Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
tert-Butyl 4-((2-isopropylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.15 mmol, 1.0 eq) was dissolved in DCM (3.6 mL) and the mixture cooled in an ice-water bath before the dropwise addition of TFA (3.6 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.260 g, 1.15 mmol, 1.1 eq) was suspended in iPrOH (3.5 mL) and DIPEA (0.9 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.270 g, 1.05 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.300 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 1.31 (d, J=7.0 Hz, 6H, iPr—CH3), 2.53-2.65 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.20-3.33 (m, 1H, iPr—CH), 3.61 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.31 (s, 1H, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.81 min—4411443 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[CH:16][CH:15]=3)=[CH:7][CH:8]=2)[NH:3]1.[Br:27]Br.[Br-].[K+]>C(O)(=O)C>[Br:27][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:12][CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)c1ccc(COc2ccc3c(c2)NC(=O)CC3)cc1
Reactant: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1CCc2cc(Br)c(OCc3ccc(C(=O)O)cc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a suspension of tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (550 mg, 1.56 mmol) in glacial acetic acid (5 mL) was added dropwise a solution of bromine (800 mg, 5.00 mmol) and potassium bromide (595 mg, 5.0 mmol) in acetic acid (10 mL) under an atmosphere of dry N2, and the mixture stirred at room temperature for 1 hour. The reaction mixture was warmed to 60° C. for 18 hours, then cooled, and the solvent evaporated under reduced pressure. The residue was poured slowly into water (40 mL) with stirring, diethyl ether (3 mL) was added, and the mixture sonicated, filtered, the solid thus obtained was washed with saturated sodium carbonate (30 mL), water (50 mL), diethyl ether (10 mL), and dried under reduced pressure to afford 4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid (334 mg, 0.89 mmol, 57%). LCMS mz 375.9 (M−H) and 377.9 (M+H), anal HPLC >91% in purity, 1H NMR (400 MHz; CD3CN) δ8.25 (bs, 1H); 8.09 (d, J=8.6 Hz, 2H); 7.65 (d, J=8.6 Hz, 2H); 7.42 (s, 1H); 6.62 (s, 1H); 5.26 (s, 2H); 2.91 (m, 2H); 2.53 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:19][C:20]([CH3:22])=O>C(COC)OC>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:2][CH3:1])=[C:20]([CH3:22])[CH3:19])[CH3:8]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CC)=C(C)C
Yield: 73 %

Procedure:
In a manner similar to the method described in example 102a, triethyl 2-phosphonobutyrate (25.2 g, 0.1 mol) was reacted with NaH (2.64 g, 0.11 mol), and then acetone (5.8 g, 0.1 mol) in dimethoxyethane to give 2-ethyl-3-methyl-but-2-enoic acid ethyl ester as colorless oil (Yield: 11.4 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:18](=[O:36])[N:17]([CH2:37][C:38]([O:40]CC)=[O:39])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:18](=[O:36])[N:17]([CH2:37][C:38]([OH:40])=[O:39])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)O
Temperature: 50 °C
Yield: 91.8 %

Procedure:
A mixture of 4-[7-(2-butynyl)-3-ethoxycarbonylmethyl-1-(2-phenylethyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (190 mg), ethanol (3 ml), and 1N aqueous sodium hydroxide solution (0.5 ml) was stirred with heating in an oil bath of 50° C. for 2 hours. 1N aqueous hydrochloric acid solution (0.55 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from ethyl acetate-hexane to give 166 mg of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].C1(N=[C:20]=[O:21])C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:20]1([OH:21])[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C=Nc1ccccc1
Reactant: NNc1ccc2ccccc2n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1nnc2ccc3ccccc3n12
Reaction time: 8 h

Procedure:
2-Hydrazinoquinoline (15.9 grams; 0.1 mole) was placed in a 250-milliliter three-necked flask equipped with a condenser, along with 70 milliliters of diphenyl ether. To the flask was then added 11.9 grams (0.1 mole) of phenyl isocyanate. The reaction mixture was allowed to reflux for three hours, cooled, and allowed to stand at room temperature overnight. In the morning the precipitate, the desired s-triazolo(4,3-a)quinolin-1-ol product, was filtered off and recrystallized from water. The product so obtained melted at 133.5°-4.5°C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.BrC1C=CC(S(O[CH2:24][C@@H:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([CH2:6][CH2:7][NH:8][CH2:24][CH:25]2[O:39][C:29]3=[C:30]4[C:35](=[CH:36][CH:37]=[C:28]3[O:27][CH2:26]2)[N:34]=[C:33]([CH3:38])[CH:32]=[CH:31]4)=[CH:5]1
Reactant: NCCc1csc2ccccc12
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCc1csc2ccccc12)O3
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 2-benzo[b]thiophen-3yl-ethylamine (354 mg, 2.0 mmol) in 1 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromo-benzenesulfonate (300 mg, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 4 days. The reaction was diluted with H2O (10 mL), poured into saturated aqueous sodium bicarbonate (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with 1:1 H2O/brine (40 mL) and brine (40 mL), then were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography (2×20 cm SiO2, CH2Cl2 to 3% MeOH/CH2Cl2 gradient) afforded 225 mg (86%) of the (S)-enantiomer of the title compound as a thick oil. The fumarate salt was prepared by treating the amine in ethyl acetate with a solution of 66 mg (0.57 mmol) fumaric acid in methanol. The precipitated salt, a pale yellow solid, weighed 190 mg (m.p. 124-127° C.); MS (ESI) m/z 391 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([CH:21]([C:23]([OH:25])=[O:24])[CH3:22])(=[O:20])=[O:19])(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+].N>C(O)C>[C:23]([CH:21]([S:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][S:7]([CH:5]([CH3:6])[C:4]([OH:26])=[O:3])(=[O:9])=[O:8])(=[O:20])=[O:19])[CH3:22])([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)S(=O)(=O)CCCCCCCCS(=O)(=O)C(C)C(=O)O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)S(=O)(=O)CCCCCCCCS(=O)(=O)C(C)C(=O)O

Procedure:
2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid was prepared according to general method as outline in example 1. Starting from 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid ethyl ester (3.0 g, 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide (15 mL). Yield 2.7 g (98%); white solid mp 99-102° C.; MS 387 (M+NH3)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([OH:33])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1.[CH2:38]1[CH2:48]CN2C(=NCCC2)C[CH2:39]1.C(Br)C=C>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[C@H:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C@H:10]2[C:31]([O:33][CH2:48][CH:38]=[CH2:39])=[O:32])=[C:5]([O:34][CH2:35][O:36][CH3:37])[CH:4]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCOC)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCOC(=O)[C@H]1[C@H](c2ccc(OC)cc2OCOC)c2cc(OCCC)ccc2[C@@H]1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
(1S,2R,3S)-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (4.8 g, 9.5 mmol) was dissolved in dry acetonitrile (30 ml) and DBU (1.7 ml, 11.4 mmol) was added followed by allyl bromide (3.4 g, 28. mmol). After stirring for 0.5 h. the product was partitioned between 3M aqueous HCl and ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography to provide the title compound as a pale yellow oil (5.7 g, quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][N:19]([C@H:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([O:31]CC3C=CC(OC)=CC=3)=[O:30])[CH2:18]2)[CH2:12][CH2:11]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][N:19]([C@H:28]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:29]([OH:31])=[O:30])[CH2:18]2)[CH2:14][CH2:15]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4ccccn4)CC3)[C@@H](c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccn3)CC2)[C@@H](c2ccccc2)C1
Yield: 93.9 %

Procedure:
The title compound was prepared from 58 mg (0.093 mmol) of 2-(R)-(3-(S)-((4-(3-(2-pyridyl)propyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 72, Step C) using a procedure analogous to that described in EXAMPLE 10, Step F. Flash chromatography using 90:10:1 v/v/v CH2Cl2/MeOH/NH4OH as the eluant afforded 44 mg (94%) of the title compound: 1H NMR (500 MHz) δ 0.82-3.90 (35H), 7.07-7.58 (8H), 8.49 (d, J=4.8 Hz, 11H); ESI-MS 504 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([CH3:3])=[CH2:2].[H][H]>CO.CCOC(C)=O.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(O)cc(C(F)(F)F)c1
Yield: 99 %

