Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2ccccc2)sc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-1,3-thiazole (1.0 g), potassium carbonate (0.57 g), vanillin (0.62 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.28 g, 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 133-134° C.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)C(=O)O1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCOCC>[O:8]=[C:6]1[C:12]2[C:11](=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[CH:13]=2)[NH:10][CH:9]=[CH:5]1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#Cc1ccc2[nH]ccc(=O)c2c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Intermediate (a) (27.5 g, 0.101 mol) was slowly added over five minutes to refluxing Dowtherm A (200 ml). After an additional five minutes at reflux, the mixture was allow to cool to room temperature then ether (200 ml) was added. The product was filtered off, thoroughly washed with ether then air dried to afford the product as a gold coloured solid (16.2 g, 94%).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:10]=[CH:9][N:8](COC(=O)C(C)(C)C)[C:7]2=[O:31]>CO.C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:10]=[CH:9][NH:8][C:7]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
A saturated solution of ammonia in methanol (14 ml) was added to a solution of 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.38 g, 3.3 mmol) in methanol (5 ml). After stirring for 20 hours at ambient temperature, the suspension was diluted with methylene chloride (10 ml). The solution was filtered. The filtrate was evaporated under vacuum and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin-4-one (910 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][CH:31]([NH2:33])[CH3:32])[CH:26]=[CH:27][C:28]=1[F:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:33][CH:31]([CH3:32])[CH2:30][C:25]2[CH:26]=[CH:27][C:28]([F:29])=[C:23]([F:22])[CH:24]=2)=[O:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)O
Reactant: CC(N)Cc1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(F)c(F)c1)NC(=O)c1c(N)ccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
4-amino-2-(trifluoromethyl)nicotinic acid (4.4 g, 18.14 mmol) was suspended in a mixture of anhydrous DMF (100 mL) and anhydrous dichloromethane (200 mL). To this was added triethylamine (6 g, 60 mmol), followed by 1-(3,4-difluorophenyl)propan-2-amine (3.75 g, 21.90 mmol). HBTU (9.63 g, 25.4 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo to remove dichloromethane. The resultant DMF solution was poured into water and extracted twice with ethyl acetate. The organic layer was washed successively with 1N NaOH and water, then dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography using 20-40% acetone/hexanes as eluant to provide the product as a colorless solid (6.57 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.1 (m, 2H), 6.95 (m, 1H), 6.7 (d, 1H), 4.07 (m, 1H), 4.9 (bd, 2H), 4.4 (m, 1H), 2.7-2.9 (dd, 2H), 1.2 (d, 2H). MS m/z 360.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:17](Br)[C:18]#[CH:19]>CN(C=O)C>[CH2:19]([O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]#[CH:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCOC[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 66.9 %

Procedure:
To a stirred solution of 18 (0.40 g, 2 mmol) in dry DMF (10 mL) was added potassium hydroxide (0.56 g, 10 mmol), followed by dropwise addition of propargyl bromide (80 wt. % in toluene) (0.48 g, 4 mmol) over 5 min. After 18 h the reaction mixture was poured onto water (30 mL) and washed with DCM (3×15 mL). The combined organic fractions concentrated in vacuo and the liquid remaining taken up in diethyl ether (15 mL) and washed with water (2×10 mL), then brine (1×10 mL) and dried over Na2SO4. Chromatography (hexanes/ethyl acetate) gave the desired product as a colorless oil (0.32 g, 67%). HRMS (ESI)=240.1597 (M+H)+. Calcd. for C13H22NO3 240.1594. 1H NMR (600 MHz, CDCl3) δ 4.13 (s, 2H), 3.96-3.88 (m, 1H), 3.64 (dd, J=9 Hz, J=3.6 Hz, 1H), 3.49-3.22 (m, 3H), 2.40 (s, 1H), 1.94-1.78 (m, 4H), 1.46 (s, 9H). TLC (I2) Rf=0.67 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH3:5].[CH2:6]([NH-:11])[CH2:7][CH:8]([CH3:10])[CH3:9].Cl>O1CCCC1.CO>[CH2:6]([NH:11][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CC[NH-]
