Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[C:12]1([C:18]#[C:19][CH:20]2[CH:25]=[CH:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([C:19]#[C:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: C(#CC1C=CNCC1)c1ccccc1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CC=C(C#Cc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.19 g (0.00098 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 20 ml of dimethyl-formamide was treated with 0.15 g (0.82 mol) of 4-phenylethynyl-1,2,3,4-tetrahydro-pyridine and 0.34 ml (0.0024 mol) of triethylamine and the mixture was stirred at room temperature under argon for 16 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.10 g (34%) of 2-methyl-5-(4-phenylethynyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine as white crystals; m.p. 187°-188°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH2:37]([S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCS(=O)(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(S(=O)(=O)CC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-ethanesulfonyl-piperazine (example 14) in an analogous manner as described in example 25. LR-MS: 682.3 [(M+H)+]
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:8][N:7]=[N:6]1)#N.O.[OH-].[Li+]>C1COCC1.O.Cl>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Preparation H7, Step 3: To a solution of methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate (180 mg, 0.7 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (50 mg, 2.1 mmol) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 100 mg (58% yield) of 3-(1H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=191.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4-iodobenzoate (5.8 mL), (R)-4-isopropyloxazolidin-2-one (5 g), potassium carbonate (15 g) and copper (I) iodide (1.3 g) were added toluene (35 mL) and N,N′-dimethylethylenediamine (1.5 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in methanol (35 mL) and 1,4-dioxane (35 mL), 1N aqueous sodium hydroxide solution (70 mL) was added, and the mixture was stirred at room temperature overnight. 1N hydrochloric acid (70 mL) was added, and the mixture was filtered to give the title compound (9 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([F:19])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].C1COCC1>[F:19][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: [H][H]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c(F)c2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(N)c(F)c2)n1
Yield: 39.2 %

Procedure:
A mixture of 570 mg (2.03 mmol) 2-methylsulfanyl-4-(3-fluoro-4-nitrophenoxy)-pyrimidine, 10 ml ethanol, 10 ml THF, and 200 mg 10% palladium/C is hydrogenated at 50 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 10 ml ethanol and evaporated. The residue was purified by chromatography on silica (ethyl acetate/n-heptane 1:2) to give 200 mg (39%) 2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1([N:33]=[C:34]=[O:35])[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[C:24]1([NH:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[C:10]([NH2:19])[C:9]=3[N:8]=[C:7]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:35])[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[C:10]([NH2:19])[C:9]=3[N:8]=[C:7]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:32])[CH:25]=1
Reactant: O=C=Nc1cccc(N=C=O)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1cccc(NC(=O)NCCCCn2c(CCCC)nc3c(N)nc4ccccc4c32)c1
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A suspension of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.11 g, 10.0 mmol) in 100 mL of CH2Cl2 was treated with 1,3-phenylene diisocyanate (800 mg, 5.0 mmol) and stirred under N2 overnight. The reaction mixture was then concentrated under reduced pressure to give a white solid. The white solid was then dissolved in 150 mL of hot 15% MeOH/CHCl3. After slow evaporation of the solvent, a white precipitate had formed. The solid was isolated by filtration, washed with 10% MeOH/CHCl3 (3×10 mL) and dried under vacuum to give the desired product (400 mg) as a white powder. M. p. 160.3–165.6° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.01 (d, J=7.9 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.43 (s, 1H), 7.38 (t, J=7.6 Hz, 2H), 7.22 (t, J=7.0 Hz, 2H), 7.05–6.94 (m, 3H), 6.45 (s, 4H), 6.07 (t, J=5.4 Hz, 2H), 4.53 (t, J=7.4 Hz, 4H), 3.15 (m, 4H), 2.92 (t, J=7.7 Hz, 4H), 1.88–1.74 (m, 8H), 1.66 (m, 4H), 1.43 (m, 4H), 0.92 (t, J=7.3 Hz, 6H);
Reaction SMILES: C(N)CCCCCCCCCCC.[CH2:14]([CH2:16][NH2:17])[OH:15].C=O.[CH2:20]([N:32]1[CH2:37]N(CCCCCCCCCCCC)[CH2:35][N:34]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:33]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C.CCOCC>[CH2:50]([N:34]1[CH2:35][N:17]([CH2:16][CH2:14][OH:15])[CH2:37][N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33]1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCCCCCCN1CN(CCCCCCCCCCCC)CN(CCCCCCCCCCCC)C1
Reactant: NCCO
Agent: C=O
Agent: CCCCCCCCCCCCN
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCCCCCN1CN(CCO)CN(CCCCCCCCCCCC)C1
Reaction time: 24 h

