Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:34])=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoate (D147) (330 mg) in isopropanol (7 mL) and water (7 mL) was added NaOH (6.79 mL, 0.5 M aqueous solution) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours, and the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E104) (136 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.29 (6H, s), 2.53 (2H, t), 2.87 (2H, t), 3.29 (3H, s), 4.83 (1H, m), 7.02 (1H, m), 7.10 (1H, s), 7.39 (1H, d), 7.75 (1H, m), 8.07 (1H, dd), 8.14 (1H, d), 12.07 (1H, s). MS (ES): C23H21ClFN3O4 requires 457; found 458.2 (M+H+).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(CC)CC>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
Boc-Val-OSu (12.6 g, 40 mmol) and H-Val-OH (4.68 g, 40 mmol) were condensed in DMF (250 ml) for 96 hours in the presence of 2 ml Et3N. More Et3N was added when needed to maintain the reaction slightly basic. The remaining insoluble material was filtered off and the filtrate evaporated to dryness (45°). The residue was partitioned between ether and dilute H2SO4 (~1%) and the organic layer washed with water (3×), dried over Na2SO4 and evaporated to a foamy glass. The product was crystallized from ether and petroleum ether: Yield, 12.2 g (96.4 %); mp 155°-158°; [α]D25 = +1.10° (c 1, DMF.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[N:36](C(OC(C)(C)C)=O)[CH3:37]>ClCCl>[CH3:28][S:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:52])[C@H:35]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[N:36]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:37]
Reactant: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CSCCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
BOC-Gly-OH (0.69 g) was dissolved in dichloromethane (10 ml) and cooled at -20°. Isobutylchloroformate (0.53 g) and NMM (0.4 g) were added with stirring. After 2 minutes Cl-H2+MePhe-NHTmp (1.2 g) and NMM (0.4 g) were added and the reaction mixture was allowed to attain room temperature. The stirring was continued for additional 3 hours when the reaction was worked up as described for (II). The dipeptide amide (IV) was obtained as a gum.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 63 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine (72.79 mg, 63% yield) as a white powder. 1H-NMR (CDCl3) δ 8.24 (d, J=8.81 Hz, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.24 (m, 2H), 7.03 (d, J=8.16 Hz, 1H), 6.84 (s, 1H), 6.54 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 5.83 (m, 1H), 3.90 (m, 7H), 3.15 (m, 4H), 3.00 (m, 2H), 2.80 (m, 3H), 2.67 (m, 2H), 2.07 (m, 2H), 1.32 (m, 2H). LC/MS (ESI+)=559 (M+H). MP=181-183° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH:39]=[C:38]([CH3:40])[C:37](SC#N)=[N:36][C:35]3=[O:44])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:45]([F:48])([F:47])[F:46])[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH2:33][N:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:36][C:35]3=[O:44])[CH2:26][CH2:25]2)[CH:21]=[C:20]([C:45]([F:46])([F:48])[F:47])[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1SC#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
81.3 mg (0.9 mmol) of phenol and 325.5 mg (2.4 mmol) of K2CO3 were added to 400.0 mg (0.78 mmol) of 1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl thiocyanate from Example 7.1 in 40 ml of acetonitrile and 500.0 mg of molecular sieves (3 Å). The reaction mixture was then stirred at room temperature for 12 hours. Insolubles were filtered off, methylene chloride was added to the filtrate, followed by extraction with aqueous brine. The residue after drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent in vacuo was taken up in 100 ml of diisopropyl ether and heated. The precipitate was filtered off with suction and the mother liquor was concentrated somewhat. The mother liquor was then mixed with pentane and cooled in an ice bath. The precipitated solid was filtered off with suction, washed and dried in vacuo at 40° C., resulting in 120 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.CN(C)C=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Reaction time: 5 h
Yield: 14.1 %

Procedure:
2-{6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (56.6 mg, 0.104 mmol) was dissolved in methanol (0.5 mL) and dimethylformamide (0.5 mL) and 50% w/v aqueous potassium hydroxide (0.2 mL) was added. After 5 hours, the reaction was quenched by addition of acetic acid (0.2 mL). The mixture was carefully poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and dried to a residue which was purified by preparative HPLC to afford 2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-N,N-dimethyl-acetamide (5.7 mg, 14.1%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.74 (s, 3H), 2.90 (s, 3H), 3.78 (s, 3H), 3.96 (s, 2H), 7.01 (dt, J=1, J=7.5 Hz, 1H), 7.11 (br d, J=8 Hz, 1H), 7.28 (dt, J=1.5, J=8.5 Hz, 1H), 7.50 (dd, J=1.5 Hz, J=7.5 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H). MS: m/z 388 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11](=[O:14])[C:12]#[CH:13].C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11](=[O:14])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#CC(C)=O
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), copper(l)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[OH:19])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[O:19][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCS(=O)(=O)CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
In 180 ml of acetone was suspended 6 g (0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9 followed by a serial addition of 5.7 g (0.0292 mole) of t-butyl bromoacetate, 0.9 ml of water and 10.8 g of anhydrous potassium carbonate. The mixture was stirred at 40° C. for 2 hours and the insoluble matter was filtered off. To the filtrate was added 200 ml of water and 200 ml of ethyl acetate was added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 6.0 g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals. (Yield, 73.0%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:12]#[C:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:14][C:13]#[CH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(tert-butyl)phenol (5.0 g, 34 mmol) and progargyl bromide (4.8 g, 40 mmol) in dry ACN (50 mL) was added K2CO3 (5.5 g, 40 mmol) and the solution was stirred for 2 d at rt, concentrated, redissolved in water and extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE) to give compound P4a (4.5 g, 72%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (0.27 mL, 2.0 mmol) in THF (5 mL) at −78° C. was added nBuLi (0.72 mL of a 2.8 M solution in Hexane, 2.0 mmol). The reaction was stirred at −78° C. for 15 minutes then added to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (0.33 mL, 2.0 mmol) in THF (5 mL) at −78° C. The reaction was stirred to room temperature over 1 hour, quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and reduced to dryness to afford tert-butyl 2-hydroxy-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (I-27) as a clear oil. MS m/z 276.1 (M−55)+.
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:15]([CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[OH:20])([CH3:18])([CH3:17])[CH3:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:20][CH:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(O)C(C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(COC(C(C)(C)C)C(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and di-t-butylmethanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-2-amino 1-[di-(t-butyl)methoxy]propane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1C=CC=CC=1.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1cnc(-c2ccc(OCCCCCCC)cc2F)nc1
Reaction time: 12 h

Procedure:
0.1 mol of 2-(4-heptyloxy-2-fluorophenyl)-5-hydroxypyrimidine (prepared from 4-heptyloxy-2-fluorobenzamidine in accordance with Example 1) is dissolved together with 0.12 mol of pyridine in toluene and 0.1 mol of nonanoyl chloride is then added at room temperature. Stirring is then carried out for 12 hours and standard working-up is carried out. 2-(4-Heptyloxy-2-fluorophenyl)-5-nonanoyloxypyrimidine is obtained, C 65 I, Δε=-0.2.
Reaction SMILES: [Na+].Br[CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].C[O-].[Na+].[CH2:13]([SH:16])[CH2:14][SH:15].Cl>CCO.O>[CH2:13]([S:16][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7])[CH2:14][S:15][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7]
Reactant: O=S(=O)([O-])CCCBr
Reactant: SCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCCSCCSCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromopropane sulfonic acid sodium salt (24.7 g, 110 mmol) and sodium methoxide (7.06 g, 131 mmol) in EtOH (300 mL) at ambient temperature was added, dropwise, 1,2-ethanedithiol (4.4 mL, 52.3 mmol) in ethanol (25 mL). Allowed to stir at room temperature for one hour, and then heated to reflux overnight. Cooled to room temperature and acidified with 2 N HCl to pH 1-2. The resulting suspension was heated to 75° C. and water was slowly added in small portions until a clear solution was obtained. Cooled to room temperature, and then to 5° C. The resulting white precipitate was filtered off, washed with cold EtOH and dried, giving 11.9 g (67.4%) as a white powder. 1H NMR (400 MHz, D2O) δ 3.10 (t, J=7.2 Hz, 4H), 2.92 (s, 4H), 2.82 (t, J=7.2 Hz, 4H), 2.11 (m, 4H). 13C NMR (101 MHz, D2O) δ 52.26, 33.38, 32.27, 26.80.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.Cl.[CH3:11][C:12](=[CH2:14])[CH3:13]>>[C:12]([C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7])([CH3:13])([CH3:11])[CH3:14]
Reactant: Cc1ccc(N)cc1N
Reactant: C=C(C)C
Agent: Cl
Product: Cc1cc(C(C)(C)C)c(N)cc1N
Temperature: 180 °C

Procedure:
A 300 cc Hastalloy C pressure vessel equipped with a mechanical stirrer was used for producing t-butyltoluenediamine. Approximately 100 grams or 0.819 moles of 2,4-toluenediamine were charged to the vessel along with 5 grams of 36% aqueous hydrochloric acid. The vessel was sealed and purged with nitrogen, leaving a 33 psig nitrogen blanket. The vessel contents then were heated to 180° C. with continuous stirring. Isobutylene then was introduced into the reactor and 53.4 grams or 0.06 moles were added over 15 minutes. On addition of the isobutylene, the pressure in the reactor increased to 766 psig. The reaction mixture was maintained at 180° C. for 24 hours with constant stirring. At the end of the 24 hour period the pressure had dropped to 524 psig. The contents were then cooled to 160° C. and stirring discontinued. At that time the reactor was vented and the reaction product analyzed for composition.
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[C:34]([CH3:35])=[C:33]2[C:28]([C:29](=[O:43])[C:30]([C:40]([OH:42])=[O:41])=[CH:31][N:32]2[C@@H:36]2[CH2:38][C@@H:37]2[F:39])=[CH:27][CH:26]=1>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[C:34]([CH3:35])=[C:33]4[C:28]([C:29](=[O:43])[C:30]([C:40]([OH:42])=[O:41])=[CH:31][N:32]4[C@@H:36]4[CH2:38][C@@H:37]4[F:39])=[CH:27][CH:26]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 427.3 %

Procedure:
After adding 3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (185 mg, 817 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (190 mg, 68 μmol) was added thereto and it was heated under reflux for 17 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (50 ml). After washing the organic layer with a 10% aqueous citric acid solution (25 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, stirring at room temperature was performed for 30 minutes. 1 mol/l Hydrochloric acid (5 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (20 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution and the insolubles were removed by filtration. After adjusting the pH of the basic aqueous solution to 7.4 using 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by preparative chromatography (development at the lower layer of a 7:3:1 mixture of chloroform:methanol:water), recrystallized in ethanol, and dried under a reduced pressure. 112 mg (43%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((S)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (460 mg, 1.7 mmol) in dichloromethane (12 mL). The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (243 mg, 84%). 1H NMR (400 MHz, DMSO, d6): δ 4.28-4.18 (1 H, m), 3.72-3.17 (10 H, m), 2.11-2.10 (1 H, m), 1.81-1.80 (2 H, m)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].COC(OC)OC.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:19][CH2:20][CH2:21][CH2:22][OH:23])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=[N+]([O-])c1cccc(CNCCCO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of m-nitrobenzaldehyde (94.23 mmol) and trimethylorthoformate (15.5 mL, 141 mmol) in MeOH (300 mL) is added dropwise 3-amino-1-propanol (7.21 mL, 94.23 mmol) at room temperature. The reaction is allowed to stir at room temperature for 5 hours followed by cooling to 0° C. in an ice bath. Sodium borohydride (3.56 g, 94.23 mmol) is added in two portions and when the bubbling stops the solvent is evaporated. The resulting residue is partitioned between ethyl acetate (75 mL) and water (75 mL). The aqueous layer is extracted twice with ethyl acetate (75 mL) The ethyl acetate extracts are collected and washed twice with Brine (50 mL), dried over MgSO41 filtered, and concentrated. Drying will give the title compound.