Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]4[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[NH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([NH:20][C:21]3[N:26]=[C:25]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[N:24]=[C:23]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:43][CH:44]5[CH2:48][CH2:47][CH2:46][CH:45]5[CH2:49][NH:50][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:39])=[CH:41][CH:42]=4)[N:22]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CCOC(=O)C(=O)NCC1CCCC1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (300 mg), ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetate (205 mg) and TBTU (201 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [Br-].OC[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=O)=[CH:6][CH:5]=1.[C:13](=[O:16])([O-])[O-:14].[Cs+].[Cs+].CN([CH:22]=[O:23])C>C(OCC)(=O)C.O.CO>[CH2:8]([O:14][C:13](=[O:16])[C:4]1[CH:12]=[CH:11][C:7]([CH2:22][OH:23])=[CH:6][CH:5]=1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Benzy bromide (7.8 mL, 66 mmol) was added to a suspension of 4-hydroxymethylbenzoic acid (10 g, 66 mmol) and cesium carbonate (11 g, 34 mmol) in mixed solvent (DMF 0.10 L-methanol 30 mL-water 30 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Water (0.50 L) and ethyl acetate (0.50 L) were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (0.30 L) and water (0.30 L) twice, respectively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained solid was filtered and dried at 35° C. under reduced pressure to give 13 g of the title reference compound as a white solid. (Yield 81%)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[N:14][C:15]=2[NH2:17])[N:10]=[CH:9]1)([CH3:4])[CH3:3].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O.C(OCC)(=O)C>CS(C)=O>[C:29]([O:28][C:26]([N:20]1[CH2:25][CH2:24][N:23]([C:13]2[N:12]=[C:11]3[C:16]([N:8]([CH2:7][C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:19])[CH:9]=[N:10]3)=[C:15]([NH2:17])[N:14]=2)[CH2:22][CH2:21]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Cn1cnc2nc(Cl)nc(N)c21
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cnc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc(N)c21
Reaction time: 14 h

Procedure:
To a stirred mixture of (6-amino-2-chloro-purin-7-yl)-acetic acid 1,1-dimethylethyl ester, 3 (5 g, 17.6 mmol) in dimethylsulfoxide (50 ml) was added tert-butyl piperazine-1-carboxylate (10 g, 53.8 mmol) at 120° C. After the addition, the mixture was stirred for about 14 h. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture. The organic layers was then washed with H2O several times, dried with Na2SO4 and concentrated to give crude product 4-(6-amino-7-tert-butoxycarbonylmethyl-7H-purin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 (7 g) which was not purified and used for the next reaction directly.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([O:11][CH2:10][CH2:9][C:2]1([CH2:6][CH2:7][O:8][S:19]([CH3:22])(=[O:21])=[O:20])[O:3][CH2:4][CH2:5][O:1]1)(=[O:21])=[O:20]
Reactant: OCCC1(CCO)OCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)OCCO1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2′-(1,3-dioxolane-2,2-diyl)diethanol (1.3 g, 8.0 mmol) in methylene chloride (100 mL) was added triethylamine (3.4 mL, 24 mmol) at room temperature. The solution was cooled down to −40° C. and then mesyl chloride (1.65 mL, 20 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30 min, then warmed up to 0° C. gradually. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, then evaporated to afford the crude product, 1,3-dioxolane-2,2-diyldiethane-2,1-diyl dimethanesulfonate: MS (m/e): 319 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1COCC1.[Cl-].[Na+].O>[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[C:4]#[C:3][CH:2]([CH3:5])[CH3:1]
Reactant: C#CC(C)C
Reactant: O=C=Nc1ccccc1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C#CC(=O)Nc1ccccc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0° C. The resulting mixture was stirred for 30 minutes. Then a solution of 1-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was dropped into the mixture. After stirring for 2 hours at 0° C., the mixture was treated with brine (100 ml) and extracted with ether (200 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as a yellow oil which was used in next step without purification. MS calcd. for C12H12INO 313.1, obsd. (ESI+) [(M+H)+] 314.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].O.[C:26]([OH:30])(=[O:29])[CH:27]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([NH:1][CH:27]([C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:26]([OH:30])=[O:29])[CH:3]=1)(=[O:6])[NH2:7]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: O=CC(=O)O
Reactant: Cc1ccc(C(N)=O)cc1N
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2cc(C(N)=O)ccc2C)C(=O)O)cc1OC
Temperature: 100 °C