Reactant: CCCSC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CSCCCNCCC(C)C
Reaction time: 8 h

Procedure:
The amide from (a) (1.9 g) in tetrahydrofuran (20 ml) was treated under nitrogen at 0° with boranetetrahydrofuran complex (1 Molar in tetrahydrofuran 20 ml) and stirred overnight. 2 Molar hydrogen chloride in methanol (20 ml) was added and the mixture was boiled for 30 minutes, evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was basified and extracted with ether. The dried extract was evaporated to give the amine an oil (1.6 g). Rf3A=0.72, Rf7B=0.63, Rf4A=0.74
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[N:8]=[C:9]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1Cl.CN([CH:30]=[O:31])C>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[CH:30]=[O:31]
Reactant: CN(C)S(=O)(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
nBuLi (0.21 ml of a 2.4M solution in hex, 0.51 mmol) was added dropwise to a −78° C. solution of 4,5-dichloro-N,N-dimethyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide (0.18 g, 0.47 mmol) in THF (3 ml). The reaction mixture was stirred for 30 mins and DMF (0.4 ml, 5.17 mmol) was added. After 10 mins, the cooling bath was removed and the reaction mixture was warmed to RT. Sat'd NaHCO3 was added and the solution was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, evaporated, and purified by silica gel chromatography (0-20% EtOAc/hexanes) to provide the title compound (0.085 g, 49%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.93 (s, 1H), 5.94 (s, 2H), 3.63-3.70 (m, 2H), 3.09 (s, 6H), 0.89-0.98 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4]2([CH2:11][CH2:10][C@H:9]3[C@H:12]4[C@H:21]([CH2:22][CH2:23][C@:7]23[CH3:8])[C@@H:20]2[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)[CH2:3]1.Cl.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CO.CC(C)=O>[O:5]1[CH2:6][C:2](=[O:1])[CH2:3][C:4]21[CH2:11][CH2:10][C@H:9]1[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:7]21[CH3:8])[C@@H:20]1[C:15](=[CH:16][C:17](=[O:24])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC21CC(O)CO1
Agent: O=[Cr](=O)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC21CC(=O)CO1

Procedure:
The compound of this invention defined by the introductory formula when R therein represents hydrogen can be prepared as follows: 21-(Hydroxymethyl)-3-methoxy-17α-pregna-1,3,5(10), 20-tetraen-17-ol, upon prolonged contact with p-toluenesulfonyl chloride in pyridine, affords 3-methoxyspiro[estra-1,3,5(10)-triene-17,2'(5'H)-furan]. Consecutively contacting the latter intermediate in cold tetrahydrofuran under nitrogen with borane and sodium peroxide (formed in situ) affords 4',5'-dihydro-3-methoxyspiro[estra-1,3,5(10)-triene-17,2'(3'H)-furan]-4'-ol, from which, upon consecutively contacting in tetrahydrofuran and 1,1-dimethylethanol with liquid ammonia and lithium, 4',5'-dihydro-3-methoxyspiro[estra-2,5(10)-diene-17,2'(3'H)-furan[-4'-ol is obtained. Conversion of this enol ether to the corresponding 5(10)-en-3-one occurs upon contact with 90% acetic acid, and from the 4',5'-dihydro-4'-hydroxyspiro[estr-5(10)-ene-17,2'(3'H)-furan]-3-one thus obtained, 4',5'-dihydro-4'-hydroxyspiro[estr- 4-ene-17,2'(3'H)-furan]-3-one eventuates on contact with hydrochloric acid in methanol. Finally, the hydroxyl therein is oxidized with Jones' reagent in acetone, affording 4',5'-dihydrospiro[estr-4-ene- 17,2'(3'H)-furan]-3,4'-dione.
