ccc1O
Reaction time: 0.5 h
Yield: 347.6 %

Procedure:
In a bottle 1-(5-bromo-2-hydroxyphenyl)ethanone (25 g, 0.02 mol), 3-chlorobenzaldehyde (16.35 g, 0.12 mol), EtOH (96%, 144 mL), and NaOH (42.1 g, 1.06 mol) were combined. The mixture was stirred vigorously for 0.5 h. 2-Methoxy-2-methylpropane was added and the mixture was filtered. The filtrate was poured into HCl (1 N, 800 mL) and filtered. The combined solid was dried to give 1-(5-bromo-2-hydroxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one (23.47 g, 60%). 1H-NMR (CDCl3): 6.88 (d, 1H), 4.35 (m, 2H), 7.49 (m, 3H), 7.61 (s, 1H), 7.80 (m, 1H), 7.93 (m, 1H), 12.56 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:3]([C:6]([CH2:20][C:19]#[CH:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC(CC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60%, 0.480 g) was added to a cold (0° C.) solution of diethyl 2-allylmalonate (2.002 g) in DMF (10 mL) and the mixture was allowed to warm to rt over 30 min. Then a solution of 3-bromoprop-1-yne (1.487 g) in DMF (3 mL) was added dropwise at 0° C. and the mixture was allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ether and then quenched with sat. NH4Cl, washed with water, brine and dried (Na2SO4). The crude product was purified by silica gel FCC (1:1 DCM-hexane) to afford diethyl 2-allyl-2-(prop-2-ynyl)malonate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=3[CH3:22])[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:22])[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1c2cccc(Cl)c2nn1C(C)C
Yield: 33.2 %

Procedure:
Prepared according to Method D step C from 7-chloro-2-isopropyl-3-(4-methoxy-2-methylphenyl)-2H-indazole (0.05 g, 0.16 mmol), boron tribromide (0.19 mL, 2.0 mmol) and 1.0 mL of cyclohexene to give the product (0.016 g) as a white solid.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)=[CH:7][C:6]=1[C:26]([NH:28][CH2:29][C:30]12[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2)=[O:27].S([O-])(O)(=O)=O.[K+].[CH2:46]([O:48]CC)C>>[Cl:4][C:5]1[CH:25]=[CH:24][C:8]([CH:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:15][CH2:16]2)[CH2:46][OH:48])=[CH:7][C:6]=1[C:26]([NH:28][CH2:29][C:30]12[CH2:37][CH:36]3[CH2:35][CH:34]([CH2:33][CH:32]([CH2:38]3)[CH2:31]1)[CH2:39]2)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C(CO)c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To methyl magnesiumbromide (3M solution in diethyl ether, 0.225 ml) in anhydrous diethyl ether (7 ml) under a nitrogen atmosphere was added slowly 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (0.23 g, Example 76a) in anhydrous diethyl ether (7 ml). The reaction mixture was stirred for 14 h at room temperature, then poured onto crushed ice. A solution of 10% aqueous potassium hydrogen sulphate was added keeping the pH of the solution >4. The layers were separated, and the aqueous layer was extracted with ethyl acetate (4×25 ml). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (3 ml) and hydrochloric acid (4N solution in dioxane, 2 ml) and stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product (0.11 g) was redissolved in dichloromethane (3 ml). Triethylamine (0.066 ml) was added followed by di-tert-butyl-dicarbonate (0.055 g) and the reaction mixture was stirred for 1 hour at room temperature. Water was added and the layers were partitioned. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane, then by RPHPLC eluting with a gradient of 75-5% of 0.1% aqueous ammonium acetate in acetonitrile to give the subtitle compound as a white foam (0.06 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1-c1nc(C(=O)O)cs1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2-o-Tolyl-thiazole-4-carboxylic acid ethyl ester (550 mg, 2.22 mmol) was dissolved in a mixture of THF (1.0 mL) and MeOH (1.0 mL). To this was added NaOH (20% aqueous, 0.444 mL). The reaction mixture was stirred overnight and was then diluted with CH2Cl2 (30 mL) and washed with 1M NaHSO4 (30 mL). The aqueous layer was extracted with CH2Cl2 (2×30 mL), then the combined organic layers were washed with water (1×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (434 mg, 1.98 mmol, 89%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16]>>[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:7]2[CH:2]=[CH:3][C:4]([C:8]3[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=3)=[N:5][CH:6]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: O=Cc1ccc(-c2cc(Br)ccn2)o1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)nc2)cc1
Yield: 91 %

Procedure:
The same procedure described for 12 was used by employing compound 41 (1 equiv.) and 4-formylphenyl boronic acid (1 equiv.). Yield 91%, mp 217-219° C. 1H NMR (DMSO-d6); δ 7.46 (d, J=3.6 Hz, 1H), 7.71 (d, J=3.6 Hz, 1H), 8.03-8.05 (m, 5H), 8.37 (dd, J=1.8, 8.4 Hz, 1H), 9.11 (d, J=1.8 Hz, 1H), 9.69 (s, 1H), 10.07 (s, 1H). Anal. Calc. for C17H11NO3: C %, 73.63; H %, 3.99; Found. C %, 73.51; H %, 4.23.
Reaction SMILES: [CH2:1]([O-:4])[CH2:2][CH3:3].[Na+].[Na].C(O)CC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[N:13]=1>CCOC(C)=O>[Br:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:4][CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCOc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a sodium propan-1-olate solution, prepared by addition of sodium (36 mg, 1.58 mmol) to propanol (1 mL), was added 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 189 mg of Intermediate 161.1 as a colorless oil. LCMS (2 min gradient) RT=1.82 min, 216.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:10]=[C:11]([C:12]([F:14])([F:13])[F:15])[C:6]3=[N:5][CH:4]=2)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)cn23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.18) (310 mg, 0.88 mmol) and 5-Bromo-2,4-difluorobenzenesulfonamide (226 mg, 0.83 mmol) according to general procedure II. Obtained as an off-white solid (56 mg, 12%). MS (ISP) 546.2 [(M+H)+]; mp 306-307° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([CH:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:39]([NH2:44])(=[O:43])[CH:40]([CH3:42])[CH3:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1>[F:24][C:22]([F:23])([F:25])[CH:21]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([NH:44][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[CH:3][CH:4]=4)[N:9]=3)=[N:13][N:14]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CC(C)C(N)=O
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C(=O)Nc1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 90 °C
Yield: 108.3 %

Procedure:
tert-Butyl (3S)-1-(1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (50 mg, 0.085 mmol), isobutyramide (18.4 mg, 0.211 mmol), K3PO4 (53.8 mg, 0.254 mmol), and Cu(I)I (1.61 mg, 0.0085 mmol) were weighed into a 40 mL Teflon® capped vial. The vial was purged with N2, followed by addition of toluene (20 mL) and N1,N2-dimethylethane-1,2-diamine (4.55 μL, 0.042 mmol). The reaction was sealed and heated to 90° C. overnight, after which the reaction complete by TLC. The crude reaction was concentrated, then purified by flash column chromatography (eluting with 10% MeOH/DCM), affording the desired product (55 mg, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: ClCCCCSc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-chloro-phenylmercapto)-butylchloride.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH:16]([NH2:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:24][CH:16]([C:15]1[CH:25]=[CH:26][C:12]([F:11])=[CH:13][CH:14]=1)[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(C(Nc2nc3ccccc3[nH]2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4,4′-difluoro-benzhydrylamine (prepared by Procedure B from 4,4′-difluorobenzophenone) by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 241-243° C.). MS(ES+) m/z 336 ([M+1]+, 100). 1NMR (DMSO-d6) δ 6.20 (d, 1H), 6.80-6.91 (m, 2H), 7.09-7.20 (m, 6H), 7.38-7.43 (m, 4H), 7.69 (d, 1H), 10.6 (s, 1H).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[CH3:16])=[CH:8][CH:9]=[CH:10][C:3]1=2.[C:20](=O)([O-])O.[Na+]>ClCCl>[ClH:1].[CH3:16][C:15]1[S:14][C:13]2=[N:17][CH2:18][CH2:19][N:12]2[C:11]=1[C:7]1[C:4]2[CH:5]=[C:6]([CH3:20])[S:2][C:3]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC1=C(c2cccc3sccc23)N2CCN=C2S1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(c2cccc3sc(C)cc23)N2CCN=C2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(benzo[b]thiophen-4-yl)-2-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (2 g; prepared in a manner similar to that described in Example 9 Method A), 5M aqueous sodium hydrogencarbonate solution (50 ml) and dichloromethane (50 ml) was stirred at ambient temperature for 30 minutes, then the free base was extracted into dichloromethane (2×50 ml). The combined extracts were dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (40 ml), then the stirred solution was cooled to −70° C. and n-butyllithium (2.5M solution in hexanes; 2.85 ml) was added dropwise under nitrogen. The mixture was stirred at −70° C. for 1 hour, then methyl iodide (0.45 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour then it was poured into saturated aqueous ammonium chloride solution (50 ml). The product was extracted into ethyl acetate (2×50 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified via flash chromatography over silica using a 9:1 mixture of dichloromethane and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was dissolved in ethanol, concentrated hydrochloric acid (10 drops) was added, the solvent was removed in vacuo, and the residue was triturated with ether (30 ml). The mixture was allowed to stand at ambient temperature for 72 hours then the resulting solid was collected by filtration and dried in vacuo to give 2-methyl-3-(2-methylbenzo[b]thiophen-4-yl)-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (1.15 g) as a colourless solid, m.p. 271° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(O)=O>[CH3:15][O:14][C:11]1[C:12](=[O:13])[C:7]([C:5]2[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:2]=[CH:3][CH:4]=2)=[N:8][N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[CH:10]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (3.41 g, 9.29 mmol) and phenylhydrazine (1.83 mL, 18.6 mmol) in AcOH (25 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M HCl aqueous solution, 1 M NaOH aqueous solution, and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (2.70 g, 71% yield) as colorless crystals: mp 139-141° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.98 (3H, s), 7.05 (1H, dd, J=1.9, 7.9 Hz), 7.19 (1H, s), 7.34-7.47 (7H, m), 7.56 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.92 (1H, s). LC-MS (ESI) m/z 413 [M+H]+. Anal. Calcd for C21H15F3N4O2: C, 61.17; H, 3.67; N, 13.59. Found: C, 61.15; H, 3.65; N, 13.57.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].N[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[NH:27])=[CH:17][CH:16]=1.[C:40]([BH3-])#[N:41].[Na+]>CO>[ClH:39].[ClH:39].[OH:4][C@@H:3]([C@H:5]([OH:6])[C@H:7]([OH:8])[CH2:9][OH:10])[CH2:2][N:41]([CH2:40][C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]([OH:6])[CH2:3][OH:4])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29]([C:31]2[C:36]([NH2:37])=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=2)=[O:30])=[NH:27])=[CH:17][CH:16]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: [BH3-]C#N
Reactant: N=C(NCCCCc1ccc(OCCN)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(NCCCCc1ccc(OCCN(C[C@@H](O)[C@H](O)[C@H](O)CO)C[C@@H](O)[C@H](O)[C@H](O)CO)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
D-(+)-xylose (0.35 g, 2.6 mmol) was added to a solution of hydrochloride 4 (0.3 g, 0.65 mmol) in methanol (20 mL) and the mixture was stirred for 20 min at room temperature. Then the solution was cooled to −78° C. and sodium cyanoborohydride (0.17 g, 2.6 mmol) was added. The reaction mixture was stirred at −78° C. for 2 h and at room temperature for 4 d. After this time, the solvent was removed under reduced pressure and the residue was washed with water. The formed yellow solid was isolated and dried under vacuum. Then the residue was re-dissolved in 5% HCl and the solvent was removed at reduced pressure. The obtained compound was dissolved in water containing 0.1% TFA and purified by preparative HPLC (C 18 Luna column from Phenomenex 250×21.2 mm, 5μ, isocratic method, water/acetonitrile=80%:20%). The fractions containing the target compound were combined and the solvent was removed under reduced pressure. The residue was dissolved in 5% HCl and solvent was removed under reduced pressure (twice). The resulting yellow powder was dissolved in water and the solution was lyophylized to give 34 mg (7%) of compound 23 as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.64 (br s., 4H), 2.62 (m, 2H), 3.30 (m, 4H), 3.35-3.70 (m, 13H), 4.23 (m, 2H), 4.47 (m, 2H), 6.95 (d, 2H), 7.15 (d, 2H). m/z (APCI)=689 [C28H45ClN8O10+H]+. [α]D25=−16.1° (c=0.5, MeOH).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1C=C[C:7](CC(O)=O)=[CH:6][CH:5]=1.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C1C=CN=CC=1.ClCCl>[Br:3][C:4]1[CH:15]=[C:16]([CH2:17][C:18]([NH:2][CH3:1])=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: CN
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide 4-hydrochloride (8.88 g), 4-dimethylaminopyridine (5.67 g) and a 2M solution of methylamine in tetrahydrofuran (23 ml) were added to a solution of 4-bromophenylacetic acid (5.0 g) in dichloromethane (100 ml). The mixture was stirred overnight at room temperature. The reaction mixture was washed with 2M hydrochloric acid (3×100 ml), the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The sub-title compound was obtained as a solid (4.74 g) after recrystallisation from 1% hexane in ethyl acetate.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 402.69 g/mol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.NC1C=CC(C([NH:73][CH:74]2[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]2)=O)=CC=1OC>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:73][CH:74]4[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]4)=[O:52])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HATU (221 mg, 0.55 mmol) in DMA (10 mL) was added to a mixture of the 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242; 220 mg, 0.5 mmol), DIPEA (261 uL, 1.5 mmol) and 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 72 mg, 0.62 mmol) in DMA (10 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was retrieved from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid. (154 mg, 58%)