Procedure:
A mixture of 3-amino-4-methylbenzamide (75 mg, 0.5 mmol), 3,4-dimethoxyphenylboronic acid (91 mg, 0.5 mmol) and glyoxylic acid monohydrate (46 mg, 0.5 mmol) in acetonitrile (2.0 mL) and DMF (0.2 mL) was heated at 100° C. for 20 min in a microwave reactor. After removal of solvent, the crude was triturated with methylene chloride. The precipitate formed was collected by filtration and washed with methylene chloride to give 5A after drying. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.79 (s, 3H) 3.81 (s, 3H) 5.15 (s, 1H) 6.91 (d, J=8.35 Hz, 1H) 6.95 (s, 1H) 7.05-7.14 (m, 4H); LC-MS 345 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1cc(Cl)ccc1Cl
Yield: 59.1 %

Procedure:
1.12 g (4.42 mmol) of 2,5-dichlorobenzenesulfonylisocyanate and 882 mg (4.42 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.06 g of the above-identified compound (yield 58.6%). Properties: colorless crystal, Melting point: 254°-256° C., PMR (δppm, DMSO-d6):7.17 (1H,s), 7.24 (1H,d), 7.71 (1H,d), 7.80-7.89 (2H,m), 8.18 (1H,s).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH2:18].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@@H:14]1[CH2:16][C@H:15]1[CH2:17][NH:18][C:26](=[O:28])[CH3:27]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)c(F)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@@H]1C[C@H]1c1c(F)ccc2nn(C)cc12
Yield: 98.4 %

Procedure:
A solution of 1-[(1R,2R)-2-(5-fluoro-2-methyl-2H-indazol-4-yl) cyclopropyl]methanamine dihydrochloride (258 mg, 0.883 mmol) and triethylamine (615 μL, 4.415 mmol) in tetrahydrofuran (9 mL) was stirred at room temperature for 20 min. To the reaction solution was added acetic anhydride (125 μL, 1.325 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (227 mg, yield 98%).
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[C:22]1([CH3:30])[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:30][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: Cc1ccccc1C=O
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Cc1ccccc1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was suspended in 400 ml of toluene to which morpholine (3.5 g) and o-tolualdehyde (3.0 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.5 g of aldehyde was added. Reflux was continued for an additional six (6) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the pure product were concentrated and recrystallized from benzene/pentane to give 3.32 g of analytically pure product, m.p. 160°-162° C.
Reaction SMILES: [Cl-].[NH4+:2].[F:3][C:4]1[C:9]([S:10](Cl)(=[O:12])=[O:11])=[C:8]([F:14])[C:7]([F:15])=[C:6]([F:16])[C:5]=1[F:17].[OH-].[Na+]>CC(C)=O>[F:3][C:4]1[C:9]([S:10]([NH2:2])(=[O:12])=[O:11])=[C:8]([F:14])[C:7]([F:15])=[C:6]([F:16])[C:5]=1[F:17]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
To an aqueous solution of ammonium chloride was added dropwise an acetone solution of pentafluorobenzenesulfonyl chloride at room temperature. During addition, pH was adjusted to 7 by an aqueous sodium hydroxide solution. Precipitated product was filtered and recrystallized from toluene to give pentafluorobenzenesulfonamide. The structure was confirmed by 1H-NMR, 19F-NMR and IR.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7].[OH2:13].CN([CH:17]=[O:18])C>>[O:13]1[CH2:10][CH2:11][CH2:4][CH2:5][CH:6]1[CH2:17][O:18][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CN(C)C=O
Reactant: O
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccccc1OCC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 60% sodium hydride (0.160 g; 4.00 mmol) in DMF (5 mL) at 0° C. was added dropwise (2-hydroxymethyl)tetrahydropyran (0.465 g; 4.00 mmol) and the mixture was stirred at 0° C. for 30 minutes. The mixture was added to a solution of 2,6-difluorobenzonitrile (0.556 g, 4.00 mmol) in DMF (5 mL) at 0° C. and stirred for 18 hours at ambient temperature. The solution was poured into a mixture of ice and water, and extracted with ethyl acetate. The organic layer was washed with water and then brine, dried over magnesium sulfate, and solvent removed. Purification by column chromatography (CH2Cl2) to yield 0.587 grams of 2-(tetrahydropyran-2-ylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(N3CCC4(CC3)OCCO4)nn2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of 8-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane, prepared as in STEP 2 above (1.8 g, 6 mmol) in acetone/H2O (30 mL/30 mL) was added p-TSA.H2O (1.37 g, 7.2 mmol). The resulting mixture was stirred at 65° C. for 6 h and then concentrated to remove most of organic solvent. The residue was poured into CH2Cl2/H2O/Na2CO3(aq) (50 mL/25 mL/25 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layer was dried (Na2SO4), and filtered. The solvent was removed by roto-evaporator to yield 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11](I)=[CH:10][N:9]=2)=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:10][N:9]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cnc(I)cn1
Reactant: C#C[Si](C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1cnc(C#C[Si](C)(C)C)cn1

