Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCCN1c1ccccc1
Reaction time: 10 h
Yield: 94.2 %

Procedure:
N-phenylethylenediamine (24.4 g, 0.18 mole) and benzylaldehyde (19.1 g, 0.18 mole) were mixed neat, let stand for 1 hour, diluted with Et2O, and dried over NA2SO4. Removal of the solvent under reduced pressure gave 34.5 g of the benzaldehyde imine. To 5.0 g (22.3 mmol) of the imine dissolved in 80 mL of ethanol was added 3.0 g of NaBH4 (78.9 mmol) portion-wise while stirring. After 3 hours at room temperature, all solvent was stripped under reduced pressure and the residue was dissolved in dilute HCl. This mixture was filtered, and the filtrate was made basic with dilute NaOH before extracting with Et2O. This extract was dried over Na2SO4 and stripped of all solvent to provide 3.9 g of the desired diamine. A mixture of this diamine (31 g, 0.137 mole) and triethylamine (28 g, 0.277 mole) was added dropwise over 30 minutes to a stirred solution of ethyl-2,3-dibromopropionate (35.0 g, 0.135 mole) dissolved in 200 mL of toluene and heated to 40° C. After the addition was complete, the reaction was heated at 80°-85° C. for 7 hours, cooled to room temperature, and partitioned between water and toluene. The organic layer was separated, dried, and stripped of all solvent under reduced pressure to yield 38 g of the crude product. Chromatographic purification gave 12.8 g of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate. An ethanol (EtOH) (75 mL) solution of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate (2.20 g, 6.8 mmol) and 500 mg of 4% Pd/C was subjected to hydrogenolysis in a standard Parr apparatus. The reaction was carried out for 10 hours at 55° C. and under a hydrogen pressure of 5 psi After the catalyst was removed by filtration, and the solvent was removed by stripping under reduced pressure, 1.5 g of ethyl 1-phenyl-2-piperazinecarboxylate was obtained as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCO)c1nc2ccccc2o1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
To a solution of 2-[N-methyl-N-(2-benzoxazolyl)amino]ethanol (9.6 g), triphenylphosphine (13.1 g) and 4-hydroxybenzaldehyde (6.1 g) in dry tetrahydrofuran (150 ml) was added dropwise a solution of diethyl azodicarboxylate (9.0 g) in dry tetrahydrofuran (30 ml), under a blanket of nitrogen with stirring at room temperature. The solution was stirred overnight at room temperature following which the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (300 ml), filtered and the ether solution was washed with dilute sodium hydroxide solution (200 ml), saturated brine (200 ml), dried (MgSO4), filtered and the solvent evaporated. The title compound (mp 97°-98° C.) was obtained after chromatography on silica-gel, eluting with dichloromethane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])#[C-:11]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]1[O:7][CH:11]=[N:10][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14].[N:15]1([CH:13]=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: O=Cc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccco1)N1CCCC1
Product: O=CN1CCCC1
Yield: 276.2 %

Procedure:
BLE 04136D was prepared in accordance with method D using 2-furaldehyde (0.449 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.42 mmol). After work-up the residue was purified by column chromatography (SiO2, cyclohexane:EtOAc=100:0 to 0:100) to led, after evaporation, to trans-5-(furan-2-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04138D (0.742 g, 58.5% yield) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[C:50]([C:54](O)=[O:55])=[N:51][O:52][N:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[C:49]([CH3:48])=[N:53][O:52][N:51]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: Cc1nonc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nonc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid as starting materials in 44% yield. LCMS for C28H29ClN9O3 (M+H)+: m/z=574.2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C=O.[BH3-][C:22]#N.[Na+]>CC#N>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[O:4][CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH3:22])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCC2CCNCC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC(COc2cc([N+](=O)[O-])ccc2Cl)CC1
Reaction time: 4 h

Procedure:
4-(2-Chloro-5-nitro-phenoxymethyl)-piperidine (4 g, 14.8 mmol) was dissolved in CH3CN (20 ml), and formaldehyde (5.9 ml, 37% aqueous) and NaBH3CN (1.49 g, 23.68 mmol) were added. After 4 h, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with brine. The EtOAc portion was dried with Na2SO4, and evaporated. The title compound was purified by column chromatography using 0-75% of a 90:10:1 (CH2Cl2:MeOH: NH4OH) solution as the eluent to yield a yellow solid. MS(MH+)=NA; Calc'd 284.09 for C13H17ClN2O3.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[S:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(c2ccc(CO)s2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)s2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (2.00 g, 19.11 mmol) in dry CH2Cl2 (18.4 mL) was treated at 0° C. with Et3N (1.81 mL, 12.98 mmol) followed by DMAP (122 mg, 1.00 mmol) and Ms-Cl (0.93 mL, 11.98 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (15 mL), extracted with CH2Cl2 (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. The crude material in acetone (12 mL) was added, under inert atmosphere (N2) to a solution of 4-nitro-1H-pyrazole (1.23 g, 9.60 mmol) in acetone (12 mL). K2CO3 (3.98 g, 28.81 mmol) followed by TBA bromide (619 mg, 1.92 mmol) were added and the reaction mixture was stirred at rt overnight. Water (60 mL) and EA (80 mL) were added. The aq. layer was extracted with EA (80 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=0.35. LC-MS-conditions 02: tR=0.96 min.
Reaction SMILES: C[CH:2]([C@H:4]1[CH2:8][O:7]C(=O)[N:5]1[C:10](=[O:37])[CH2:11][CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[CH3:3].[CH3:38][N:39]([CH3:52])[C:40](=[O:51])[CH2:41][NH:42][C@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44].[CH3:53][CH:54]([C@H:56]1[CH2:60][O:59]C(=O)N1)[CH3:55]>>[CH3:52][N:39]([CH3:38])[C:40](=[O:51])[CH2:41][N:42]([C@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])[C:8](=[O:7])[CH2:4][C@@H:11]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:10]([NH:5][C@@H:4]([CH2:2][CH:3]1[CH2:17][CH2:13][CH2:12][CH2:11][CH2:10]1)[C@@H:8]([OH:7])[C@@H:60]([OH:59])[CH2:56][CH:54]([CH3:53])[CH3:55])=[O:37]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C[C@H](NCC(=O)N(C)C)c1ccccc1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)N(CC(=O)N(C)C)[C@@H](C)c1ccccc1)Cc1c[nH]cn1

Procedure:
4(S)-(1-Methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl}-2-oxazolidinone: By following the procedure of example 2, section (b) and using the product of section (a) of this example (11.5 g, 30.1 mmol) to prepare the corresponding mixed anhydride which in turn is reacted with the (S)-4-(1-methylethyl)-2-oxazolidinone (3.53 g, 27.3 mmol), the desired product was obtained as a pale yellow solid (11.38 g, 84%); 1H NMR(CDCl3) δ7.36-7.29 (m,10H), 7.17-7.10 (m,6H), 6.58 (d, J=0.7 Hz,1H), 4.40 (td, J=3.8 Hz, 7.5 Hz,1H), 4.29-4.14 (m,2H), 3.32-3.23 (m,2H), 2.96-2.88 (m,2H), 2.33 (hept d, J=3.8 Hz, 6.9 Hz, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.9 Hz,3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2C=CN=CC=2)C(C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:24][OH:25])[CH2:17][C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(c1ccncc1)c1ccc(F)cc1
Reactant: NO
Reactant: c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccncc1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 4-fluorophenyl-2-(4-pyridyl)acetophenone (8.08 g, 37.6 mmol) [See PCT/US93/00674, Adams et al., WO93/14081] in EtOH (80 mL) was added hydroxylamine hydrochloride (4.12 g, 59.7 mmol) and pyridine (4.8 mL, 59.7 mmol). The mixture was stirred at 60 ° C. for 1 h, then poured into H2O and stirred an additional 1 min. The resulting precipitate was filtered and washed with H2O. The precipitate was recrystallized from EtOH/H2O to give the title compound as a white solid (6.29 g): mp 135-136° C.
Reaction SMILES: C[Si]([CH2:5][C:6]#[N:7])(C)C.C([N-]C(C)C)(C)C.[Li+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:25](=O)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][Si:30]([C:33]([CH3:36])([CH3:34])[CH3:35])([CH3:31])[CH3:32])/[C:25](=[CH:5]\[C:6]#[N:7])/[CH2:24]1)=[O:22])([CH3:18])([CH3:17])[CH3:19]
Reactant: C[Si](C)(C)CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)/C(=C\C#N)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of trimethylsilylacetonitrile (1.3 ml) in tetrahydrofuran (THF) (30 ml) was added at −78° C. lithium diisopropylamide (2.0 M in hexane, 4.7 ml). The resulting mixture was stirred at −78° C. for 0.5 hours, and then a solution of 1-(t-butoxycarbonyl)-4-(t-butyldimethylsilyloxy)piperidin-3-one (3 g) in THF (10 ml) was added at the same temperature. The resulting mixture was stirred for one hour while the temperature was raised to room temperature. The mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate (9:1) as the eluent to afford the title compound (880 mg, yield: 27%) as the less polar isomer as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][CH:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCc1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
A suspension of the quinazolinone (17) (50.0 g, 0.56 mmol) and anhydrous sodium acetate (56 mg) in glacial acetic acid (1.0 mL) was heated to 40° C. and treated dropwise with a solution of bromine (90 mg, 0.56 mmol) in glacial acetic acid (5 mL). Once the starting material was fully consumed by TLC analysis, the mixture was poured onto water (5 mL), basified with saturated aqueous sodium hydrogen carbonate and extracted with tert-butylmethyl ether. The combined organic phases were dried (MgSO4), filtered, and concentrated to a solid which was purified by silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 50:50, v/v] to give the title bromide (18) (166 mg, 85%) as an off white solid:
Reaction SMILES: ClC1N=[C:9]2[C:5](N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=[C:4](NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=C(CO)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:66][CH2:67][N:68]3[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[N:3]=[C:4]([CH2:5][CH3:9])[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46). MS (ES+) m/e 637.42 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[Cl-].[Li+]>CN(C=O)C.C(#N)C.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>[CH2:16]([C:2]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(F)c(F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(F)c(F)cc1C(=O)OC
Temperature: 90 °C
Yield: 78.1 %

Procedure:
A mixture of methyl 2-bromo-4,5-difluorobenzoate (0.5 g, 1.992 mmol), allyltributylstannane (0.679 mL, 2.191 mmol), lithium chloride (0.169 g, 3.98 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.070 g, 0.100 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution for 5 times, then dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4,5-difluorobenzoate (330 mg, 1.555 mmol, 78% yield) as an oil. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J=11.1, 8.2 Hz, 1H), 7.11 (dd, J=11.1, 7.7 Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.16-5.02 (m, 2H), 3.91 (s, 3H), 3.76 (d, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]([F:25])([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[C:9]([OH:11])=[O:10])[CH:7]=1.[CH3:28][CH:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(C)C>[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C@@:8]([F:25])([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CC(N)c1ccccc1
Reactant: COc1ccc(Cl)cc1C(F)(C(=O)O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CC(C)O
Product: COc1ccc(Cl)cc1[C@](F)(C(=O)O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: C[C@H](N)c1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A 5-L three-necked round-bottomed flask, equipped with a mechanical stirrer and thermocouple, was charged with the racemic acid of Example 4 (392.87 g, 0.964 mol) and dissolved in isopropanol (2.0 L) to afford a light yellow solution. While stirring vigorously the reaction mixture was heated to 50° C. and then (S)-(α-methylbenzylamine was added over five minutes, causing the reaction tp turn slightly green in color. Heating was discontinued and a seed crystal was preferably added. Crystallization was observed within 15 minutes. The reaction mixture was cooled to room temperature over 2 hours while stirring and then the crystals were collected by filtration and washed with isopropanol (500 mL). After drying under vacuum, 208 g of the title compound as a 1:1 salt with (S)-α-methylbenzylamine (41% yield corrected for about 9% of 2-propanol as determined by 1H NMR; about 99.9% by HPLC) was obtained as a fluffy white solid. The product was found to be 99.3% enantiomerically pure as determined by capillary electrophoresis.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]([NH2:15])=[S:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16]C(C)=O.C[I:21]>CO>[IH:21].[CH3:16][S:14][C:13](=[NH:15])[NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)=O
Reactant: CI
Reactant: NC(=S)Nc1ccccc1N1CCCC1
Solvent: CO
Product: CSC(=N)Nc1ccccc1N1CCCC1
Product: I

Procedure:
A mixture of 1-[2-(1-pyrrolidinyl)phenyl]thiourea (12.2 g), acetone (100 ml) and methanol (20 ml) was heated to 90°-95° C. Methyl iodide (8.36 g) was added and the mixture heated under reflux for 3 hours. The solvent was removed by evaporation to give a residue which was dried under vacuum (5 mm/Hg) to give 2-methyl-1-[2-(1-pyrrolidinyl)phenyl]-2-thiopseudourea hydroiodide (m.p. 139°-141° C.).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]1[CH:26]=[N:25][CH:24]=[CH:23][N:22]=1)([CH3:19])([CH3:18])[CH3:17].CN(C)[CH:29]=[O:30]>O1CCCC1.C(OCC)(=O)C.O>[C:16]([O:20][C:21]1[C:26]([CH:29]=[O:30])=[N:25][CH:24]=[CH:23][N:22]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)Oc1cnccn1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1C=O
Temperature: -50 °C
Reaction time: 0.42 h
Yield: 45 %

Procedure:
After dissolving 2.50 ml of 2,2,6,6-tetramethylpiperidine in 40 ml of tetrahydrofuran, the solution was cooled to −50° C. Next, 5.25 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise thereto under a nitrogen atmosphere. The mixture was stirred for 25 minutes, cooled on ice, and stirred for an additional 35 minutes. It was then cooled to −78° C., and a solution of 1.89 g of 2-tert-butoxypyrazine [CAS No. 70090-30-1] in tetrahydrofuran (5 ml) was added dropwise. After stirring the mixture for 15 minutes, 1.25 ml of N, N-dimethylformamide was added dropwise. After 10 minutes, water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.00 g, 45% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10](N)[CH2:11][NH2:12]>O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>[NH:5]1[CH2:10][CH2:11][N:12]=[C:4]1[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: NCCN
Reactant: N#Cc1ccccc1N
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Product: Nc1ccccc1C1=NCCN1
Temperature: 0 °C
Yield: 81.4 %

Procedure:
2-Aminobenzonitrile (9.00 g, 76.2 mmol) was added at 0° C. to ethylenediamine (25.5 ml, 381 mmol) in small portions with stirring. After phosphorus pentasulfide (200 mg, 0.900 mmol) was added, the mixture was stirred at 100° C. overnight. After cooling to 0° C., the reaction was diluted with water. The resulting white precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (10.0 g, 81% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[Cl-].[CH3:14][O:15][C:16]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:16]=1[O:15][CH3:14])[N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[C:7]2[OH:12]
Reactant: Nc1cccc2c(O)cccc12
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Agent: [Cl-]
Product: COc1cccc(C(c2ccc3c(N)cccc3c2O)N2CCOCC2)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-amino-1-naphthol and 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 21.