Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][C:49]1[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH3:47])[C:49]4[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1cccc(C)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)c2cccc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-methyl-N-m-tolylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C44H52Cl2N5O3 [(M+H)+] 768.3442, observed 768.3440.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Nc1ccc(F)cc1
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc(F)cc3)ccc12
Yield: 25.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 4-fluoroaniline (0.03 mL, 0.33 mmol) to provide 235 (17 mg, 23% yield) as a green/brown solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]1[O:14][CH:5]21.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C@@H:6]([OH:14])[C@@H:5]2[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]1=[O:15]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(Cl)cc2C2OC21
Product: CC1(C)Oc2ccc(Cl)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
Following the procedure of Example 3, 6-chloro-2,2-dimethyl-3,4-epoxychromane is prepared and reacted with 2-hydroxypyridine to give the expected product. Melting point: 250° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:30]1([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:33]2[CH2:32][CH2:31]1
Reactant: c1cnc2c(c1)CCN2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cccnc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.42 mmol) 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised. Then the substance was dissolved in DMF and purified again by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([CH:9]=O)[CH2:8][O:7][CH2:6]1)[CH3:4].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]#[N:36])=[C:16]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][N:21]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20](=[O:34])[CH:19]=2)[CH:17]=1>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]#[N:36])=[C:16]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][N:21]([C:26](=[CH:9][C:5]3([CH2:3][CH3:4])[CH2:6][O:7][CH2:8]3)[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:20](=[O:34])[CH:19]=2)[CH:17]=1
Reactant: CCC1(C=O)COC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C=C(C(=O)OC(C)(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Reaction time: 0.25 h

Procedure:
38.4 mg (1.60 mmol, 2 eq., 60% in mineral oil) of sodium hydride and 457 mg (4.00 mmol) of 3-ethyloxetane-3-carbaldehyde in 1 ml of dimethylformamide were added in succession to a solution of 300 mg (800 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 8 ml of dimethylformamide. After 15 min at RT, the reaction was terminated by addition of 10 ml of saturated aqueous ammonium chloride solution and the reaction mixture was then extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (24 g cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 320 mg (82% of theory)
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH3:21])=[C:7]([NH2:19])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:20][CH3:21])=[C:7]([NH:19][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(N)c(OC)c(C(C)(C)C)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1ncccc1-c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
step 3—To a solution of 100 (0.24 g, 0.85 mmol) and TEA (0.18mL, 1.3 mmol) in DCM (10 mL) at 0° C. was added 4-nitrobenzoyl chloride (0.19 g, 1.0 mmol). The resulting mixture was stirred at 0° C. for 3 h, and then warmed to RT. The mixture was then diluted with additional DCM, washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue so obtained was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.36 g (97%) of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-nitrobenzamide (102) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(N)ccc1F
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1cc(Nc2nc3ccccc3[nH]2)ccc1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoro-3-methylaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 246-248° C.). MS(ES+) m/z 242 ([M+1]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[O:30]=[C:10]1[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][N:11]1[CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCNCC2)C1=O
Yield: 83 %

Procedure:
To a solution of (S)-benzyl 4-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation E, Step C, 7.0 g, 17 mmol) in methanol (300 mL) purged with nitrogen was added Pd/C (10%, 2 g) and the reaction was stirred overnight at ambient temperature under a balloon of hydrogen gas. The reaction was next purged with nitrogen and filtered through Celite®, and the filter cake was washed with methanol (about 100 mL). The combined organic phases were concentrated under vacuum to yield (S)-tert-butyl 2-oxo-1-(piperidin-4-yl)pyrrolidin-3-ylcarbamate (4.0 g, 83%)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(Br)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(Br)cccc1C=O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a 500 mL two-neck round flask charged with 3-bromo-2-hydroxybenzaldehyde (D98) (13 g, 64.7 mmol) was added DMF (300 mL). Then K2CO3 (17.88 g, 129 mmol) was added, followed with methyl iodide (18.36 g, 129 mmol) at room temperature. The resulted mixture was stirred at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered through celite and washed with EtOAc. The resulted filtration was concentrated under reduced pressure. The residue was dissolved in EtOAc (250 mL), and washed with water (100 mL), 1N HCl (100 mL×2) and brine (100 mL×2). The organic layers was dried with sodium sulphate and concentrated. The residue was purified with ISCO column chromatography to afford 3-bromo-2-(methyloxy)benzaldehyde (D99) (4.05 g) as pale yellow oil. MS (ES): C8H7BrO2 requires 213.9. found 215.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][CH3:19])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C@@H:17]1[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:9]=1)[CH3:19]
Reactant: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Temperature: 145 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (4R)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (1.46 g, 4.13 mmol), prepared in step 2 of Example 9, in dry DMF (15 mL) was added zinc cyanide (0.266 g, 2.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (150 mg), under nitrogen, and the mixture heated to 145° C. After 1 h, the mixture was cooled to room temperature, diluted with ethyl acetate, which was then washed with water, brine, dried (anhydrous sodium sulfate) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes, gradient elution) to afford the title compound (0.67 g, 54%), mp 153-157° C., MS m/z 300 [M+H]+. ANLC 100% at 210-370 nm, 9.5 min; 100% at 240 nm, 9.5 min, Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[K+].C([O:15][C:16]([S-])=[S:17])C>CCO>[C:16]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)([OH:15])=[S:17]
Reactant: Oc1cccc2cccnc12
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: OC(=S)c1ccc2cccnc2c1O
Temperature: 160 °C
Yield: 23.1 %

Procedure:
A mixture of 8-hydroxyquinoline (0.055 mol, 8.0 g) and O-ethylxanthic acid potassium salt (0.056 mol, 9.0 g) in abs. EtOH (20 mL) was placed in a pressure reactor and heated at 160° C. for 40 hours. After cooling, the reaction mixture was washed with a small amount of EtOH. The insoluble material was filtered off and treated with aqueous hydrochloric acid. The insoluble thioacid was separated by filtration and purified by heating with barium carbonate in water. The mixture was filtered off, the filtrate was acidified with hydrochloric acid, and precipitate was collected by filtration to give 7-thiocarboxy-8-hydroxyquinoline (2.61 g) in 18.4% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[CH:6]=1.[C:25]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH:25]1([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:23])[C:13]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=4[CH3:20])=[C:9]3[N:8]=[C:7]([CH3:24])[CH:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCCCC1
Reactant: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(NCCNC2CCCCC2)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo [1,5-a] pyrimidine (0.183 g, 5.4×10−4 mol, 339.2 g/mol) in dichloroethane (5 mL) and add cyclohexanone (100.12 g/mol) and sodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultant slurry, add glacial acetic acid (0.032 mL, 5.4×10−4 mol) and stir at ambient temperature under N2 for 3 h. Partition between CH2Cl2 (3 mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatograph the CH2Cl2 layer using [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent. Obtained 0.16 g white solid-foam upon evaporation.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.O>[CH:18]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cccc(C=O)c1OC1CCCC1
Reaction time: 55 h
Yield: 615 %

Procedure:
A mixture of 2-hydroxy-3-methoxy-benzaldehyde (10 g, 6.57 mmoles), K2CO3 (18.16 g, 131 mmoles), cyclopentyl-bromide (14.05 ml, 131 mmoles) in absolute ethanol (150 ml) under nitrogen was refluxed under stirring for 55 hours. The mixture was diluted with water, thrice extracted in ethyl acetate, washed with water, anhydrified over Na2SO4 and evaporated to dryness, the yielded oil was purified by flash chromatography on silica gel (eluent petrolatum/ethyl acetate 95:5) to give 8.9 g of the title product (yield: 61%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([P:8]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])([O:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=1)=[O:9])[CH2:5][CH2:6][Cl:7].C(N(C(C)C)CC)(C)C.[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH2:45])[CH3:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:27][CH2:26][CH2:25][N:24]([P:8]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][Cl:7])([O:10][CH2:11][CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:45][CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:46])=[O:22])=[CH:17][CH:16]=1)=[O:9])[CH2:28][CH2:29][Cl:30]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccc(CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)cc1
Temperature: 0 °C

Procedure:
To α-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-4-carboxytoluene, 411 mg, in 10 mL dichloromethane was added 400 μL diisopropylethylamine and glycine ethyl ester, 212 mg. The solution was cooled to 0° C. and HBTU, 317 mg, in 2 mL dimethylformamide was added, after which the mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane, then washed 3 times with 1 M hydrochloric acid, 5 times with saturated aqueous sodium bicarbonate, and once with brine. The organic layer was dried over MgSO4, filtered, and the solvents removed under vacuum to give α-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-4-[(ethoxycarbonylmethyl)aminocarbonyl]toluene as a clear oil, 411 mg, with product identity verified by LC-MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:4][N:3]=1
Reactant: OCc1ccc(Br)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)nc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred mixture of 2-bromo-5-hydroxymethylpyridine (4.7 g, 0.023 mol) and triethylamine (3.4 mL, 0.024 mol) in DMF (30 mL) was added tert-butyldimethylsilyl chloride. After 1 h, the mixture was diluted with ether and washed with water. The ether phase was dried (MgSO4) and concentrated to give 6.8 g (97%) of product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8]([CH3:12])=[N:9][NH:10][CH:11]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].O=[C:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][CH2:18]1.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:12][C:8]1[NH:9][N:10]=[CH:11][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:17]3([CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][CH2:22]3)[NH:1][C:2]=2[CH:6]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: Cc1n[nH]cc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(NC(=O)OCc3ccccc3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(3-methyl-1H-pyrazol-4-yl) thiophene-2-carboxamide (111 mg, 0.50 mmol), benzyl (4-oxocyclohexyl)carbamate (495 mg, 2.00 mmol), MgSO4 (120 mg, 1.00 mmol), CSA (11.61 mg, 0.050 mmol) and DMA (3 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc then to 80:20 EtOAc/MeOH). The obtained residue was triturated with 2-propanol-EtOAc, and the precipitate was collected by filtration to afford the title compound (58.4 mg, 26%, a mixture of 4:1 cis/trans isomers, absolute structure not determined) as a yellow solid:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:27]2([CH3:28])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:22])[CH2:18][CH2:19][CH2:20][OH:21])[CH2:8][C@@H:7]([O:30][C:31](=[O:33])[CH3:32])[CH2:6]1)(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@:27]2([CH3:28])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:22])[CH2:18][CH2:19][CH:20]=[O:21])[CH2:8][C@@H:7]([O:30][C:31](=[O:33])[CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 650 mg (1.42 mmols) of 1α,3β-diacetoxychol-5-en-24-ol in 35 ml of methylene chloride was added 750 mg (3.48 mmols) of pyridinium chlorochromate, and the resulting mixture was stirred at room temperature for 2 hours. Subsequently, 100 ml of ether was added to the mixture and the solution was eluted through a column filled with 15 g of Florisil to give 550 mg of 1α,3β-diacetoxychol-5-en-24-al (Compound B).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:21]=[C:20]2[C:14]([C:15]([Cl:26])=[C:16]([O:22][CH2:23][CH2:24][Br:25])[O:17][C:18]2=[O:19])=[CH:13][CH:12]=1.NC(N)=S>>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:21]=[C:20]3[C:14]([C:15]([Cl:26])=[C:16]([O:22][CH2:23][CH2:24][Br:25])[O:17][C:18]3=[O:19])=[CH:13][CH:12]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc2c(Cl)c(OCCBr)oc(=O)c2c1
Agent: NC(N)=S
Product: O=c1oc(OCCBr)c(Cl)c2ccc(NC(=S)Nc3ccccc3)cc12
Yield: 59 %

Procedure:
7-(Phenylthiocarbamoylamino)-4-chloro-3-(2-bromoethoxy)isocoumarin was prepared from the reaction of phenyl isothiocyanate with 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarin, yield 59%, m.p. 157°-158° C.; mass spectrum m/e 361 (m+ -PhNH+1). Anal. Calc.: C, 48.36; H, 3.39. Found: C, 48.26; H, 3.40. The bromoethoxy compound was then reacted with thiourea by the same procedure to give the final product, yield 32%, mass spectrum (FAB+) m/e 449 (M+ -Br).
Reaction SMILES: CC(=C)C[O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]>CN1CCCC1=O.O>[OH:4][C:5]1[C:6]([CH2:8][C:7]([CH3:12])=[CH2:6])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)COc1cccc(C(=O)OC)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C(C)Cc1c(O)cccc1C(=O)OC
Temperature: 200 °C
Reaction time: 30 h
Yield: 92.8 %

Procedure:
Methyl 3-(2-methylallyloxy)benzoate (Intermediate 167, 1.100 g, 5.3 mmol) was dissolved in 1-Methyl-2-pyrrolidinone (12 ml) and heated to 200° C. The solution was stirred for 30 h at the same temperature. After cooling, the mixture was diluted with water and extracted with ethyl acetate. Organic phase was dried over Na2SO4 and evaporated in vacuo to afford a crude product that was purified via Biotage SP1 with Cyclohexane/EtOAc as eluents (from 10/0 to 7/3 for 12 CV, 50 g SNAP Silica column). Fractions were collected and evaporated to afford the title compound (507 mg).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@@H:9]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:8]2[CH2:7]1)=O)C.[OH-].[Na+]>C(O)C>[C:13]1([C@@:9]23[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C@@H:8]2[CH2:7][NH:6][CH2:11][CH2:10]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N1CC[C@@H]2Oc3ccccc3[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Yield: 98.4 %

Procedure:
To a solution of 3.56 L g of cis-2-ethoxycarbonyl-1,2,3,4,4a,9b-hexahydro-benzofuro[3,2-c]pyridine in 42 ml of absolute ethanol was added 28 ml of 20% aqueous NaOH solution. The resulting mixture was heated at reflux under nitrogen for 32 hours. Most of the ethanol was removed in vacuo. The residue was diluted with 50 ml of water and extracted with methylene chloride (2×100 ml). There were initially some problems with emulsions. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo to give 2.72 g (98.4%) of crystalline solid. Recrystallization from hexane afforded 1.98 g (71.6%) of crystals, m.p. s 91, 95°-98°.