Procedure:
The product was prepared analogously to Example 48.1c from 1.70 g (5.14 mmol) of 2-(4-chloro-2-methylphenyl)-5-iodopyrazine and 0.80 mL (5.66 mmol) of trimethylsilylacetylene (using triethylamine as base). Yield: 700 mg (45% of theoretical); C16H17ClN2Si (M=300.858); calc.: molpeak (M+H)+:301/303 (Cl); found: molpeak (M+H)+:301/303 (Cl); Rf value: 0.5 (silica gel, PE/EtOAc 9:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)[CH:5]=[C:4]([CH3:33])[N:3]=1.[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:14]([CH2:13][C:12]1[CH:30]=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=2)[CH:9]=[CH:10][C:11]=1[O:31][CH3:32])[CH:15]1[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 92 (100 mg, 0.22 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (61 mg, 0.26 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:56])[N:47]([CH2:49][CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:53]1[CH2:54][CH2:55][CH:50]([CH2:49][N:47]2[CH2:48][C:44]3=[CH:43][N:42]=[C:41]([CH3:40])[N:45]3[C:46]2=[O:56])[CH2:51][CH2:52]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Cc1ncc2n1C(=O)N(CC1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc2n1C(=O)N(CC1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2
Yield: 90.5 %

Procedure:
To a solution of Boc-D-tert-leucine (0.69 g), HOBt (0.69 g) and WSC (0.86 g) in acetonitrile (20 ml) was added a solution of 5-methyl-2-(4-piperidinylmethyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.91 g) as described above, DBU (0.6 ml) and triethylamine (0.61 ml) in acetonitrile (20 ml), and mixed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (1.2 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[C:9]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: COC(=O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic add is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation and recrystallized from ethyl acetate/hexane, yielding the title compound in the form of yellow crystals, 1H-NMR (CDCl3): δ7.40 (s, 2H), 7.10-6.80 (m, 8H), 5.70 (br s, 2H) 3.83 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)#[CH:2].[N:14]([CH2:17][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([F:20])[F:19])=[N+:15]=[N-:16].C(N(CC)C(C)C)(C)C>O1CCCC1.[Cu]I>[F:19][C:18]([F:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:17][N:14]1[CH:2]=[C:1]([C:3]2[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=2)[N:16]=[N:15]1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Reactant: [N-]=[N+]=NCC(F)(F)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-c2cn(CC(F)(F)c3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.4 %

Procedure:
To a degassed solution of ethyl 2-ethynyl-4-methylthiazole-5-carboxylate (0.10 g, 0.51 mmol) and (2-azido-1,1-difluoroethyl)benzene (0.14 g, 0.77 mmol) in tetrahydrofuran (5 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and copper(I) iodide (0.002 g, 0.01 mmol). The reaction mixture was stirred at ambient temperature under nitrogen for 17 hours, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid (0.13 g, 67%): 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.45-7.31 (m, 5H), 5.02-4.93 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>CCCCC>[CH3:4][CH:2]1[O:3][CH:8]([CH:7]([CH3:17])[CH3:12])[O:5][C:1]1=[O:6]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCC
Product: CC1OC(C(C)C)OC1=O
Yield: 869816.19 %

Procedure:
43.6 g (0.60 mol) of isobutyl aldehyde, 62.5 g (0.55 mol) of L-lactic acid, and 1.06 g (0.05 mmol) of p-toluene sulfonic acid were dissolved in 50 ml of n-pentane, and the mixture was refluxed for 8 hours in a 500-ml flask attached to a reflux condenser comprising a Dean-Stark fractionator. After the reaction, the reaction mixture was neutralized and washed with a sodium bicarbonate aqueous solution, followed by extraction with ether. Thereafter, the extract was dried with anhydrous magnesium sulfate. Thereafter, ether was distilled off, thereby giving 62.7 g (yield=79.2%) of 5-methyl-2-isopropyl-1,3-dioxolan-4-one as a diastereomer mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1I)[CH2:8][C:9]1[O:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][C:25]=1[O:32][CH3:33])[CH2:8][C:9]1[O:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ncco1)c1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1ncco1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-oxazol-2-ylmethyl-carbamic acid tert-butyl ester and 4-fluoro-2-methoxyphenyl-boronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless solid (70%). MS (ESI): m/z=400.167 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>N1C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)nc12
Yield: 79.4 %

Procedure:
To a stirred solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (512 mg, 2 mmol) in pyridine at 90° C. was added benzyl chloroformate (3.3 ml, 23.4 mmol) in three portions over 6 hours. The reaction mixture was then evaporated to dryness and partioned between CH2Cl2 (50 ml) and saturated aqueous NaCl solution (50 ml), the aqueous phase was separated and extracted further with CH2Cl2 (2×50 ml) and the combined organic phases dried, filtered and evaporated. The crude residue was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/EtOAc (4:1) to afford the title compound as a white foam (620 mg, 79% yield), MS: m/e=391.2 (M+H+).