Procedure:
A mixture of 3-isopropenyl-5-trifluoromethyl-phenol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 3-isopropyl-5-trifluoromethyl-phenol (120 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:28])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])#[CH:20]>>[OH:28][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:18]=2)[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC1(O)CCN(C)C1=O
Product: CN1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)C1=O
Yield: 7 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (WO2009/158011A1) to give the titled compound as a light yellow solid (17 mg, 7%).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[OH:15][C:16]([CH3:46])([CH3:45])[CH2:17][C@@:18]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:23][C:22](=[O:24])[N:21]([C@H:25]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH3:26])[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[C:8]([N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([C@@H:25]([N:21]3[CH2:20][CH2:19][C@:18]([CH2:17][C:16]([OH:15])([CH3:45])[CH3:46])([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:23][C:22]3=[O:24])[CH3:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (0.10 mL), acetic anhydride (50 μL), and 4-dimethylaminopyridine (5 mg) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (0.12 g) dissolved in tetrahydrofuran (5 mL) at room temperature. The solution was stirred at room temperature for 4 h and then diluted with ethyl acetate. The resulting solution was washed with aqueous saturated NaHCO3 solution and brine and dried (Na2SO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2→90:10) to afford the title compound as a colorless foam-like solid.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1N.SC1SC2C=CC=C(C(F)(F)F)C=2N=1.[Cl:27][C:28]1[S:29]C2C=CC(Cl)=CC=2[N:32]=1>>[Cl:27][C:28]1[S:29][C:3]2[CH:2]=[CH:8][CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]=2[N:32]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: FC(F)(F)c1cccc2sc(S)nc12
Product: FC(F)(F)c1cccc2sc(Cl)nc12
Temperature: 100 °C

Procedure:
The title compound was prepared from 2-fluoro-5-trifluoromethylaniline via 2-mercapto-4-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 100° C. for 6 h.
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH3:18][C@H:19]1[CH2:47][O:46][C@@:22]2([O:26][C@H:25]3[CH2:27][C@H:28]4[C@@H:33]5[CH2:34][CH2:35][C@@H:36]6[CH2:42][C:40](=[O:41])[CH2:39][CH2:38][C@:37]6([CH3:43])[C@H:32]5[CH2:31][CH2:30][C@:29]4([CH3:44])[C@H:24]3[C@@H:23]2[CH3:45])[CH2:21][CH2:20]1>C1COCC1>[CH3:18][C@@H:19]1[CH2:47][O:46][C@@:22]2([O:26][C@H:25]3[CH2:27][C@H:28]4[C@@H:33]5[CH2:34][CH2:35][C@@H:36]6[CH2:42][C@H:40]([OH:41])[CH2:39][CH2:38][C@:37]6([CH3:43])[C@H:32]5[CH2:31][CH2:30][C@:29]4([CH3:44])[C@H:24]3[C@@H:23]2[CH3:45])[CH2:21][CH2:20]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: -26.5 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
A solution of lithium tri-tert-butoxyaluminohydride in THF (1M, 41.71 kg) was added (over ca. 2 hours) to a stirred solution of sarsasapogenone (17.38 kg,) in dry THF (ca 70 kg) at −23 to −30° C. under dry nitrogen. The process line was washed with THF and the mixture stirred at −23 to −30° C. for ca. 3 hours. The resulting solution was carefully quenched with aqueous aqueous sodium sulfate solution (5.67 kg in 28.67 kg of water). The inorganic salts were removed by filtration and washed with THF (184 kg). Water (63.18 kg) was added and the bulk of the THF was removed by distillation. Additional water (126.44 kg) was added and the product isolated by filtration. The product was washed with water (2×17.3.8 kg) and acetone (4×13.73 kg). The product was dried at 35-40° C. to afford episarsasapogenin (14.48 kg).
Reaction SMILES: [F:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])P(=O)(OCC)OCC.[Li+].CC([N-]C(C)C)C.[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][C:34]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[CH3:48])=[CH:33][C:32]=2[C:31]2[CH:49]=[CH:50][C:51]([CH:53]=O)=[CH:52][C:30]=2[N:29]=1>C1COCC1>[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][C:34]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[CH3:48])=[CH:33][C:32]=2[C:31]2[CH:49]=[CH:50][C:51](/[CH:53]=[C:2](/[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])\[F:1])=[CH:52][C:30]=2[N:29]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reactant: CCOP(=O)(OCC)C(F)P(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)/C(F)=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tetraethyl fluoromethylenediphosphonate (2.5 equiv.) in THF (0.27 M) cooled at −78° C. was added LDA solution (1.8 M in ethylbenzene/pentane/hexane, 2.0 equiv.). The resulting reaction mixture was warmed up to room temperature and stirred for 30 minutes, before it was cooled back down to −78° C. A solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9−Step 1) (1.0 equiv.) in THF (0.18 M) was added, and the reaction mixture was allowed to warm up to room temperature slowly. The reaction was quenched with saturated NH4Cl solution. Aqueous phase was extracted with DCM (3×). The combined organic phases were combined and concentrated in vacuo. The residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide (E)-Diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonate (3-2) as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10]([O:21][CH3:22])([O:19][CH3:20])[C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH3:23][O:24][CH2:25]Cl.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:22][O:21][C:10]([O:19][CH3:20])([O:9][CH3:8])[C:11](=[O:18])[CH2:12][CH:13]([CH2:23][O:24][CH3:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COCCl
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCC(CC(=O)C(OC)(OC)OC)C(=O)OC
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.85 ml diisopropylamine in 30 ml anhydrous tetrahydrofuran 12.5 ml 1.5M n-butyllithium (in hexane solution) was added at -78° C. under a nitrogen gas atmosphere, and the mixture was stirred for 15 minutes. To this mixed solution a solution of 3.45 g dimethyl 2-oxoglutarate dimethyl ketal in 15 ml anhydrous tetrahydrofuran was added over a period of 10 minutes, and the resulting mixture was stirred for 15 minutes. A solution of 1.32 ml chloromethyl methyl ether and 1.36 ml hexamethylphosphoramide in anhydrous tetrahydrofuran was added over a period of 10 minutes. The resulting mixture, after raising temperature to -20° C. over a period of 30 minutes, was stirred at the same temperature for 3 hours. To the reaction mixture a saturated aqueous solution of ammonium chloride was added, and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with water and dried (MgSO4), then the solvent was evaporated. The resulting residue was eluted with hexane-ethyl acetate (2:1) via column chromatography using silica gel to yield 2.28 g dimethyl 4-methoxymethyl-2-oxoglutarate dimethyl ketal in the form of a light yellow oily substance.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[OH:16].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.9 %

Procedure:
Add triethylamine (28.6 mL, 205 mmol) dropwise to a mixture of 2-fluoro-5-methylphenol (5.18 g, 41.1 mmol), copper(II) acetate (7.46 g, 41.1 mmol), phenylboronic acid (10.0 g, 82.1 mmol), powdered 4 Å sieves (7 g), and methylene chloride (400 mL). Stir at ambient temperature. After 22 h, filter and concentrate the filtrate. Purify the residue by silica gel chromatography (50% methylene chloride/hexanes), concentrate and purify again by silica gel chromatography (100% hexanes) to give 2.4 g (29%) of the title compound: MS(m/e): 202 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:9][C:8](=[O:10])[CH2:7][O:6][CH2:5]1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:22]([N:9]1[CH:4]([CH3:3])[CH2:5][O:6][CH2:7][C:8]1=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCBr
Reactant: CC1COCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN1C(=O)COCC1C
Yield: 71.1 %

Procedure:
A mixture of 3.00 g of 60% sodium hydride and 100 ml of benzene was incorporated dropwise with a solution of 3.00 g of L-2-amino-1-propanol in 10 ml of benzene, thereafter agitated at room temperature for a whole day, freed from the solvent by distillation off at reduced pressure to obtain a residue which was dissolved in ethyl acetate and subjected to column chromatography thereby to obtain 3.25 g of 5-methyl-3-morpholinone. A mixture of 1.24 g of 60% sodium hydride and 100 ml of toluene was incorporated dropwise with a solution of 3.25 g of 5-methyl-3-morpholinone in 10 ml of toluene, refluxed for one hour, incorporated with 7.05 g of lauryl bromide, further refluxed for a whole day, filtered to remove insoluble materials. The filtrate obtained was washed, dried and freed from the solvent by distillaton off at reduced pressure, subjected to column chromatography and finally distilled to obtain 5.69 g of colorless 4-(n-dodecyl)-5-methyl-3-morpholinone having the following appearance, column temperature and analysis: