Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH:22]=C)[C:16](=[O:24])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:25]1[CH2:31][CH2:30][CH2:29][C@@H:26]1[CH2:27][OH:28].B.N1C=CC=CC=1.C(O)(=O)C.[OH-].[NH4+]>CC(C)=O.O.ClCCCl.C(O)C.[Os](=O)(=O)(=O)=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:25]2[CH2:31][CH2:30][CH2:29][C@@H:26]2[CH2:27][OH:28])[C:16](=[O:24])[CH2:15]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: OC[C@H]1CCCN1
Reactant: C=CCCN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: B
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(CCCN2CCC[C@@H]2CO)C(=O)C1
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Sodium metaperiodate (505 mg, 2.36 mmol) and osmium(VIII) oxide (2.5% solution in tert-butylalcohol, 80 μl, 7.9 μmol) were added at 0° C. to a solution of 4-but-3-enyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.79 mmol) in acetone/water 1:1 (10 ml). After 30 min, the reaction mixture was allowed to reach room temperature over 45 min, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. The crude aldehyde intermediate (3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid tert-butyl ester) and D-prolinol (95 mg, 0.94 mmol) were dissolved in 1,2-dichloroethane (2 ml), then a freshly prepared solution of pyridine borane complex (8 M in pyridine, 0.24 ml, 1.9 mmol) and acetic acid (170 mg, 2.83 mmol) in ethanol (2 ml) was added dropwise at room temperature. The reaction mixture was stirred overnight, then 25%. aq. ammonium hydroxide solution (0.39 ml) was added, and volatile material was removed by rotary evaporation. The residue was purified by chromatography (SiO2; CH2Cl2/MeOH/NH4OH 80:20:0.25) to afford the title compound (160 mg, 60%). Light brown oil, MS (ISP) −342.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.[N:13]([CH2:16][CH2:17][CH2:18][CH3:19])=[C:14]=[O:15].[H-].[Na+].Cl>O.O1CCCC1>[CH2:16]([N:13]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: CCc1cc(C(=O)OC)c(N)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)[nH]c2sc(CC)cc2c1=O
Temperature: 60 °C
Yield: 54 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (2.5 g), 1-isocyanatobutane (1.52 mL) and tetrahydrofuran (20 ml) was added sodium hydride (1.2 g), and the mixture was stirred at 60° C. for. 5 hr. The reaction mixture was diluted with water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid, the precipitated solid was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give the title compound as colorless crystals (1.85 g, 54%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>COCCOC.O.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:14]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccccc1-c1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Under air, to 2-bromopyridine (4.54 g, 28.7 mmol, 1.00 equiv) in DME—H2O (1:1, 100 mL) at 23 ° C. was added K2CO3 (5.96 g, 43.1 mmol, 1.50 equiv), 2-aminophenylboronic acid pinacol ester (6.30 g, 28.7 mmol, 1.00 equiv), and tetrakis(triphenylphosphine)palladium (1.66 g, 1.44 mmol, 5.00 mol%). The reaction mixture was stirred at 100 ° C. for 3.0 h. After cooling to 23 ° C., the phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 4:1 (v/v) to afford 4.20 g of the title compound as a red-brown oil (86%). Rf=0.38 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.61-8.60 (m, 1H), 7.78-7.75 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.6 Hz, 1.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.80-6.76 (m, 2H), 5.72 (br s, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 159.5, 147.9, 146.6, 136.9, 129.9, 129.4, 122.2, 122.2, 121.0, 117.6, 117.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6]2[NH:15][N:16]=[CH:17][C:5]=12)[CH3:2].I[CH2:19][CH2:20][CH2:21][C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:12][C:10]([C:9]1[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:17]=[N:16][N:15]([CH2:23][CH2:22][CH2:21][C:20]#[CH:19])[C:6]2=[N:7][CH:8]=1)=[O:11])[CH3:14]
Reactant: C#CCCCI
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCn1ncc2c(OCC)c(C(=O)OCC)cnc21
Reaction time: 1 h
Yield: 111.9 %

Procedure:
