Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][O:7][P:6]1Cl)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][OH:22])[CH3:19]>C1COCC1>[CH2:18]([CH:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21][O:22][P:6]1[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:8][O:7]1)[CH3:19]
Reactant: CC(C)(C)N1CCOP1Cl
Reactant: CCCCC(CC)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COP1OCCN1C(C)(C)C
Yield: 81 %

Procedure:
The procedure of Example 3 is repeated using 18.16 g (0.10 mol) of 3-tert-butyl-2-chloro-1,3,2-oxazaphospholidine in 115 ml of THF and 13.16 ml (0.10 mol) of triethylamine and 13.2 g (0.10 mol) of 2-ethylhexanol in 115 ml of THF to give 22.3 g (81.0%) of a clear liquid: b.p. 89°-92° C. (0.05 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9](=[O:11])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:13])[CH3:12])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 79 was prepared from 2-(4-chlorophenyl)-2-methyl propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 2H), 7.34–7.25 (m, 6H), 6.95 (d, 1H, J=7.2 Hz), 6.65 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.45 (m, 1H), 2.36 (t, 2H, J=6.0 Hz), 2.20 (s, 3H), 1.94 (t, 2H, J=12.4 Hz), 1.78 (d, 2H, J=13.2 Hz), 1:65 (m, 2H), 1.57 (s, 6H), 1.55–1.46 (m, 2H); ESMS m/e: 456.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=4)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[C:42](O)(=O)C.C=O.C([BH3-])#N.[Na+]>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([N:28]([C:29]4[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=4)[CH3:42])[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl 4-[N-[-2-acetoxymethyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]amino]benzoate (0.060 g, 0.106 mmol) in THF (6 ml) was added glacial acetic acid (2 ml) followed by 37% aqueous formaldehyde (0.090 ml). The solution was stirred for 2.5 hours at room temperature and then sodium cyanoborohydride (0.017 g, 0.27 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was extracted with more ethyl acetate (2×25 ml). The combined organics were washed with saturated aqueous sodium bicarbonate (30 ml), brine (30 ml), dried (Na2SO4) and concentrated in vacuo to leave an oil (0.060 g, 98%); 1H-NMR (CDCl3) 1.20 (s, 9H, POM C(CH3)3), 1.58 (s, 9H, CO2C(CH3)3), 2.15 (s, 3H, CH3CO), 2.02, 2.52 (2×m, 2H, 7-CH2), 2.74 (s, 3H, N10-Me), 3.13 (m, 2H, 8-CH2) 5.21 (s, 2H, 2-CH2), 5.66 (t, 1H, J=8.1 Hz, 6-H), 6.12 (AB system, J=10.8 Hz, 2H, POM CH2), 6.85 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.58 (s, 1H, 9-H), 7.90 (d, J=8.9 Hz, 2H, 2,6′-ArH), 8.08 (s, 1H, 5-H); MS (ESI, m/z) 578 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]#[N:37]>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:35][C:36]#[N:37])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc21
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a yellow gum (7%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=2)=[O:9])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: Cc1nn(CCc2ccccc2)cc1C(=O)O
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1nn(CCc2ccccc2)cc1C(=O)Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C#N)c1
Yield: 57.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 3-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid (0.64 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.8 g), the title compound (0.8 g) was obtained, melting point: 188° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:39]=[CH:40][CH:41]=1)[CH2:12][N:13]1[C:21]2[C:16](=[C:17]([NH:22][C:23]([C:25]3[N:29]4[CH:30]=[CH:31][C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:33][C:28]4=[N:27][CH:26]=3)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:39]=[CH:40][CH:41]=1)[CH2:12][N:13]1[C:21]2[C:16](=[C:17]([NH:22][C:23]([C:25]3[N:29]4[CH:30]=[CH:31][C:32]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:33][C:28]4=[N:27][CH:26]=3)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1
Reactant: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(OCc4ccccc4)c3)cnc2c1
Agent: [Pd]
Solvent: CO
Product: COCCOc1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3cccc(O)c3)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
A solution of N-(1-(3-(benzyloxy)benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.022 g, 0.040 mmol) in MeOH (2 mL) was purged with Argon, treated with 10% palladium on carbon (0.002 g), purged with more Argon, and then attached to a hydrogen balloon. The mixture was stirred at ambient temperature overnight, filtered through glass fiber filter paper, washed with MeOH, concentrated and the residue purified on silica gel (1-3% MeOH in DCM) to provide N-(1-(3-hydroxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.003 g, 18% yield) as a beige oil. MS (APCI) m/z=458 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[CH:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[O:25].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:27]1[C:26]([CH:24]=[O:25])=[CH:30][N:29]=[CH:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: O=Cc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1C=O
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(methanesulfonyloxy)ethyl}pyrrolidine (38.8 g) in N,N-dimethylformamide (380 ml) were added 4-formylimidazole (13.0 g) and potassium t-butoxide (15.2 g) and the mixture was stirred at 50°-60° C. for 2 hours. The reaction mixture was poured into water (600 ml) and extracted three times with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (750 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (14.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].C(N(CC)CC)C>ClCCl>[CH3:18][N:19]([CH3:20])[CH2:21][C:22]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:23]
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.490 g, 2.20 mmol), dimethylamino-acetyl chloride hydrochloride (0.4181 g, 2.646 mmol), and Triethylamine (0.7683 mL, 5.512 mmol) in dichloromethane (11 mL) and the reaction was stirred overnight at room temperature. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with EtOAc and the combined organic extract was washed with water, dried (MgSO4), filtered, and concentrated, and the product, 2-dimethylamino-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone, was isolated by flash chromatography (SiO2, MeOH/dichloromethane 0-10%) as an oil (600 mg, 90%). LC/MS (ESI+): 308.04 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N)cc1

Procedure:
To a suspension of 4-aminophenylacetic acid (7.4 g; 59.0 mmol) in ca. 90 ml of methanol, was added ca. 6.0 ml of concentrated sulfuric acid. After refluxing the brown solution for 2.5 hrs, it was concentrated to a dark oil. The oil was diluted with water and basified with 10 wt % NaHCO3 to pH 9 and extracted with ethyl acetate. The organic layer was washed with water, brine and dried with Na2SO4. Evaporation in vacuo afforded 5.0 g of methyl 4-aminophenylacetate as a dark oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[C:9](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:10].O>C1COCC1>[CH3:7][C@H:8]([C@H:23]([CH3:27])[CH2:24][CH2:25][CH3:26])[CH2:9][OH:10]
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H](C)[C@@H](C)CO
Reaction time: 3 h
Yield: 100 %

Procedure:
A 1M THF solution of LAH (95.9 mL, 95.9 mmol) was added to (R)-3-((2R,3R)-2,3-dimethyl-hexanoyl)-4-phenyl-oxazolidin-2-one in THF (300 mL) under nitrogen at −78° C. and stirred for 3 hours at that temperature. Water was added dropwise to quench the excess LAH and the solution was poured into a mixture of ice and ether. The mixture was extracted into ether, washed with water and dried over MgSO4. The solution was concentrated followed by the addition of excess hexane. The resulting white precipitate was filtered and washed with haxane. The filtrate was concentrated to afford the titled compound (5.05 g, 100% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 9H) 1.0 (d, J=6.8 Hz, 1H) 1.1 (m, 1H) 1.2 (m, 3H) 1.6 (m, 2H) 3.4 (m, 1H) 3.6 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+]([O-])=O)=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])(=[O:27])C.[K+]>CS(C)=O.O>[F:21][C:20]([F:23])([F:22])[C:19]([N:9]1[CH2:10][CH:11]2[CH2:18][CH:7]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:14]([OH:27])=[CH:13][C:12]=32)[CH2:8]1)=[O:24]
Reactant: CC(=O)[O-]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c(O)cc12)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (900 mg, 2.61 mmol) and potassium acetate (KOAc) (2.6 g, 26.1 mmol) were dissolved in DMSO (10 mL) and warmed with stirring to 100° C. for 16 hours. The mixture was cooled and diluted with H2O (50 mL) then extracted with 80% EtOAc/hexanes (6×25 mL). The organic layer was washed with H2O (3×20 mL), dried (Na2SO4), filtered and concentrated and purified by chromatography to give an oil (575 mg, 70%). (TLC 50% EtOAc/hexanes (NH3) Rf 0.56).
Reaction SMILES: C(O)#C[OH:3].[CH3:5][C@H:6]1[C:13](S[C@@H]2CN[C@H]([C@H](O)[C@H]3CNCC3)C2)=C(C(O)=O)N2[C@H:7]1[C@@H:8]([C@H:30](O)[CH3:31])[C:9]2=O.Cl>>[CH3:5][CH:6]([CH2:7][C:8]([OH:3])([C:30]#[CH:31])[CH3:9])[CH3:13]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H]([C@H](O)[C@@H]4CCNC4)C3)[C@H](C)[C@H]12
Reactant: OC#CO
Agent: Cl
Product: C#CC(C)(O)CC(C)C

Procedure:
For example, any commercially available product may be used for the acetylene diol compound. The commercially available product includes, for example, “Olfin (trade name) E1010” and “Olfin (trade name) E1004” as well as “Surfynol (trade name) 440” and “Surfynol (trade name) 465” produced by Nissin Chemical Industry Co., Ltd.; and “Acetylenol (trade name) E40” and “Acetylenol (trade name) E100” produced by Kawaken Fine Chemicals Co., Ltd.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C[Li].O>C(OCC)C>[CH2:5]([C:3]1[CH2:4][CH:2]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC1(Br)CC1(Br)Br
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CCCCCCC1=CC1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of 1.01 g (0.00278 mol) of 1,1,2-tribromo-2-hexyl-cyclopropane in 4 ml of diethyl ether was placed under a nitrogen atmosphere via use of a Firestone valve. While cooling in an ice water bath, 6.3 ml (0.00835 mol) of 1.4M methyl lithium in diethyl ether was added slowly by syringe. After 15 minutes, 2 ml of water was added via syringe. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo with a bath temperature under 20° C. to yield 0.300 g (87% of theoretical) of 1-hexyl-cyclopropene pure as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@@:11]([CH3:24])([NH:17][S@@](C(C)(C)C)=O)[C:12]([F:16])([F:15])[CH2:13][OH:14])=[O:7])(C)(C)[CH3:2].S(Cl)(Cl)=O>C(O)C>[CH2:1]([O:5][C:6]([C@H:8]1[CH2:10][C@@H:9]1[C@:11]([NH2:17])([CH3:24])[C:12]([F:16])([F:15])[CH2:13][OH:14])=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H]1[C@@](C)(N[S@](=O)C(C)(C)C)C(F)(F)CO
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H]1[C@@](C)(N)C(F)(F)CO
Temperature: 85 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A solution of (1S,2S)-rel-2-[(R)-2,2-difluoro-3-hydroxy-1-methyl-1-((R)-2-methyl-propane-2-sulfinylamino)-propyl]-cyclopropanecarboxylic acid tert-butyl ester (1.16 g, 3.14 mmol) in ethanol (22.5 ml) was treated dropwise at 0° C. with thionyl chloride (1.89 g, 1.15 ml, 15.7 mmol). The yellow mixture was then stirred at 85° C. for 2 hours. For the workup, the solvent was evaporated at reduced pressure, then water and diethyl ether were added. The aqueous layer was treated with carbonate, thereafter extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The light yellow oil (708 mg) was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (1S,2S)-rel-2-((R)-1-amino-2,2-difluoro-3-hydroxy-1-methyl-propyl)-cyclopropane-carboxylic acid ethyl ester (566 mg, 76% yield) was obtained as a light yellow oil. MS (ISP): m/z=238.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[C:23](=O)([O-])[O-:24].[K+].[K+].C(OCC)(=O)C>C(O)=O>[CH:23]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)=[O:24]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CN)nc1
Agent: [K+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(CNC=O)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a stirred solution of methyl 3-(6-(aminomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.24 g, 0.80 mmol) in formic acid (3 mL) was added potassium carbonate (0.2 g) portionwise. The reaction mixture was stirred at 90° C. overnight under argon and then concentrated. The residue was made basic with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried (Na2SO4) and concentrated. Silica gel flash chromatography (20-100% ethyl acetate in hexanes) gave methyl 3-(6-(formamidomethyl)pyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (0.19 g, 0.58 mmol, 73% yield) as a solid. MS found: (M+H)+=327.35.
Reaction SMILES: Br.[NH2:2][C:3]1[N:12](CC2C=CC(OC)=CC=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:22])[N:4]=1.I[CH2:24][C:25](OCC)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][NH:12][C:3]1[N:4]2[CH2:24][C:25](=[O:26])[N:2]=1
Reactant: COc1ccc(CN2Cc3c(Cl)cccc3N=C2N)cc1
Reactant: CCOC(=O)CI
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN2C(=N1)NCc1c(Cl)cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.15 mol of 2-amino-5-chloro-3,4-dihydro-3-(p-methoxybenzyl)-quinazoline hydrobromide in 800 ml of dimethylformamide is treated with 0.18 mol of ethyl iodoacetate and 0.2 mol of potassium carbonate and stirred at room temperature for 18 hours. Then, the mixture is stirred at 90° for an additional 5 hours, cooled and poured into 5 l of ice/water. The precipitated product, 6-chloro-4-(p-methoxybenzyl)-5H-imidazo[1,2-a]quinazolin-2(1H)-one, is removed by filtration and washed well with water. In order to prepare the hydrochloride, the product is recrystallized from ethanol/hydrochloric acid; m.p. 230° (decomposition).
Reaction SMILES: Br[CH2:2][C:3]1[C:21]([O:22][Si](C(C)(C)C)(C)C)=[CH:20][C:19]([O:30][CH3:31])=[C:18]([CH3:32])[C:4]=1[C:5](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:6].[CH3:33][O:34][C:35](=[O:53])[C@H:36]([CH2:51][SH:52])[NH:37][C:38](=[O:50])[C@@H:39]([CH2:48][OH:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[OH:22][C:21]1[C:3]2[CH2:2][S:52][CH2:51][C@@H:36]([C:35]([O:34][CH3:33])=[O:53])[NH:37][C:38](=[O:50])[C@H:39]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])[CH2:48][O:49][C:5](=[O:6])[C:4]=2[C:18]([CH3:32])=[C:19]([O:30][CH3:31])[CH:20]=1
Reactant: COC(=O)[C@H](CS)NC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)c(CBr)c(C(=O)OCc2ccc([N+](=O)[O-])cc2)c1C
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1

Procedure:
Crude p-nitrobenzyl 2-bromomethyl-3-(tert-butyldimethylsilyloxy)-5-methoxy-6-methylbenzoate, as obtained in Example 23 (d), was reacted with N-[N-(tert-butoxycarbonyl)-D-seryl]-L-cysteine methyl ester in an analogous manner to the procedure described in Example 1 (f), and the product was subjected in an analogous manner to the sequence of procedures used in Example 23 to yield tert-butyl (4R, 7R)-1,3,4,5,6,7,8,10-octa-hydro-14-hydroxy-12-methoxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O-:28])=[O:27])=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=C([O-])C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS, 2RS, 3SR)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (60 mg, 0.15 mmol) in EtOH (0.5 ml) was added 6M KOH (0.14 ml, 0.84 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as an off-white crystalline solid (22 mg, 39%); m.p. 146-149° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1Cl)[C:7]([NH2:9])=[O:8])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:16][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])([O-:3])=[O:2]
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN
Product: CCNc1ccc(C(N)=O)cc1[N+](=O)[O-]

Procedure:
II (160 g - 0.8 mole) was added portionwise with stirring at 60° C to 720 g of 50 % by weight aqueous ethylamine. The mixture was cooled, the precipitate was collected and crystallized from the monomethyl ether of ethylene glycol (5 ml per gram of dried product).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrCCOC1CCCCO1
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOC2CCCCO2)c(C=O)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 26.1 g (125 mmol) 2-(2-Bromo-ethoxy)-tetrahydro-pyran (J. Org. Chem.; 50; 22; (1985); 4238-4245) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 6 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulphate and evaporated. The crude product was purified by silica column chromatography (ethylacetate:hexane 1:3). The desired product 1a was obtained in 81% yield (22.7 g, 81 mmol) as yellow oil.