Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[C:18]1([CH3:37])[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([NH:27][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:37])=[CH:19][CH:20]=3)(=[O:26])=[O:25])=[CH:36][CH:35]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)Cl)cc2)cc1
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC
Reaction time: 1 h

Procedure:
6.4 g of (+/-)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene are dissolved in 150 ml of methylene chloride and 9 ml of triethylamine. A solution of 11.2 g of 4-p-toluenesulfonamidobenzoyl chloride in 200 ml of methylene chloride is added dropwise at RT in the course of 3 h, and the mixture is extracted after stirring for 1 h with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulfate, concentrated and crystallized from ethyl acetate. 3.9 g (28.2% of theory) of the title compound of m.p. 174-176° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([C:22]([N:24]3[CH2:27][CH:26]([O:28][C:29]4[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=4)[CH2:25]3)=[O:23])=[N:19][N:18]=2)=[CH:13][CH:12]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:33][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH:26]3[CH2:27][N:24]([C:22]([C:20]4[O:21][C:17]([C:14]5[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=5)=[N:18][N:19]=4)=[O:23])[CH2:25]3)=[CH:36][CH:35]=2)[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(CO)CC5)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidin-4-ylmethanol (0.04 g, 0.35 mmol) was dissolved in dichloromethane (2 mL) and TEA (0.052 ml, 0.38 mmol) was added. Intermediate 55A (0.11 g, 0.29 mmol) was added followed by addition of sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The mixture was stirred at RT overnight. Dichloromethane (10 mL) and NaHCO3 (sat. 2 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 81 mg (58%). 1H NMR (600 MHz, DMSO) δ 1.05-1.17 (m, 2H), 1.28-1.39 (m, 1H), 1.57-1.66 (m, 2H), 1.82-1.92 (m, 2H), 2.75-2.84 (m, 2H), 3.19-3.27 (m, 3H), 3.83-3.92 (m, 3H), 4.06-4.13 (m, 1H), 4.37-4.45 (m, 1H), 4.5-4.67 (m, 2H), 5.04-5.19 (m, 2H), 6.85 (d, 2H), 7.16-7.27 (m, 4H), 8-8.05 (m, 2H), MS (APCI+) m/z 479 [M+H]+, LC-purity: 99%.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([S:17][S:18][CH2:19][C@H:20]1[C:24](=[O:25])[O:23][CH2:22][N:21]1C(OC(C)(C)C)=O)[CH3:16]>ClCCl>[CH2:15]([S:17][S:18][CH2:19][C@H:20]([NH:21][CH3:22])[C:24]([OH:25])=[O:23])[CH3:16]
Reactant: CCSSC[C@H]1C(=O)OCN1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCSSC[C@H](NC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Triethylsilane (4.46 ml, 27.9 mmol) and trifluoroacetic acid (6.88 ml, 89.0 mmol) were added to a solution of (R)-tert-butyl 4-((ethyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2e-F) (819 mg, 2.79 mmol) in dichloromethane (14 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=100/0→60/40) to afford (R)-3-(ethyldisulfanyl)-2-(methylamino)propanoic acid (Compound 2f-F) (232 mg, 43%).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>O1CCCC1>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([S:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)(=[O:30])=[O:29])[CH:18]=[C:17]([CH:20]=[O:21])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% in oil, 68 mg) was added to a solution of 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 mL) at room temperature. The mixture was stirred for 20 min, 3-pyridinesulfonyl chloride (0.19 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→2:1) to give the title compound as crystals (yield 0.26 g, 97%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[F:19].C([Li])CCC.[I:25]I>O1CCCC1.O>[F:19][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[N:5][C:6]2[C:11]([C:2]=1[I:25])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: II
Reactant: Fc1ccccc1-c1nc2ccccc2c(Cl)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccccc1-c1nc2ccccc2c(I)c1F
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 4-chloro-3-fluoro-2-(2-fluoro-phenyl)-quinoline (from step E, 0.160 g, 0.47 mmol) in tetrahydrofuran (3 mL) at −78° C. was added butyl lithium (0.6 mL, 2.5 M in hexane, 1.3 mmol). The mixture was stirred for 3 h. and iodine (0.148 g, 0.58 mmol) in 0.8 mL of THF was added. The reaction mixture was stirred for an additional 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, concentrated and purified by silica gel column chromatography to yield the title compound (0.148 g, 84%). MS (ES) 368.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18](O)=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]1([C@H:43]2[CH2:47][O:46][C:45](=[O:48])[NH:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:21])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([N:44]2[C@@H:43]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:47][O:46][C:45]2=[O:48])=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: Cc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C2(CSCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
({[5,5-Dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)acetic acid (8.7 g, 28.0 mmol) was dissolved in dry CH2Cl2 (120 ml) and cooled to 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 6.35 g, 30.8 mmol) in 30 ml of CH2Cl2 and 4-(dimethylamino)pyridine (DMAP, 6.85 g, 56.1 mmol) were added. The mixture was stirred at 0° C. for 30 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (4.57 g, 28.0 mmol) was added and the mixture was stirred at room temperature for 19 h. The mixture was filtered, concentrated under reduced pressure and purified by flash-chromatography (hexane:EtOAc 5:1 then 4:1). This afforded 7.07 g (55%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 2.4 (s, 3H), 2.8 (s, 2H), 3.4 (s, 4H), 3.8 (s, 2H), 4.3 (dd, 1H), 4.7 (t, 1H), 5.4 (dd, 1H), 7.2-7.5 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9]Br)[CH:3]=1.C(OCC)(=O)[CH2:12][C:13]([O:15]CC)=[O:14].CC1ON=C(CCC(O)=O)C=1>>[C:13]([CH2:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(CCCBr)no1
Agent: Cc1cc(CCC(=O)O)no1
Product: Cc1cc(CCCCC(=O)O)no1
Yield: 56 %

Procedure:
3-(4-Carboxybutyl)-5-methylisoxazole was prepared from 5-methyl-3-(3-bromopropyl)isoxazole and diethyl malonate according to the procedure of part (c) above, and was obtained in 56% yield as a colorless solid, m.p. 58°-60° C. when recrystallized from carbon tetrachloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[NH:11][C:10]2=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:29][O:30][CH:31]([O:34][CH3:35])[CH2:32][NH2:33].C(OO)(C)(C)C.OS([O-])=O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]([CH3:27])([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[NH:11]/[C:10]/2=[N:33]\[CH2:32][CH:31]([O:34][CH3:35])[O:30][CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(CN)OC
Reactant: C[C@]1(Cc2ccc(OC(F)(F)F)cc2)NC(=S)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: CC(C)(C)OO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C/N=C1\N[C@](C)(Cc2ccc(OC(F)(F)F)cc2)C(=O)N1c1cc(Cl)cc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 100.6 %

Procedure:
To a solution of the above thiohydantoin (4.47 g, 9.95 mmol) and aminoacetaldehyde dimethylacetal (6.50 mL, 59.7 mmol) in 20 mL of MeOH was added 7.69 mL (59.7 mmol, 70% in water) of t-butyl hydroperoxide solution, dropwise over 25 min. During the addition and for about 1 h after, the internal temperature of the mixture was kept below 20° C. with an ice water bath. The mixture was stirred at room temperature for 86 h, and 25 mL of saturated NaHSO3 solution was added slowly dropwise, maintaining the internal temperature below 20° C. with an ice water bath. The resulting cloudy white mixture was concentrated. To the residue was added EtOAc, and this mixture was concentrated again. The oily residue was partitioned between 30 mL of EtOAc and 20 mL of water, and the aqueous phase was separated and extracted with 20 mL of EtOAc. The combined organic layers were washed with 25 mL of water and brine, dried over Na2SO4, filtered and concentrated to give 5.21 g of (R)-3-(3,5-dichloro-phenyl)-2-[(E)-2,2-dimethoxy-ethylimino]-5-methyl-5-(4-trifluoromethoxy-benzyl)-imidazolidin-4-one as a thick yellow oil.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Cl[CH:14]=[C:15]([CH3:17])[CH3:16].O>C1COCC1>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CC(C)=CCl
Reactant: CCOP(=O)(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COCP(=O)(OCC)OCC
Reaction time: 1 h

Procedure:
Diethyl hydroxymethylphosphonate (3 g, 17.8 mmol, 1 eq) is dissolved in 50 ml of THF to which sodium hydride (0.43 g, 17.8 mmol, 1 eq) is added. 1-chloro-2-methylpropene (1.62 g, 17.8 mmol, 1 eq) is then added. After one hour under magnetic stirring, at ambient temperature and in a nitrogen atmosphere, hydrolysis is performed with 100 ml of water. Extraction is performed with ether (3×50 ml). The organic phases are collected, washed with 100 ml of a saturated sodium chloride solution and dried on sodium sulphate. After evaporation of the solvent, the residual oil obtained is purified by silica gel chromatography (Eluent=ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH2:13](OC1C=CC(C(OC)=O)=CC=1)C>>[CH2:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:10])[CH3:11])=[CH:5][CH:4]=1)[CH3:13]
Reactant: CCOc1ccc(C(=O)OC)cc1
Reactant: COc1ccc(C(C)(C)N)cc1
Product: CCOc1ccc(C(C)(C)N)cc1
Yield: 60 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 4-ethoxybenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 60%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]([NH:14][NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=O)=[CH:10][CH:9]=[N:8]1>C(#N)C>[CH3:6][N:7]1[C:11]([C:12]2[O:27][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)=[N:15][N:14]=2)=[CH:10][CH:9]=[N:8]1
Reactant: Cn1nccc1C(=O)NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1nccc1-c1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 90 °C
Yield: 81.4 %

Procedure:
Phosphorus oxychloride (1.80 mL) was added to an acetonitrile (4.8 mL) suspension of 1-methyl-N′-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide (300 mg) at a room temperature, and the obtained solution was then heated to reflux at 90° C. for 15 hours. Thereafter, the reaction solution was concentrated under a reduced pressure. A saturated sodium carbonate aqueous solution was added to the residue to convert it to a basic solution, and the resulting solution was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration, so as to obtain the title compound (230 mg) in the form of a brown solid.
Reaction SMILES: CO.C([O:6][C@@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@H:8]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)[CH:27]=1)(=O)C.[OH-].[Na+].Cl>O>[S:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[CH:38]=[C:34]1[CH2:33][C:28]1[CH:27]=[C:26]([C@@H:8]2[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]2[OH:6])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 44.54999923706055 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a methanol (427.4 kg) solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]glucitol (76.9 kg) was added a water (230 liters) solution of sodium hydroxide (26.9 kg) at a temperature of 25° C. or lower, followed by stirring at 40.0 to 49.1° C. for 4 hours. Water (850 liters) was added to the reaction mixture, and 12.9 kg of 38% hydrochloric acid was added thereto at a temperature of 25° C. or lower. The mixture was heated to 60° C., followed by stirring at 20.2 to 25.0° C. for 9.5 hours. The separated-out crystals were collected by filtration, washed with tap water (80 liters), and vacuum-dried to obtain, as white crystals, (1S)-1,5-anhydro-1-C-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-glucitol [52.7 kg, yield: 97.0%, purity: 99% (HPLC)].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1)#[N:2].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>CO.[Ni]>[C:23]([O:22][C:20]([NH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(-c2ccccc2C#N)s1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccccc2CNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a slurry of ethyl 5-(2-cyanophenyl)thiophene-2-carboxylate (1.09 gm 4.24 mmol) in MeOH (8 mL) was added (BOC)2O (1.11 g, 5.08 mmol) and Raney Nickel (3.6 mL). The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen overnight and then filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography to give ethyl 5-(2-{[(tert-butoxycarbonyl)-amino]methyl}phenyl)thiophene-2-carboxylate (1.32 g, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.[OH-].[NH4+]>ClC(Cl)Cl>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[N:6]=[N:7][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=4)[CH2:25][CH2:26]3)=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCc1ccc(Oc2ccc(Cl)nn2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Oc2ccc(N3CCN(c4cccc(C)c4)CC3)nn2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of 4 parts of 6-chloro-3-(4-ethylphenoxy)pyridazine and 6 parts of 1-(3-methylphenyl)piperazine was stirred and heated for 3 hours in an oil bath at 110° C. The whole was allowed to stand overnight. Concentrate ammonium hydroxide and trichloromethane were added. The precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7 parts (27%) of 3-(4-ethylphenoxy)-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 106.6° C. (compound 221).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH:16]([CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[NH:25])[C:17]([O-:19])=[O:18].[NH4+]>>[C:1]([O:18][C:17](=[O:19])[CH:16]([NH2:15])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[NH:25])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCCC(N)C(=O)[O-]
Agent: [NH4+]
Product: CCCCCCCCCCCC(=O)OC(=O)C(N)CCCNC(=N)N
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31 g (70 mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 16.06 g (84 mmol) of ammonium 2-amino-5-guanidinopentanoate. The round bottomed flask is placed in an ice bath and the dodecanoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-amino-5-guanidinopentanoic dodecanoic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(C)=C)[C:7]1=[O:18].CO.O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)CCn1c(=O)[nH]c2ccccc21
Temperature: 60 °C
Yield: 93 %

Procedure:
3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (2.2 g, 8.3 mmol) was treated with MeOH (5 mL) followed by water (5 mL) To this heterogeneous reaction mixture was added 37% hydrochloric acid (4 mL). This reaction mixture was heated to 60° C. for 20 min. The reaction remained as a clear homogeneous solution after heating. The reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.7 g of the desired product as a white solid. This product was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1
Reactant: COCCOCCl
Reactant: O=Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxyethoxymethyl chloride (MEM) (19 g, 153 mmol) was added to a solution of 5-hydroxy-2-pyridinecarboxaldehyde (18.4 g, 149 mmol) in 300 ml DMF. NaH (6.3 g of 60% oil dispersion, 158 mmol) were added in portions while cooling the mixture to maintain 20°-30° C. The mixture was stirred an additional 1 hour at 25° C. 5 ml water were added, most of the solvent was evaporated, and water was added to the residue,The mixture was extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and evaporated to a residue. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (35:65) to obtain 5-[(2-methoxyethoxy)methoxy]-2-pyridinecarboxaldehyde: C10H13NO4 (211.22); 1H-NMR (CDCl3) δ10.01 (s,1), 8.52 (d,1), 7.93 (d,1), 7.49 (m,1), 5.39 (s,2), 3.80 (m,2), 3.53 (m,2), 3.32 (s,3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:36][CH:37]([CH2:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:35].C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C>C1(C)C=CC=CC=1.O>[CH2:34]([O:36][CH:37]([CH2:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][CH2:5]2)=[CH:48][CH:49]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:35]
Reactant: O=C1c2ccccc2OCN1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
To a stirred mixture of 3-(2-hydroxyethyl)-4-oxo-3,4-dihydro-1,3-benzoxazine (325 mg, 1.68 mmol) and triphenylphosphine (660 mg, 2.52 mmol) in toluene (10 mL) was added a solution of (+)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (400 mg, 1.68 mmol) at 25° C. and stirred for 10 min. To the reaction mixture was added diisopropyldiazodicarboxylate (0.5 mL, 2.52 mmol) at 25-30° C. and stirred for further 40 h. Water was added to the reaction mixture and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% ethyl acetate in pet ether as eluent to afford the title compound (527 mg, 76%): mp 76-78° C.