Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([O:28]C)=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Yield: 85.6 %

Procedure:
To a mixture of methyl 5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-2-carboxylate (909 mg) synthesized above, ethanol (20 mL) and tetrahydrofuran (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heating under reflux for 5 hr, and concentrated under reduced pressure. 1N Hydrochloric acid (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (751 mg, 86%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(Cl)c1Cl
Yield: 119.8 %

Procedure:
To a stirred suspension of 2,3-dichloroaniline (35 g, 216.02 mmol, 1.0 eq.) in conc. HCl (150 mL) was added a solution of NaNO2 (17.9 g, 259.22 mmol, 1.2 eq.) in water (50 mL) dropwise at −5 to 0° C. until the reaction mixture formed a clear solution. The reaction mixture was added dropwise to a stirred solution of SnCl2 (90.1 g, 475.24 mmol, 2.2 eq.) in conc. HCl (300 mL) at −5° C. for 30 min. A solid precipitate obtained was filtered out and washed with excess of ice cold water to get (2,3-dichlorophenyl)hydrazine (45.8 g, 98%, pale yellow solid; TLC system: EtOAc/PE (3:7) Rf: 0.55).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Br:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][S:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH:9]=[N:8][CH:7]=1
Reactant: Nc1ccc2c(Br)cncc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(Br)cncc2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
In 1.5 ml of pyridine was dissolved 20 mg (0.09 mmol) of 7-amino-4-bromoisoquinoline (Preparation Example 20), 23 mg of 4-chlorobenzenesulfonyl chloride was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extracting with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel thin layer chromatography, to give 13 mg of the title compound. Melting point: gradually decomposed from 229 degrees.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36]2[CH:45]=[C:44](O)[C:43]3[C:38](=[CH:39][C:40]([O:47][CH3:48])=[CH:41][CH:42]=3)[N:37]=2)[N:35]=1)([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:24]([O:23][C:21]([C@@:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([O:13][C:44]3[C:43]4[C:38](=[CH:39][C:40]([O:47][CH3:48])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:34]4[N:35]=[C:31]([NH:30][CH:27]([CH3:29])[CH3:28])[S:32][CH:33]=4)[CH:45]=3)[CH2:12][C@H:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:26])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3csc(NC(C)C)n3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of compound 35 (0.10 mmol) in dry THF (4 mL) was added the quinoline 12 (0.16 mmol) and Ph3P (0.40 mmol). After cooling to 0° C. DIAD (0.40 mmol) was added dropwise during 5 min. The solution was stirred at 0° C. for 1 h and at rt for 48 h. The solvent was evaporated and the remainder was purified using flash column chromatography (toluene/EtOAc 1:1) to give the title compound (10%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[NH:29][N:28]=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:14]=3)[N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:30][C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1.O[C@@H](C)C(N1CCN(CC2C=CC3C(=CC=C(OC4C=CC(C5NN=CC=5)=CC=4)C=3)N=2)CC1)=O>>[OH:30][C:31]1([C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]5[CH:20]=[CH:21][C:22]([C:25]6[NH:29][N:28]=[CH:27][CH:26]=6)=[CH:23][CH:24]=5)[CH:14]=4)[N:9]=3)[CH2:2][CH2:3]2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(O)C1(O)CC1
Reactant: c1cc(-c2ccc(Oc3ccc4nc(CN5CCNCC5)ccc4c3)cc2)[nH]n1
Agent: C[C@H](O)C(=O)N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1
Product: O=C(N1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cc4)ccc3n2)CC1)C1(O)CC1

Procedure:
The title compound 15 is synthesized from intermediate F (35 mg, 0.076 mmol), and 1-hydroxy-1-cyclopropanecarboxylic acid (19 mg, 0.19 mmol) according to the procedure described for the synthesis of compound 13.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH3:17])=[O:15].[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[O:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[C:14]([O:16][CH3:17])[O:15][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CCCO1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(O[Si](C)(C)C)=C1CCCO1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a suspension of LDA (2.6 g, 24.3 mmol) in THF (30 mL) at −78° C. was slowly added methyl tetrahydrofuran-2-carboxylate (3.0 g, 23.0 mmol). The resulting mixture was stirred at −78° C. for 20 minutes, and TMS chloride (2.6 g, 24.3 mmol) was slowly added. The reaction was stirred for 1 hour at −78° C. and then warmed to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, avoiding contact with water. Hexanes (20 mL) was then added, and the mixture was passed through a short plug of celite, eluting with hexanes (10 mL). The solution was then concentrated, affording the crude product in good purity.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]O.S(=O)(=O)(O)O.[F:10][C:11]1[CH:25]=[CH:24][C:14]([CH:15](O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:15]([C:14]1[CH:24]=[CH:25][C:11]([F:10])=[CH:12][CH:13]=1)[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(CCCl)c2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
To a solution of 29,3 g of 2-chloroethanol in toluene 2 ml of concentrated sulphuric acid were added, after which 50 g of 4,4'-difluorobenzhydrol were added under stirring. The mixture was refluxed for 2 h, cooled and more toluene added. The organic phase was washed successively with water, aqueous sodium carbonate, and water and then dried. The solvent was evaporated to give 65 g of a crude product which was distilled to obtain 57.5 g (89,5%) of [1-(2-chloroethyl)]-bis-(4-fluorophenyl)methane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH:11]=[CH:12][C:13]([OH:15])=O)=[CH:2]1>C(O)(=O)C>[S:10]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[NH:1][C:2]=2[C:13](=[O:15])[CH:12]=[CH:11]1
Reactant: O=C(O)C=CSc1c[nH]c2ccccc12
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccccc12
Yield: 53.7 %

Procedure:
A solution of 76.7 g (0.35 mole) of 3-(indol-3 ylthio) acrylic acid in 4 liters of 10% polyphosphoric acid in acetic acid is stirred at room temperature for 65 hours. The supernatent is decanted from the sticky precipitate, which is partitioned between chloroform and 5% NaOH solution. The organic phase is washed with water, dried, evaporated and the residue recrystallized from 3 liters of 95% ethanol to give 37.8 g of product, mp 242°-243° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH3:25]O>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Reactant: CO
Solvent: CCO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O

Procedure:
The mother liquor from the recrystallization of (−) 20-cinchonidine salt was concentrated under reduced pressure. The enriched (+) 20 isomer was obtained from the mother liquor by neutralizing the salt to obtain the free acid, as described previously for compound 18. The optical rotation showed that the isomer was approximately 80% enantiomeric excess, optical rotation was measured at 21° C.: [α]D +18:2° (c=1.2, methanol). A stock solution (1 mg/mL) of the racemic mixture (20) was prepared in ethanol/mobile phase (1:1). The injected sample volume was 250 μL. The compound was eluted with a mobile phase of heptane/ethanol. with 1% TFA (88:12) at a flow rate of 2.5 mL/min. Under these conditions, the (−) isomer eluted at 15.8 min and the (+) isomer eluted at 18.2 min retention times. The collected fractions were concentrated under reduced pressure at room temperature. (+) 20 was collected as a white solid, 0.14 g. mp 146-148° C. The optical rotation was measured at 21° C.: [α]D +25.3° (c=0.5, methanol).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.O.[BrH:14]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:14])=[CH:5][CH:4]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Br
Solvent: O
Product: FC(F)(F)c1ccc(CBr)cc1

Procedure:
A mixture of 5.5 g of p-trifluoromethyl-benzyl alcohol in 50 mL of 48% HBr was heated on a steam-bath for 6 h with stirring, and cooled. Water (100 mL) was added to the above mixture, and the aqueous layer was extracted with ether, and the organic layer was concentrated in vacuo to afford 4.8 g of p-trifluoromethyl-benzyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]2[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:16]=3[CH2:15][CH2:14]2)[N:23]=[C:22]([CH3:26])[N:21]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:20]4=[O:35])[CH:9]=[CH:8][C:3]=1[CH:4]=[C:5]([CH3:7])[CH3:6].[CH2:36](Br)[C:37]#[CH:38].C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[F:1][C:2]1[CH:11]=[C:10]([N:12]([CH:13]2[C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:16]=3[CH2:15][CH2:14]2)[N:23]=[C:22]([CH3:26])[N:21]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:20]4=[O:35])[CH2:38][C:37]#[CH:36])[CH:9]=[CH:8][C:3]=1[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: C#CCBr
Reactant: CC(C)=Cc1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C#CCN(c1ccc(C=C(C)C)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 80 °C

Procedure:
A mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-β,β-dimethylstyrene (1.4 g), propargyl bromide (6.1 g), calcium carbonate (0.88 g) and DMA (20 ml) was stirred and heated to 80° C. for 6 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially increasingly polar mixtures of hexane and ethyl acetate and then increasingly polar mixtures of methylene chloride and ethyl acetate as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-β,β-dimethylstyrene (1.04 g);
Reaction SMILES: [CH2:1]([NH:18][C:19]([S:21][C@H:22]1[CH2:27][CH2:26][CH2:25][O:24][C@H:23]1[CH2:28][O:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Br:37])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[S:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>C1(C)C=CC=CC=1>[Br-:37].[CH2:1]([NH:18][C:19]([S:21][C@H:22]1[CH2:27][CH2:26][CH2:25][O:24][C@H:23]1[CH2:28][O:29][C:30]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N+:41]1[CH:42]=[CH:43][S:39][CH:40]=1)=[O:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)S[C@H]1CCCO[C@H]1COC(=O)NCCCCCBr
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)S[C@H]1CCCO[C@H]1COC(=O)NCCCCC[n+]1ccsc1
Product: [Br-]
Reaction time: 64 h

Procedure:
600 mg of dl-[cis-3-(N-heptadecylcarbamoylthio)tetrahydropyran-2-ylmethyl]N-(5-bromopentyl)carbamate (prepared as described in Preparation 42) were dissolved in 1 ml of toluene, and then 0.68 ml of thiazole were added to the resulting mixture. The mixture was then heated on an oil bath kept at 80° C. for 64 hours. At the end of this time, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to column chromatography through 15 g of silica gel. 595 mg of the title compound were obtained as a white powder, melting at 122°-125° C., from the fractions eluted with mixtures of methylene chloride and methanol ranging from 9:1 to 4:1 by volume.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH:5]([CH2:7][CH2:8][CH3:9])O.[CH2:11]([SH:16])[CH:12]([SH:15])[CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:12]1[CH2:11][S:16][C:4]([CH2:3][CH2:2][CH3:1])=[C:5]([CH2:7][CH2:8][CH3:9])[S:15]1)[CH3:14]
Reactant: CCC(S)CS
Reactant: CCCC(=O)C(O)CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1=C(CCC)SC(CC)CS1

Procedure:
Butyroin (12.2 g), butane-1,2-dithiol (14.4 g) and p-toluenesulfonic acid (0.5 g) were dissolved in toluene (50 g) and the solution refluxed under a Dean-Stark trap. It was worked up as in Example 3 to give 2-ethyl-2,3-dihydro-5,6-dipropyl-1,4-dithiin as a clear greenish liquid, boiling range 92°-105°/0.025 mm, yield 8.5 g (44%). NMR(CDCl3), 0.78-1.14 δ (overlapping triplets), 1.21-1.80 δ (multiplet) 2.07-2.37 δ (complex quartet), 2.6-3.4 δ (multiplet).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[C:10]([N:5]1[CH2:6][C@H:7]([O:9][C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:8][C@H:4]1[C:3]([O:2][CH3:1])=[O:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: CN(C)C(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N(C)C)CN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (Example 1, part b) in chloroform is treated dropwise with an equivalent quantity of dimethylcarbamyl chloride. The mixture is stirred for two hours, washed with water and the organic phase is dried over MgSO4. The solution is filtered and solvent evaporated to give trans-N-carbobenzyloxy-4-[[(dimethylamino)carbonyl]oxy]-L-proline, methyl ester.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.N1C=CC=CC=1>ClC(Cl)C.ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])=[O:4]
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9.1 g (0.05 mol) of trichloroacetyl chloride in 40 ml of dichloroethane is added at -5° C. to a solution of 6.25 g (0.05 mol) of 4-fluoro-2-methylaniline in 75 ml of dichloromethane and 3.95 g (0.05 mol) of pyridine. This solution is stirred at room temperature for one hour and then poured into ice-cold water, and the organic phase is separated after settling has taken place, washed with water and dried over sodium sulphate. It is filtered, the filtrate is evaporated and the residue is dispersed in hexane; a pink solid is thereby obtained.
Reaction SMILES: [I:1]I.[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[N:4]1>C(#N)C.C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[S:3]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([I:1])=[CH:20][CH:21]=3)[CH2:11]2)=[N:4]1
Reactant: II
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccccc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(I)cc1
Reaction time: 24 h
Yield: 73.4 %

Procedure:
Iodine (0.67 g, 2.64 mmol) was added portionwise to a stirred solution of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one (0.7 g, 2.53 mmol) and silver trifluoroacetate (0.727 g, 3.29 mmol) in acetonitrile (4 ml) and chloroforrn (6 ml). The mixture was stirred for 24 hours in the dark. The mixture was filtered and the filtrate evaporated. The residue was extracted with EtOAc and the extract washed with water, dilute ammonia (0.1 ml of 0.88SG ammonia in 25 ml water), water and brine, dried (Na2SO4) and evaporated to give the title product as a solid (0.749 g, 73%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[CH2:10]([NH2:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH:15][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[S:9])[CH:2]=1
Reactant: S=C=Nc1cccnc1
Reactant: CC(C)(C)CN
Solvent: C1CCOC1
Product: CC(C)(C)CNC(=S)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 3-pyridyl-isothiocyanate (1.50 mL, 13.3 mmol) in THF (30 mL) at room temperature was added neopentylamine (2.35 mL, 19.8 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 2.64 g (89%) of 1-(3-pyridyl)-3-(2,2-dimethylpropyl)-thiourea as an off-white solid which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])([CH3:4])([CH3:3])[CH3:2].[ClH:17].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.Cl>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([O:13][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:12])[NH2:10])([CH3:4])([CH3:2])[CH3:3].[ClH:17]
Reactant: C=C(C)C
Reactant: CC(C)(C)c1cccc(C[C@H](N)C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C(C)(C)C)c1
Yield: 87 %

Procedure:
According to example 54, 0.50 g of 3-tert-butyl-L-phenylalanine·HCl was treated with 30 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.4 mL of conc. H2SO4. Work-up in the usual manner followed by acidification of the free amine with ethereal HCl afforded 0.53 g (87%) of tert-butyl 3-tert-butyl-L-phenylalaninate·HCl as a light yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:5][CH:4]=1.[OH-].[Na+].O1CCCC1.CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1cnccc1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccncc2/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of ethyl (2E)-3-[4-(4-methoxyphenyl)pyridin-3-yl]prop-2-enoate (2.75 g), 2M aqueous sodium hydroxide solution (7.3 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 5 hr. To the reaction mixture was added water. The solvent was evaporated under reduced pressure, and the pH of the residue was adjusted to 5-6 with 10% aqueous citric acid solution. The precipitated solid was collected by filtration, washed with water and dried. The obtained solid was suspended in hot ethanol, and the suspension was stirred, and slowly cooled to room temperature. The suspension was filtered, and the obtained solid was washed with ethanol, and dried to give the title compound (2.12 g).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[S:34]1[CH:38]=[C:37]([CH2:39]Cl)[N:36]2[CH2:41][CH2:42][N:43]=[C:35]12>>[S:34]1[CH:38]=[C:37]([CH2:39][O:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][CH2:15][CH2:14][CH:13]3[C:11]([N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=2)[C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)=[O:12])[N:36]2[CH2:41][CH2:42][N:43]=[C:35]12
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Reactant: ClCC1=CSC2=NCCN12
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCC4=CSC5=NCCN45)cccc32)cc1
Yield: 18.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and (5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl chloride (0.38 g) as starting materials, 5-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained.