Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH2:14](O)[CH3:15]>>[CH2:14]([O:7][C:6](=[O:8])[CH2:5][O:4][CH2:3][CH2:2][Cl:1])[CH3:15]
Reactant: CCO
Reactant: O=C(O)COCCCl
Agent: O=S(=O)(O)O
Product: CCOC(=O)COCCCl
Yield: 89 %

Procedure:
54.1 g (390 mmol) M24 obtained from the preceding reaction step was dissolved in 380 ml absolute ethanol and 9 ml conc. H2SO4 was added. The mixture was heated at reflux for 18 hours. Most of the ethanol was evaporated and the residue was dissolved in 400 ml CHCl3/100 ml water and basified with powder NaHCO3. The organic phase was washed with 2×400 ml saturated NaHCO3 and dried over Na2SO4. The solvent was evaporated to afford 58.3 g clear oil (yield: 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 56.2 %

Procedure:
A mixture of 1-[3-(4-hydroxyphenyl)propyl]imidazole (465 mg), 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole (600 mg), potassium carbonate (315 mg) and N,N-dimethylformamide (15 ml) was stirred at 80° C. for 14 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), crystals of 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole (490 mg, 56%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 83-84° C.
Reaction SMILES: [O:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH:2]2[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:1]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COCCOCCOCCO1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COCCOCCOCCO2)cc1
Yield: 91.6 %

Procedure:
Reaction in pyridine (13 ml) of 1,4,7,10-tetraoxacyclo-dodecane-2-methanol (5 g) with p-toluenesulphonyl chloride (5 g) produces 1,4,7,10-tetraoxacyclododecane-2-methanol p-toluenesulphonate (8 g; m.p. 49°-51° C. from diethyl ether). Subsequent reaction with diethyl malonate (3.36 ml) and potassium tert-butoxide (3.47 g) in N-methyl pyrrolidone (30 ml) yields [(1,4,7,10-tetraoxacyclododecane-2-yl)methyl]-malonate diethyl ester as a viscous oil that is treated with aqueous lithium hydroxide 0.8 g) to obtain pure [(1,4,7,10-tetraoxacyclododecane-2-yl)methyl]-malonic acid N.M.R. (CDCl3): 2.08-2.19; 3.48-3.82; 9.38].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[N+:21]([O-])=O)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:9]([O:11][C:12](=[O:24])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:16][C:15]=1[NH2:21])[CH3:10]
Reactant: CCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Nc1ccc(NCc2ccc(Cl)s2)cc1N
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A solution of 5-chlorothiophene-2-carbaldehyde (240 μL, 111 μmol, 463 mM in 1,2-dichloroethane) was added to a solution of 4-amino-2-nitrophenylcarbamic acid ethyl ester (240 μL, 111 μmol, 463 mM in 1,2-dichloroethane). Sodium triacetoxyborohydride (118 mg, 555 μmol) was added, and the resulting mixture was stirred for 3.5 hours at 40° C. The mixture was allowed to cool to ambient temperature, and water (100 μL) was added. The mixture was filtered through silica gel (500 mg) and the column was washed with 1,2-dichloroethane (3 mL). The combined organic phases were evaporated to dryness in vacuo. The resulting solid was dissolved in ethanol (3 mL). Iron (19 mg) was added to one-third of the resulting solution (1 mL), followed by an aqueous solution of hydrochloric acid (96 μL, 6M). The resulting mixture was placed in an ultrasonic bath for 10 minutes. Then, saturated aqueous sodium bicarbonate solution (2 mL) was added. The mixture was extracted with ethyl acetate (3 mL). The organic phase was washed with water (3 mL) and brine (3 mL), dried over magnesium sulphate, filtered, and evaporated to dryness in vacuo. The resulting product was dissolved in 190 μL dimethylsulfoxide and subjected to preparative LC-MS purification. The resulting solution was evaporated to dryness in vacuo. Yield (6.8 mg, 56%). LC-MS (m/z) (M+H)+ 326.1 RT=1.90 (UV, ELSD) 92%, 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:9])=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 76.9 %

Procedure:
4-Chloro-2-fluoro-phenol (264 mg, 1.8 mmol) was added to a solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (506 mg, 1.5 mmol), (prepared as described for the starting material in Example 1), in pyridine (8 ml) and the mixture heated at reflux for 45 minutes. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water. The organic layer was washed with 0.1M hydrochloric acid, water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with petroleum ether and the crude product collected by filtration and purified by flash chromatography eluting with methylene chloride/ether (9/1) to give 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (474 mg, 77%) as a cream solid. m.p. 179-180° C. 1H NMR Spectrum: (DMSOd6) 3.99(s, 3H); 5.36(s, 3H); 7.35-7.5(m, 4H); 7.55-7.65(m, 5H); 7.72(d, 1H); 8.6(s, 1H) MS-ESI: 411 [MH]+
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]1C=C[N:18]=[N:17]1>>[C:1]1([C:7]2[N:18]=[N:17][S:16][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: c1csnn1
Product: c1ccc(-c2nnsc2-c2ccccc2)cc1

Procedure:
The tosylhydrazone (58.0 g, 0.16 mol) was dissolved in CH2Cl2 (200 ml) and thionyl chloride (14.1 ml, 0.2 mol) in CH2Cl2 (10 ml) was added and the entire reaction was stirred at room temperature 2.25 hours. Filtration of the mixture afforded 9.0 g of solid identified by NMR as toluenesulfonylchloride. The remaining liquid was concentrated and then heated at reflux in THF (200 ml) and H2O (50 ml) for 20.5 hours. After cooling, it was brought to pH 11 with NaOH. The aqueous layer was extracted with 2×50 ml portions of Et2O. Drying and evaporation yielded 34 g of solid material. This was recrystallized from hexane to afford 3 (7.5 g, 46%), m.p. 92°-94° C. A second crop from recrystallization afforded additional amounts of 3 (6.9 g) contaminated with a-phenylacetophenone. The thiadiazole could be sublimed at 110° C. (0.2 mm).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Cl[CH2:42][C:43]1[C:44]([C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[C:57]([F:60])([F:59])[F:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>C1COCC1.O>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C@@H:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]3[C:57]([F:59])([F:60])[F:58])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: FC(F)(F)[C@@H]1CCCC[C@H]1c1noc(C2CC2)c1CCl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c([C@@H]3CCCC[C@H]3C(F)(F)F)noc1C1CC1)C2
Reaction time: 0.17 h

Procedure:
A solution of N-Boc-nortropine (579 mg, 2.55 mmol) and 18-crown-6 (808 mg, 3.06 mmol) in THF (8.5 mL) was treated with potassium tert-butoxide (343 mg, 3.06 mmol) and stirred for 10 minutes. A solution of 4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazole (784 mg, 2.55 mmol) in THF was added. The resulting mixture was stirred at rt for 2 hours and then poured into water and extracted with EtOAc. Organics were collected, dried (MgSO4), filtered, concentrated and chromatographed (SiO2, linear gradient, 0-60% EtOAc in Hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.28 (m, 2H), 4.19 (m, 1H), 4.11 (m, 1H), 3.66 (dd, J=4.8, 4.7 Hz, 1H), 3.47 (dd, J=7.6, 3.7 Hz, 1H), 2.42 (m, 1H), 2.19 (ddd, J=25.2, 12.5, 3.4 Hz, 1H), 2.00-1.77 (m, 13H), 1.69 (m, 1H), 1.52 (m, 1H), 1.46 (s, 9H), 1.35 (m, 1H), 1.12 (m, 2H), 1.03 (m, 2H)4; MS m/z 443.2 (M-tBu+1).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.O.[NH2:32][NH2:33]>O1CCCC1>[NH:32]([C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[NH2:33]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(NN)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 60 °C

Procedure:
To a solution of the 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (30 mg, 0.062 mmol) in tetrahydrofuran (0.5 ml) was added hydrazine monohydrate (15 μL, 0.3 mmol). A yellow precipitate immediately formed and the heterogeneous mixture was heated to 60° C. for 1 hour during which time more solid separated from the reaction. After cooling, the solid product was collected by filtration, washed with ether and dried under vacuum (6 mg, 25%); 1H NMR (d6-DMSO) δ 9.70 (br s, 1H), 9.27 (br s, 1H), 6.85 (s, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.21 (d, J=8.5 Hz, 1H), 5.00 (br s, 2H), 3.73 (s, 6H), 3.71 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1(CCO[Si](C)(C)C(C)(C)C)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CCO)CC1
Yield: 60.5 %

Procedure:
A solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF.TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0˜20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid.
Reaction SMILES: O[C@:2]1([NH:27]OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C@@H:8]([O:9]C(=O)C)[C@@H:7]([O:13]C(=O)C)[C@@H:6]([C:17](=C=O)[O:18]C(=O)C)[O:5][C@@:3]1([CH:24]([NH2:26])[CH3:25])[OH:4].[OH-].[Na+].C(Cl)Cl>CO>[NH2:26][CH:24]([C@:3]1([O:5][C@H:6]([CH2:17][OH:18])[C@H:7]([OH:13])[C@H:8]([OH:9])[C@H:2]1[NH2:27])[OH:4])[CH3:25]
Reactant: CC(=O)OC(=C=O)[C@H]1O[C@](O)(C(C)N)[C@@](O)(NOCC2c3ccccc3-c3ccccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(N)[C@@]1(O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1N
Reaction time: 1 h
Yield: 82.4 %

Procedure:
0.1 g (0.17 mmol) of 2-hydroxy-N-9-fluorenylmethoxy-carbonyl-1-aminoethyl-3,4,6-tri-O-acetyl-2-deoxy-2-amino-β-D-galactopyranose (3) as obtained above in step 3) was dissolved in 5 ml of methanol and then 13.6 ml (8 eq.) of a 1N sodium hydroxide solution were added. The reaction mixture was stirred for 1 hour and then neutralized by adding a cation exchange resin sold under the name Dowex 50WX8 by the company Sigma-Aldrich. The resin was then removed by filtration through sintered glass and the filtrate was concentrated under reduced pressure. 0.32 g (0.14 mmol) of compound (4) was then isolated by crystallization from DCM with a yield of 84%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.C1COCC1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: CN(C)CCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of sodium hydride (NaH) 60% dispersion in mineral oil (4.5 g, 111 mmol, 1.1 eq.) in anhydrous DMF (200 mL) was added 2-dimethylaminoethanol (11.5 mL, 111 mmol. 1.1 eq.). The reaction mixture was heated to 50° C. for 30 min. Then, 6-chloronicotinonitrile (14.8 g, 101 mmol, 1 eq.) in THF (100 mL) was added dropwise and the mixture was stirred overnight at 50° C. The solvents were removed under reduced pressure, the resulting residue was dissolved in water and acidified with conc. HCl (hydrochloric acid) to pH 1. The solution was washed with CH2Cl2 (2×200 mL), the aqueous layer was basified with conc. NaOH (sodium hydroxide) to pH about 10 and extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4, and filtered. Removal of the solvent in vacuo gave the title compound as an off-white solid (19.32 g, 99%) (m.p.:58° C.).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[CH:5][N:6]=1.O.[CH3:17][NH2:18]>C(O)(C)(C)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:4]([OH:3])=[CH:5][N:6]=[C:2]([NH:18][CH3:17])[N:1]=2)=[CH:10][CH:11]=1
Reactant: CN
Reactant: Nc1ncc(C(=O)c2ccc(F)cc2)o1
Solvent: O
Solvent: CC(C)(C)O
Product: CNc1ncc(O)c(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
(2-Amino-1,3-oxazol-5-yl)(4-fluorophenyl)methanone (US2005032859, 1 g, 4.85 mmol) and 40% methyl amine water in excess (50 mL) were combined in tert-butanol (50 mL). The mixture was stirred at 50° C. under nitrogen for 2 hours. The mixture was concentrated in vacuo. The residue was filtered through a pad of silica gel using neat ethyl acetate as eluant. The solution was concentrated in vacuo to afford 0.73 g (66%) of 4-(4-fluorophenyl)-2-(methylamino)pyrimidin-5-ol as a crystalline brown solid. MS m/z 220 [M]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[C:24]([O:28][C:29]([NH:31][C@@H:32]([CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CCS(C)(=O)=O
Reactant: NCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)CNCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of 3-chlorobenzylamine (0.628 mL, 5.14 mmol) and crushed molecular sieves (1.5 g) in dichloroethane (10 mL) under nitrogen at 0° C. was added sodium triacetoxyborohydride (2.73 g, 12.9 mmol), followed the product from Step C (2.73 g, 5.14 mmol). The reaction was stirred overnight, allowing it to warm to room temperature. The solution was poured into EtOAc and sat NaHCO3 solution, and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was purified by silica gel chromatography (2.5-5% MeOH/CHCl3) to obtain the titled compound (1.53 g) as a white foam.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[C:10]([CH2:12][C:13](O)=[O:14])#[N:11]>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:10]([CH2:12][C:13]([O:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14])#[N:11]
Reactant: OCCc1ccccc1
Reactant: N#CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: N#CCC(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of β-phenethyl alcohol (3.6 ml, 30.0 mmol) in DMF (30 ml) was added cyanoacetic acid (2.55 g, 30.0 mmol) in DMF (20 ml) and the whole was cooled to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimido (4.66 g, 30.0 mmol) in DMF (5 ml) and 4-dimethylaminopyridine (0.37 g, 3.0 mmol) in DMF (10 ml) were then added to the mixture in that order at 0° C. and stirring was continued for 1 hour at this temperature and 18 hours at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography to afford phenethyl cyanoacetate (2.49 g, 13.2 mmol).
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[Fe].C(O)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Temperature: 25 °C
Yield: 48.9 %

Procedure:
To a suspension of methanol 38 mL and acetic acid 38 mL of tert-butyl 2-nitro-4-phenylbenzoate 7.5 g was added iron powder 4.2 g at room temperature, and it was heated and refluxed for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. To the obtained residue, saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, solid matter was filtrated to give tert-butyl 2-amino-4-phenylbenzoate 3.3 g of white solid.
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:15]1([C:14]2[O:21][CH:13]=[N:12][CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)cc1

Procedure:
A mixture of tosylmethyl isocyanide (5.86 g, 30 mmol), benzaldehyde (3.18 g, 30 mmol) and K2CO3 (6.22 g, 45 mmol) in 60 ml MeOH was refluxed for 2 hr and concentrated. 250 ml EtOAc was added and the mixture was washed with H2O, brine, dried and concentrated. The residue was chromatographed on silica gel using 15:1 hexane/EtOAc to afford the title compound of this step (2.5 g, 57%) as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48](O)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C(N(S(F)(F)[F:63])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([F:63])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-allyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 62 yields 17-Allyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[NH:5][C:6]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[O:17]1CCC[CH2:18]1>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][NH:13][C:18]2=[O:17])[CH:14]=[CH:15][CH:16]=1
Reactant: C1CCOC1
Reactant: NCc1cccnc1Nc1cccc(I)c1
Solvent: CC(C)=O
Product: O=C1NCc2cccnc2N1c1cccc(I)c1

Procedure:
To a solution of 3.3 g of 2-(m-iodoanilino)-3-aminomethylpyridine and 30 ml of dry tetrahydrofuran was added 3.2 g of N,N'-carbonyldiimidazole and the mixture was heated under reflux for 12 hours. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was dissolved in acetone. The acetone solution was placed on a column of alumina and eluted with acetone. The eluate was concentrated and left to yield 2.5 g of 1-(m-iodophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless needles, melting at 175° - 177° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)C>O1CCOCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1

Procedure:
To a solution of 12.1 g. of 4-bromophenylhydrazine hydrochloride in a mixture of 10.9 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The procedure of Example 2 is followed, giving 12.7 g. of the desired product as tan crystals, mp. 142°-144° C.