Reaction SMILES: [CH2:1]([NH:13][C@@H:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:25](Cl)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>C1COCC1>[CH2:1]([N:13]([CH:14]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16])[C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
100 g of N-dodecyl-β-D-glucopyranosylamine from EXAMPLE 4 were dissolved in 765 ml of THF, and 80 g of stearoyl chloride were added dropwise in the presence of 32 g of triethylamine, with cooling.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Cl[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[CH:57][C:58]([OH:62])=[N:59]2)=[CH:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Pd].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:52]5[CH:61]=[C:60]6[C:55]([CH:56]=[CH:57][C:58]([OH:62])=[N:59]6)=[CH:54][CH:53]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: Oc1ccc2ccc(Cl)cc2n1
Agent: Cl[Pd+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)C(c1ccc(-c2ccc3ccc(O)nc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 90 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.302 mmol) in 1,4-dioxane (1.5 mL) was treated with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.362 mmol), potassium acetate (0.453 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.030 mmol). The solution was degassed with a stream of nitrogen for 3 min, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 90° C. overnight. The reaction mixture was cooled to room temperature and was treated with 7-chloroquinolin-2-ol (0.302 mmol), 2M aq potassium carbonate (0.906 mmol), and Pd-XPhos Precatalyst (Strem 46-0268) (0.030 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an bath at 90° C. for 16 h. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (10-40% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜7 with saturated aq sodium bicarbonate. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by chiral HPLC (Chiralpak AS-H column, acetonitrile:methanol 9:1) followed by lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid (20 mg, 12%). MS(ES)+ m/e 505.2 [M+H]+, >99% ee, αD=+43 deg (c=0.02, acetonitrile:methano19:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:7][C:6]=2[CH:16]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I.O.CCOC(C)=O>[F:17][C:4]1[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:7][C:6]=2[CH:16]=[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]=1
Reactant: CS(=O)[O-]
Reactant: CCCNCC1OCc2c(F)cc(Br)cc2O1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 140 °C
Yield: 39 %

Procedure:
A mixture of N-[(7-bromo-5-fluoro-4H-1,3-benzodioxin-2-yl)methyl]propan-1-amine (0.23 g, 0.76 mmol), sodium methanesulfinate (0.14 g, 1.13 mmol, 85%), copperiodide (14 mg, 0.08 mmol), L-proline (17 mg, 0.15 mmol), potassium carbonate (21 mg, 0.15 mmol) in DMSO (2.5 ml) was degassed with nitrogen. Heating in a microwave oven at 140° C. for 30 min afforded product, but the starting material was not completely converted. Additional copperiodide (14 mg, 0.08 mmol) and L-proline (17 mg, 0.15 mmol) were added and the mixture was heated once again at 140° C. for 30 min. The mixture was brought to ambient temperature and EtOAc (100 ml) and water (50 ml) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3×50 ml). The organic phases were combined, dried (Na2SO4), filtered and evaporated. Purification had to be done three times, by flash column chromatography (EtOAc/MeOH 8:1) before affording the pure title compound (90 mg, 39%). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/DEE (55 mg). M.p. 194° C. 1H-NMR (400 MHz, MeOH): δ 7.36 (2H, m), δ 5.26 (1H, t, J 4.8 Hz), δ 5.05 (2H, dd, J1 20.8 Hz, J2 16.0 Hz), δ 3.13 (3H, s), δ 2.99 (2H, m), δ 2.66 (2H, t, J 7.6 Hz), δ 1.56 (2H, m), δ 0.95 (3H, t, J 7.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][C@H:23]([CH2:28][O:29][CH3:30])[C:24]([F:27])([F:26])[F:25])[C:19]([N+:31]([O-])=O)=[C:18]([F:34])[CH:17]=2)[CH2:11][S@@:10](=[O:35])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][C@H:23]([CH2:28][O:29][CH3:30])[C:24]([F:25])([F:27])[F:26])[C:19]([NH2:31])=[C:18]([F:34])[CH:17]=2)[CH2:11][S@@:10](=[O:35])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
The title compound was prepared in an analogous manner as described for example 1j, starting from {(1R,3R,4S,5S)-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-4-hydroxy-1-oxo-tetrahydro-thiopyran-3-yl}-carbamic acid tert-butyl ester (example 41a): TLC (EtOAc) Rf=0.30; HPLC RtF=1.99 min; ESIMS [M+H]+=515; [M+H-isobutylene]+=459.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cccc(O)c1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc(O)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 3-aminophenol, and isolated as a yellow solid (34%). LCMS (API-ES) m/z 295 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.97 (s, 1H) 9.27 (s, 1H) 8.76 (dd, J=7.78, 1.76 Hz, 1H) 8.35 (dd, J=4.77, 1.76 Hz, 1H) 7.64-7.92 (m, 2H) 7.51 (s, 1H) 6.99-7.28 (m, 2H) 6.89 (dd, J=7.53, 4.52 Hz, 1H) 6.40 (d, J=7.03 Hz, 1H) 2.45 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:38])([F:37])[C:12]1[CH:13]=[N:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)[CH:16]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N=C=NCCCN(C)C)C>O1CCCC1>[F:37][C:11]([F:10])([F:38])[C:12]1[CH:13]=[N:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:33])=[CH:35][CH:36]=3)[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)[CH:16]=1
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
To a mixture of ethyl 3-aminopropanoate hydrochloride (418 mg, 2.72 mmol), 4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzoic acid (732 mg, 1.82 mmol), 1-hydroxybenzotriazole hydrate (292 mg, 1.91 mmol), and N,N-diisopropylethylamine (1.20 mL, 7.26 mmol) in tetrahydrofuran (18.2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (557 mg, 2.90 mmol). The mixture was stirred for 48 hours at ambient temperature. The reaction mixture was concentrated and the crude material was purified by column chromatography (0-100% ethyl acetate in heptane) to afford racemic ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (684 mg, 85%) as a solid. The racemate was further purified via chiral SFC to afford 300 mg of Isomer 1 and 300 mg of Isomer 2, which were used in conversion to the final enatiopure products. 1H NMR (400 MHz, CDCl3, δ): 7.94 (q, J=0.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 6.84 (t, J=5.8 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 4.42-4.34 (m, 1H), 4.31 (d, J=4.7 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.71 (q, J=6.1 Hz, 2H), 2.63 (t, J=5.9 Hz, 2H), 1.88-1.71 (m, 2H), 1.53-1.31 (m, 2H), 1.27 (t, J=7.0 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). Chiral SFC: Chiralpak AD-H, 10×250 mm; Mobile Phase 65:35 CO2/methanol, 65 mL/min, Retention time: 3.95 min (Isomer 1), 6.81 min (Isomer 2).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[N:14](CCCCCCCCC(O)=O)=[N+:15]=[N-:16]>>[N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NCCCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCCCBr
Product: [N-]=[N+]=NCCCCCCCCCC(=O)O
Yield: 91 %

Procedure:
10-bromodecanoic acid (1.125 gr, 4.48 mmol) was reacted as described for product 5a to yield 91% of product 5b. 1H-NMR (200 MHz, CDCl3): 1.2-1.5 (m; 10H), 1.5-1.7 (m; 4H), 2.35 (t; J=7.41 Hz; 2H), 3.24 (t; J=6.81 Hz; 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])C)(=[O:12])[CH2:4][C:5](OC(C)(C)C)=O.[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27](C)=[C:28](Cl)[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27]([CH3:28])=[C:5]([CH2:4][C:3]([O:13][CH:14]([C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[CH:37]=[CH:25][CH:24]=[CH:23][CH:21]=3)=[O:12])[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cn2c1=O

Procedure:
To a suspension of NaH in DMF with ice bath cooling is added di-t-butyl malonate. After the addition, 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i above is added. The reaction is then heated to 50° to 60° C., and the mixture is poured into water and acidified. The product is extracted into methylene chloride and dried over MgSO4. The residue, after removal of the solvent, is dissolved in methylene chloride and trifluoroacetic acid at room temperature. The solvent is removed under vacuum, and the product is treated with diphenyldiazomethane in methylene chloride and methanol. When the reaction is finished, the solvents are removed under vacuum, and the product is purified by column chromatography to give the title compound.