Procedure:
48 g of dodecylamine (259 mmol) and 1.7 ml of ethanolamine (29 mmol) were dissolved in 100 ml of ethanol, after which 8.6 g of paraformaldehyde (287 mmol) were added and the mixture was stirred. The turbidity caused by 1,3,5-tridodecyl-1,3,5-triazacyclohexane was redissolved every now and again by addition of ether. After about 1 day, all the paraformaldehyde had dissolved. The solvent was then removed on a rotary evaporator, the residue was dissolved in a little toluene and the product was then again freed of solvent under reduced pressure. This left 55 g of a viscous colorless product which, according to NMR spectroscopy, consisted of about 75 mol % of 1,3,5-tridodecyl-1,3,5-triazacyclohexane and 25 mol % of 1,3-didodecyl-5-(2-hydroxyethyl)-1,3,5-triazacyclohexane and a little toluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH2:14][CH:15]=[CH2:16])[C:5]=1[OH:17].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:18])=[C:5]([OH:17])[C:6]=1[CH2:14][CH2:15][CH2:16][OH:28])(=[O:13])[CH3:12]
Reactant: [OH-]
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(C)=O)c(CCCO)c1O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 4-acetylamino-3-allyl-2-hydroxy-benzoic acid methyl ester (2.49 g, 10 mmol, prepared as described in Takuji Kakigami et. al., Chem. Pharm. Bull, 46 (1), 42-52, (1998)) in THF (10 mL) at 0° C. under Argon was added a 0.5 M solution of 9-BBN in THF (80 mL, 40 mmol). The reaction mixture was stirred at 0° C. for 40 min, then at rt for 2 h. The reaction mixture was then cooled to 0° C., and 1 N aqueous NaOH (25 mL) was added dropwise over 5 min, followed by 30% aqueous H2O2 (20 mL) over 5 min. After addition, the reaction mixture was stirred at rt for 2 h, then extracted with EtOAc (3×60 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 30% to 80% EtOAc/hexane to afford the title compound (1.82 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:12]#[N:13])[CH:3]=1.O=P(Cl)(Cl)[Cl:22].C(N(CC)CC)C>O>[Cl:22][C:14]([C:15]([F:18])([F:17])[F:16])=[C:11]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[C:12]#[N:13]
Reactant: N#CC(C(=O)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC(=C(Cl)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Temperature: 90 °C
Yield: 79.5 %

Procedure:
2-(7-chloro-1,3-benzodioxol-5-yl)-4,4,4-trifluoro-3-oxo-butanenitrile (23.9 g, 82 mmol) was treated with POCl3 (62.0 g, 0.41 mol) and then triethylamine (11.4 mL, 82 mmol) was added. The reaction mixture was heated for 3 h at 80-100° C. and then carefully poured into warm water. The product was then extracted ethyl acetate, washed with water and brine, dried, filtered and concentrated to give the title compound (20.2 g; 80%) and used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:14][C:15]2[N:16]=[C:17]([S:23][CH3:24])[N:18]=[CH:19][C:20]=2[CH:21]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: CSc1ncc(C=O)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
Into a solution of 2,6-dichlorophenylacetonitrile (0.55 g) in dimethylformamide (5 mL) was added one equivalent of 60% sodium hydride suspension (0.12 g). After 10 minutes, 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (0.50 g) obtained from Example 76 was added. After stirring overnight at room temperature, the reaction was quenched with water. The aqueous solution was acidified with 1N hydrochloric acid to a pH of 7 and extracted several times with dichloromethane. The combined dichloromethane layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. Chromatography of this residue down silica gel with ethyl acetate:hexane (2:1) gave 0.32 g of the title compound, CIMS (1% NH3 in CH4): 365=M+ +C2H5, 337=M+ +H (Base), 336=M+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][C@H:26]([CH3:28])[O:25][C@H:24]([CH3:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([N:22]6[CH2:23][C@H:24]([CH3:29])[O:25][C@H:26]([CH3:28])[CH2:27]6)[CH:17]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[cis-2,6-dimethylmorpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (29.0 mg, 0.0449 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (27.9 mg, 94.7%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:28](Cl)(=O)[C:29](Cl)=[O:30].N1C(C)=CC=CC=1C.NC1C=CN(CCCO)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:28][CH2:29][OH:30])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Nc1ccn(CCCO)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, 3-(3-amino-pyrazol-1-yl)-propan-1-ol (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (47 mg, 34%) as a white solid: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.21 (m, 2H, CH2), 1.40-1.92 (m, 8H, 4×CH2), 1.92-2.02 (m, 2H, CH2), 2.11-2.28 (m, 1H, CH), 2.88 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.50-3.67 (m, 3H, OCH2 and CH), 4.11 (t, J=6.4 Hz, 2H, NCH2), 6.63 (d, Jo=2.3, 1H, Ar), 7.26 (d, Jo=2.3, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.38 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:15][C:16]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=2[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[S:15][C:16]2[CH2:22][CH2:21][N:20]([C:2]3[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=3[N+:10]([O-:12])=[O:11])[CH2:19][CH2:18][C:17]=2[N:23]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one as prepared in example 1a was treated with 2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine [Ger. Offen. (1989), DE 3820775] in N,N-dimethylformamide in the presence of potassium carbonate at 110° C. to yield the title compound as yellow solid; m.p. >200° C.; MS: [M+H]+=323.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1.[N-:22]=[N+:23]=[N-:24].[Na+].FC(F)(F)C(O)=O.N>ClCCl.C1CCCCC1.C(OCC)(=O)C>[N:22]([C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:7]2[NH:8][C:9](=[O:10])[C:4]3[N:5]([CH:21]=[C:2]([F:1])[CH:3]=3)[CH:6]=2)=[CH:12][CH:13]=1)([CH3:19])[CH3:18])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(N=[N+]=[N-])c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 143 mg (0.5 mmol) 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one and 71.5 mg (1.1 mmol) sodium azide in 1 ml dichloromethane is added dropwise under external cooling with ice a solution of 316 μl (4.1 mmol) trifluoroacetic acid in 0.6 ml dichloromethane. The reaction mixture is stirred for 3 hours at 0° C. Ice and 25% aqueous ammonia are added to obtain a two-phase mixture with a pH of 11. Then a 1:1 mixture of cyclohexane/ethyl acetate is added. The organic phase is separated, dried over sodium sulfate and evaporated to afford 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one as beige powder; HPLC/MS 2.29 min (A), [M+H] 312.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH2:22][CH:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:22][CH:14]([OH:13])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: c1ccc(CC2CO2)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(CNCC(O)Cc2ccccc2)cc1
Yield: 45 %

Procedure:
A solution (60 ml) of 4-methanesulfonylbenzylamine (5.8 g) and (2,3-epoxypropyl)benzene (5.0 g) in 2-propanol was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (4.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:14]S(C(C)(C)C)=O)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH2:14])[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NS(=O)C(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution 3-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (crude from step 2, 264 mg, 0.87 mmol) in MeOH at 0° C. was added 4.0 M HCl in dioxane (0.28 mL, 1.13 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NaHCO3, diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 3-(1-amino-ethyl)-azetidine-1-carboxylic acid tert-butyl ester as a thick colorless oil which was used without further purification.
Reaction SMILES: [F:1][CH:2]1[CH2:6][N:5]([C@@H](C2C=CC=CC=2)C)[CH2:4][C@@:3]1([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([N:5]1[CH2:6][CH:2]([F:1])[C@:3]([CH3:22])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1CC(F)[C@](C)(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@]1(C)CN(C(=O)OCc2ccccc2)CC1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of tert-butyl(3S)-4-fluoro-3-methyl-1-[(1R)-1-phenylethyl]-pyrrolidine-3-carboxylate isomer B (1.55 g, 5.04 mmol) in dichloromethane (30 mL), benzyloxycarbonyl chloride (1.08 mL, 7.56 mmol) was added, and the mixture was stirred in an oil bath at 60° C. for 24 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 20:1→3:2) to obtain 1.38 g (81%) of the title compound (isomer B) as a colorless oily substance.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)S([O-])(=O)=O.[In+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CC(C)=O>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC(C)=O
Product: O=C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 100 °C
Yield: 58.7 %

Procedure:
To a stirred solution of phenyl 1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (0.500 g, 2.50 mmol) in acetone (20 mL) was added indium(III) trifluoromethanesulfonate (0.014 g, 0.025 mmol). The reaction was heated at 100° C. for 20 min. Then, the reaction was allowed to cool to room temperature overnight. The mixture was then concentrated, and the obtained residue was chromatographed (silica gel, hexanes to 40:60 hexanes/ethyl acetate) to give the title compound (0.322 g, 58%) as a white solid: