Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([C:11]2[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=2[F:21])=[C:5]([F:22])[C:4]=1[F:23].[F:24][C:25]([F:30])([F:29])[S:26]([O-:28])=[O:27].[Na+].O.C(OCC)(=O)C>C(#N)CC>[F:17][C:16]1[C:11]([C:6]2[C:7]([F:10])=[C:8]([F:9])[C:3]([CH2:2][S:26]([C:25]([F:30])([F:29])[F:24])(=[O:28])=[O:27])=[C:4]([F:23])[C:5]=2[F:22])=[C:12]([F:21])[C:13]([F:20])=[C:14]([F:19])[C:15]=1[F:18]
Reactant: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Reactant: O=S([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: O=S(=O)(Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F)C(F)(F)F
Temperature: 25 °C
Yield: 94 %

Procedure:
4-bromomethylperfluorobiphenyl (3.68 g, 9 mmol) and sodium trifluoromethane sulfinate (1.69 g, 10.8 mmol) were dissolved in propionitrile (30 mL), and the resultant solution was subjected to heating under reflux for 12 hours. After the reaction, the solution was cooled to room temperature, and water was added for extraction with ethyl acetate. The organic phase was dried with magnesium sulfate, filtrated, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (hexane-ethyl acetate=20:1 to 8:1 to 1:1), and the aimed {4-(pentafluorophenyl)-2,3,5,6-tetrafluorophenyl}(triflyl)methane (3.91 g, 8.46 mmol, 94% yield) was isolated.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:25]([N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
A solution of 6.0 g of methyl 3-(1H-imidazol-4-yl)propionate and 11 ml of triethylamine in 31 ml of dimethylformamide is treated with a solution of 9.65 g of triphenylmethyl chloride in 110 ml of dimethylformamide for 2 h at room temperature under nitrogen. The reaction mixture is poured onto 700 g of ice, and the resulting solid is collected by filtration and recrystallized from ether to yield 13.83 g of methyl 3-(1-tritylimidazol-4-yl)propionate, NMR (CDCl3) δ=2.75 (m, 4H), 3.05 (s, 3H), 6.5-7.5 (m, 17H).
Reaction SMILES: [C:1](/[C:3](=[CH:20]\[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH:25]=[CH:24]2)/[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]OCCOCCOC)=[O:5])#[N:2].C1C[O:40][CH2:39]C1.[CH3:42]O>>[C:1](/[C:3](=[CH:20]\[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[CH:25]=[CH:24]2)/[C:4]([O:6][CH2:7][CH:8]1[CH2:39][O:40][C:10]([CH3:11])([CH3:42])[O:9]1)=[O:5])#[N:2]
Reactant: C1CCOC1
Reactant: CO
Reactant: COCCOCCOCCOCCOC(=O)/C(C#N)=C/c1ccc2cc(N3CCCCC3)ccc2c1
Product: CC1(C)OCC(COC(=O)/C(C#N)=C/c2ccc3cc(N4CCCCC4)ccc3c2)O1
Reaction time: 20 h
Yield: 84 %

Procedure:
Compound 31 (50 mgr, 0.12 mmol) was dissolved in a mixture of THF/MeOH (1:1) and DOWEX-H+ resin (15 mgr) was added and the heterogeneous mixture was stirred for 20 hours. The resin was removed by filtration and triethylamine was added and the solvent was removed under reduced pressure. The residue was purified by flash chromatography to give compound 32. 32: 38 mgr, 84% yield; red liquid; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H, J=8.8 Hz), 7.74 (d, 1H, J=9.1 Hz), 7.63 (d, 1H, J=9.1 Hz), 7.29 (m, 1H), 7.03 (s, 1H), 4.46-4.36 (m, 2H), 4.09 (m, 1H), 3.81 (dd, 1H, J=5.5 Hz, J=11.3 Hz), 3.73 (dd, 1H, J=5.5 Hz, J=11.3 Hz), 3.41 (m, 4H), 1.74-1.67 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 163.6, 156.0, 152.0, 137.9, 135.0, 130.7, 127.3, 126.3, 125.9, 125.5, 119.2, 116.6, 108.3, 97.8, 69.9, 67.0, 63.2, 49.3, 25.5, 24.3; HRMS Calc for C22H25N2O4 (M+H)+ 381.1809 found 381.1802.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:21][C:22]1[C:23](=O)[C:24](=[O:31])[C:25]=1[O:26]CCCC)[CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:23]2[C:24](=[O:31])[C:25](=[O:26])[C:22]=2[O:21][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCO
Product: CCCCOc1c(N2CCN(C(=O)OCc3ccccc3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 25 h
Yield: 84.3 %

Procedure:
A mixture comprising 1101 mg of N-benzyloxycarbonylpiperazine, 1131 mg of 3,4-dibutoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol was stirred at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (solvent: chloroform-ethyl acetate (19:1)) to obtain 1570 mg of 1-benzyloxycarbonyl-4-(4-butoxy-1,2-dioxo-3-cyclobuten-3-yl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C:21](O)=[O:22])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:54]1([CH:60]2[CH2:64][CH2:63][CH2:62][NH:61]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:20][C:21](=[O:22])[N:61]2[CH2:62][CH2:63][CH2:64][CH:60]2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COc1cccc(S(=O)(=O)N(CC(=O)O)c2ccc(Cl)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(S(=O)(=O)N(CC(=O)N2CCCC2c2ccccc2)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(4-chlorophenyl)-(3-methoxy-benzenesulfonyl)-amino]-acetic acid (250 mg, 0.7 mmol) in dry dichloromethane (20 mL) were sequentially added EDCI (202 mg, 1.05 mmol), HOBT (142.4 mg, 1.05 mmol), and DIPEA (0.23 mL, 1.40 mmol). The reaction mixture was allowed to stir for 30 minutes under nitrogen at 25° C. 2-Phenyl-pyrrolidine (104 mg, 0.7 mmol) was added and the mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and water. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (30-40% ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: C[O:2][C:3]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13]([N+]#[C-])(S(C2C=CC(C)=CC=2)(=O)=O)[CH2:14]Cl)[CH:4]=1.[ClH:37].C([O:40]CC)C>C(Cl)Cl>[Cl:37][CH2:14][C:13](=[O:40])[C:12]1[C@:28]2([CH3:36])[C@H:9]([C@H:8]3[C@H:31]([CH2:30][CH2:29]2)[C@:32]2([CH3:35])[C:5](=[CH:4][C:3](=[O:2])[CH2:34][CH2:33]2)[CH2:6][CH2:7]3)[CH2:10][CH:11]=1
Reactant: [C-]#[N+]C(CCl)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOCC
Reactant: Cl
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CCl)=CC[C@@H]12

Procedure:
The title compound was prepared by hydrolysis of the compound prepared in Example 15a in a mixture of methylene chloride (5 ml) and diethyl ether (25 ml). This mixture was stirred vigorously with hydrochloric acid (2 ml, 38%), for 5 minutes. After work up and chromatography (methylene chloride, alumina act. II-III) the title compound was obtained (55 mg, 15%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].COC(=O)C(NC([C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[CH:37]S[C:35]=2[C:39]=1O)=O)(C)C>>[CH3:6][C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]=1[O:20][CH2:37][CH2:38][C:34]1[CH:35]=[CH:39][CH:31]=[CH:32][CH:33]=1)=[O:9])([CH3:5])[C:3]([OH:2])=[O:21]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1O
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2c(c1O)CCCC2
Product: CC(C)(NC(=O)c1ccc2c(c1OCCc1ccccc1)CCCC2)C(=O)O

Procedure:
The following examples were prepared in analogy to example 1 via a sequence of an alkylation reaction to attach a suitably substituted alkylating agent to the aromatic hydroxy group of 2-[(1-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester or 2-[(7-Hydroxy-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester and a basic hydrolysis of the amino acid ester to the free amino acid:
Reaction SMILES: C([O-])(=O)[CH2:2][CH3:3].Cl[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([OH:12])=[O:11].Cl.[OH-].[NH4+:18]>>[NH2:18][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([O:12][CH2:2][CH3:3])=[O:11]
Reactant: CCC(=O)[O-]
Reactant: [NH4+]
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: [OH-]
Product: CCOC(=O)c1ccnc(N)c1
Reaction time: 20 h

Procedure:
Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-acetamido)-pyridyl))-propionate: A solution of 2-chloroisonicotinic acid (25.0 g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C., the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C. for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhdrous HCl in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhdrous HCl in dioxane was added and the reaction was warmed to reflux for an additional 20 h. Concentration with a stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2×200 mL), dried (Na2SO4). After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 mL) at 0 C. under an argon atmosphere was added acetyl chloride dropwise over 5 min. After 2 h at 0 C., the reaction was pored into over ice 300 g, extracted with ethyl acetate (2×300 mL), washed with water (2×100 ml) followed by brine (2×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of flash chromatography (step gradient ethyl acetate: hexane 1:4 then ethyl acetate: hexane 1:1) to afford ethyl 2-acetamidoisonicotinate.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[Cl:30])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccccc1Cl
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2Cl)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2Cl)c1

Procedure:
The reaction of hydroxylamine 55 (1.97 g, 5 mmol) with 2-chlorobenzaldehyde (61) (0.70 g, 5 mmol) afforded, after workup, a light yellow oil. The crude product was purified by flash chromatography with 3:5 ethyl acetate/petroleum ether as the eluant to obtain 2.11 g (4.0 mmol, 80%) of 72 as a light yellow gum: IR (CH2Cl2) 3440, 2940, 1690, 1623, 1590, 1550, 1470, 1295, 1202, 1100; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.25 (s, 6H), 3.30 (s, 3H), 3.54 (t, J=4.8 Hz, 2H), 4.16 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.07 (s, 1H), 6.87 (s, 1H), 7.27-9.45 (m, 9H); 13C NMR (CDCl3) δ 19.69, 19.84, 22.49, 22.72, 40.43, 59.36, 63.40, 67.70, 71.18, 103.32, 104.11, 120.08, 122.09, 127.76, 128.94, 129.04, 129.76, 130.22, 130.94, 131.28, 132.16, 134.30, 145.57, 146.32, 149.83, 150.49, 167.51, 167.99. Anal. Calcd for C28H31N2O6Cl: C, 63.81; H, 5.88. Found: C, 63.51; H, 6.02.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:25]([O:15][CH2:14][C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 ml), and imidazole (164 mg) was added to the dissolution. After cooling to 0° C., tert-butylchlorodiphenylsilane (616 μl) was added to the mixture, and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: Oc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 85.3 %

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (167 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide (425.22 mg).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4](O)([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C[C:17](N1CCOCC1)([C:19](C1C=CC([S:27]C)=CC=1)=[O:20])C.[CH3:35][CH2:36][C:37](N(C)C)([C:45]([C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58]COC[CH2:54]2)=[CH:49][CH:48]=1)=[O:46])CC1C=CC=CC=1.C1C=CC(C(C(OCCOCCOC(C(C2C=CC=CC=2)=O)=O)=O)=O)=CC=1>>[CH3:35][CH:36]([C:6]1[CH:1]=[CH:2][C:3]2[S:27][C:14]3[C:9]([C:7](=[O:8])[C:4]=2[CH:5]=1)=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH3:37].[CH3:17][CH2:19][O:20][C:45]([C:47]1[CH:48]=[CH:49][C:50]([N:53]([CH3:54])[CH3:58])=[CH:51][CH:52]=1)=[O:46]
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Agent: O=C(OCCOCCOC(=O)C(=O)c1ccccc1)C(=O)c1ccccc1
Product: CC(C)c1ccc2sc3ccccc3c(=O)c2c1
Product: CCOC(=O)c1ccc(N(C)C)cc1

Procedure:
Specific examples include such as Irgacure 184, Irgacure 907, Irgacure 369, Irgacure 379, Irgacure 819, Irgacure 127, Irgacure 500, Irgacure 754, Irgacure 250, Irgacure 1800, Irgacure 1870, Irgacure OXE01, DAROCUR TPO and DAROCUR 1173, produced by Ciba Specialty Chemicals K. K.; Speedcure MBB, Speedcure PBZ, Speedcure ITX, Speedcure CTX, Speedcure EDB, Esacure ONE, Esacure KIP150, and Esacure KTO46, produced by Nihon SiberHegner K. K.; and KAYACURE DETX-S, KAYACURE CTX, KAYACURE BMS and KAYACURE DMBI, produced by Nippon Kayaku Co., Ltd. Among them, Irgacure 369, Irgacure 127, Irgacure 907, Esacure ONE, Speedcure MBB, Speedcure PBZ, and KAYACURE DETX-S are preferable.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)=[O:25].[CH3:41][NH2:42].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:42][CH3:41])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[N:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:30]=[C:29]([CH:38]([CH3:40])[CH3:39])[CH:28]=1)=[O:25]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)nn4-c4ccccc4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 52 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea (0.24, 0.43 mmol) and 2 M methylamine in THF (3 eq) were combined to provide 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea as a white solid (0.12 g, 52% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.82 (s, 1H), 8.68-8.60 (m, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.82-7.79 (m, 1H), 7.66 (s, 1H), 7.55-7.47 (m, 4H), 7.43-7.39 (m, 1H), 7.12 (d, J=12.4 Hz, 1H), 6.30 (s, 1H), 3.59-3.52 (m, 3H), 2.91-2.80 (m, 4H), 2.05 (s, 3H), 1.18 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 541.3 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23]Br)=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].[P:25]([O:34]C(C)C)([O:30][CH:31]([CH3:33])[CH3:32])[O:26][CH:27]([CH3:29])[CH3:28]>>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:25]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:34])=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CBr
Product: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Reaction time: 18 h

Procedure:
11.1 g (27.9 mmol) of benzyl 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoate and 30.5 ml (111.5 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography over silica gel with ethyl acetate/isopropanol (7:1), giving benzyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate as an orange oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)(=O)C>CN(C)C=O>[C:19]([S:21][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][OH:18])[CH2:9]1)(=[O:22])[CH3:20]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Temperature: 65 °C
Reaction time: 5 h
Yield: 85.5 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (19.32 g: 69.17 mmole) and 90% potassium thioacetate (10.73 g: 89.9 mmole) in dimethylformamide (217 ml) is heated with stirring at 65° C. for 5 hours. To the reaction mixture ethyl acetate (200 ml) and ice water (200 ml) are added. The organic layer is taken, successively washed with aqueous 0.05N-sodium hydroxide, 0.1N-hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (15.34 g). Yield: 90%.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[OH:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: OCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2CCO

Procedure:
A mixture of 4.0 g (0.016 mole) of 4-chloro-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline (from Example 118) and 30 ml of 10% ammonia in methanol was heated in a steel bomb for 12 hours at 150° C. The resulting solid was separated from the cooled mixture by filtration, and was washed sequentially with water and methanol. The air-dried solid was recrystallized from N,N-dimethylformamide to provide white solid 1-(2-hydroxyethyl)-1H-imidazo[4,5-c]-quinolin-4-amine, m.p. 260°-262° C. Analysis: Calculated for C12H12N4O: % C, 63.1; % H, 5.3; % N, 24.5; Found: % C, 63.0; % H, 5.2; % N, 24.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(Cl)=[O:34].C1(C)C=CC=CC=1.[H-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][CH2:13][C:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:19][C:33]2=[O:34])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(O)(CCCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)CC1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A solution of 7-((1S)-1-(4-bromophenyl)ethylamino)-2-methyl-4-phenylhept-1-en-4-ol (111.7 mg, 0.279 mmol) in anhydrous acetonitrile (7 mL) was cooled to 0° C. Triethylamine (78 μL, 2 equiv) and 20% phosgene in toluene solution (161 μL, 1.1 equiv) were added sequentially and slowly. After stirring 2 h at 0° C., NaH (60% in mineral oil, 22 mg, 2 equiv) was added. The mixture was stirred overnight and the ice bath was allowed to melt. LC-MS showed the reaction was complete. The mixture was cooled to 0° C. again, quenched by addition of satd aq NH4Cl (2 mL), concentrated to remove the organic solvents, diluted with ether (10 mL), washed with 1% HCl (3 mL), satd aq NaHCO3 (2 mL) and brine (2 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica cartridge, eluted with a 15˜40% EtOAc in hexanes gradient, to afford 3-((1S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one (49.6 mg, 42%) as a mixture of two diastereomers.