A mixture of 3.78 g of ethyl 4-ethoxy-1H-pyrazolo-[3,4-b]pyridine-5-carboxylate, 3.90 g of 1-iodo-4-pentyne, and 6.68 g of pulverized anhydrous potassium carbonate in 27 ml of dry DMF was stirred at 50°-60° for 1 hr. The mixture was cooled, poured into water, and the resulting mixture extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to leave 5.42 g of a dark oil which slowly crystallized. This material was chromatographed over silica gel using EtOAc/hexane 1:2 (v/v) as the eluant to give 3.03 g (62%) of the title compound as a white solid. A small quantity was recrystallized from toluene to give white crystals, m.p. 84°-85.5°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])[C:5]1=[O:30].[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24])[C:5](=[O:30])[N:4]3[CH2:3][CH2:2][NH:1][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.72 (s, 1 H), 3.13-3.20 (m, 3 H), 3.31 (s, 4 H), 3.45-3.50 (m, 5 H), 3.50-3.58 (m, 5 H), 4.13 (s, 2 H), 4.28 (t, J=6.39 Hz, 2 H), 6.77 (t, J=5.40 Hz, 1 H), 7.14 (t, J=8.84 Hz, 2 H), 7.41 (dd, J=8.49, 5.55 Hz, 2 H), 8.26 (s, 1 H), 8.55 (d, J=0.70 Hz, 1 H), 10.42 (t, J=5.62 Hz, 1 H); ES+ MS: 528 (M+H+).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[C:1](=[N:14]/[OH:15])(\[C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)/[CH3:2]
Reactant: CCOc1ccnc(C(C)=O)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccnc(/C(C)=N/O)n1
Yield: 58.6 %

Procedure:
A solution of 2-acetyl-4-ethoxypyrimidine (1.8 g), hydroxylamine hydrochloride (0.83 g) and sodium acetate (2.2 g) in a mixture of ethanol:water (30:10 ml) was heated under reflux for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (×3). the combined extracts were washed with brine, dried and concentrated to give a solid which was washed with hexane to give (E)-2-acetyl-4-ethoxypyrimidine oxime as an off-white solid (1.15 g, 60% yield); 1H NMR (270 MHz): δ1.44(3H,t), 2.38(3H,s), 4.50(2H,q), 6.68(1H,d), 8.48(1H,d), 9.80(1H,brs) ppm.
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[O:9])=[CH:5][C:4]2[C:10]([F:17])([F:16])[O:11][C:12]([F:15])([F:14])[O:13][C:3]=2[CH:2]=1.[CH3:18][O:19][C:20]([C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=2)[CH:25]=[CH:24][N:23]=1)=[O:21]>C(Cl)Cl>[F:14][C:12]1([F:15])[O:13][C:3]2[CH:2]=[CH:1][C:6]([NH:7][C:8]([NH:35][C:31]3[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=3)[O:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:27]=3)=[O:9])=[CH:5][C:4]=2[C:10]([F:16])([F:17])[O:11]1
Reactant: O=C=Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Reactant: COC(=O)c1cc(Oc2cccc(N)c2)ccn1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2cccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2,2,4,4-tetrafluoro-6-isocyanato-1,3-benzodioxene (0.816 g, 3.28 mmol) was added 4-(3-aminophenoxy)pyridine-2-carboxylic acid methyl ester (0.800 g, 3.28 mmol) in DCM (13 mL) in portions. The homogenous contents turned white and opaque within 1 min. of addition, and were allowed to stir at room temperature for 12 h. The heterogenous mixture was filtered, and solid product repeatedly washed with DCM to remove residual starting material. The desired product was collected as a white powder, 1.36 g (83%). 1H-NMR (DMSO-d6) δ 9.08 (d, 2H), 8.59 (s, 1H), 8.07 (s, 1H), 7.60 (dd, 1H), 7.37 (m, 4H), 7.25 (d, 1H), 7.20 (dd, 1H), 6.80 (d, 1H), 3.82 (s, 3H); MS LC MS [M+H]+=494.1, RT=3.23 min.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Suspend 5-(4-formylphenoxy)pyridine-2-carboxamide (0.0271 g, 0.112 mmol) In methanol (2.1 mL). Add 4-fluorophenethylamine (0.015 mL, 0.112 mmol) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (in small excess) and stir for additional 3 hours. Load the reaction mixture directly onto a 5 g SCX column. Wash the column with methanol and elute with 2.0 M NH3 in methanol. Purify by flash chromatography, eluting with 70% ethyl acetate, 5% (2.0 M NH3 in methanol) and 25% hexanes to give the title compound (0.0370 g, 90.5%): TOF MS ES+ 366.2 (M+H)+, base peak TOF MS ES+ 227.1 (M-NHCH2CH2C6H4F)+, HRMS calcd for C21H21N3O2F 366.1618 (M+H)+, found 366.1621, time 0.42 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95°/over 19 min], tR=10.2 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH2:22].Cl>O>[CH3:21][NH:22][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Reactant: CN
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g), a 40% aqueous solution of methylamine (1 g) and water (20 ml) was stirred at room temperature and allowed to stand overnight at the same temperature. The resultant mixture was made acidic with 5% aqueous hydrochloric acid to precipitate an oily substance, which was then extracted with chloroform. The organic layer was washed with a 5% aqueous solution of hydrochloric acid and water in order and dried over anhydrous magnesium sulfate, followed by concentration. The residue was allowed to stand to give crystals, which were recrystallized from toluene to give 1.1 g of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 134.5°-135.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol as light yellow oil, MS: 450 (MH+, 1Br).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=2)[CH:7]=1.CCN(S(F)(F)[F:20])CC>C(Cl)Cl>[F:20][CH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1c(CO)nc2ccc(I)cn12
Solvent: ClCCl
Product: Cc1c(CF)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
To a stirred solution of (6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)methanol (600 mg) in DCM (2 ml) was added DAST (500 mg) at −78° C. The reaction mixture was then allowed slowly to warm up to room temperature, and stirred at the same temperature for 16 h. The reaction mixture was then diluted with DCM (100 ml), washed with saturated NaHCO3 solution (100 ml), and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (280 mg) as an off-white solid.
Reaction SMILES: [O-]CC.[Na+].I[C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:25]([O:24][C:22]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:23])[CH3:26]
Reactant: CCOC=O
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cccc(C(=O)OCC)c2OCC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of sodium ethoxide (1.7 ml, 20% in ethanol) and dichlorobis(triphenylphosphine)palladium(II) (14 mg) in dichloromethane (7 ml) was added a mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (0.69 g) and ethyl formate (0.28 ml) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 40° C. for 3 hours and filtered off. The filtrate was partitioned between diethyl ether and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:19) as an eluent to give a solid of ethyl 2,3-dihydro-9-ethoxycarbonyl-1-benzoxepin-4-carboxylate (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:25])([F:24])[F:23])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].[F-].[K+].C1OCCOCCOCCOCCOCCOC1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Cl:9][C:6]1[CH:5]=[C:4]([CH:10]([C:22]([F:24])([F:23])[F:25])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:35](=[O:36])[CH2:34][NH:33][C:31](=[O:32])[O:30][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:17]=[CH:16]3)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Fc1c(Cl)cc(C(/C=C/c2ccc3[nH]ccc3c2)C(F)(F)F)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-(tert-butoxycarbonylamino)acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18-crown-6-ether (0.075 g, 0.283 mmol) and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with DCM and washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O.S([O-])([O-])(=O)=O.[Mg+2]>[Pt].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:3][O:2][CH3:1]
Reactant: COCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COCCn1c(COC)nc2cnc3ccccc3c21
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 110.6 %

Procedure:
4-(2-Methoxyethylamino)-3-nitroquinoline (16.24 g; 0.066 mol) was added to a mixture of ethyl acetate (1500 mL), 5% platinum on carbon (1 g), and magnesium sulfate (6 g). The mixture was hydrogenated on a Parr apparatus at 30 psi initial pressure. When the hydrogenation was complete, the solids were filtered off and the ethyl acetate was evaporated. The resulting diamine intermediate was heated with methoxyacetic acid (70 mL) at 150° C. for 2-3 hours and then at 120° C. for 2-3 hours. The reaction mixture was poured into water (400 mL), made strongly basic with 6N sodium hydroxide and then extracted with ether (3×200 mL). The ether extracts were combined, washed with brine then evaporated to provide 9.9 g of an oil which crystallized on standing. The aqueous layers were extracted again with ether (4×200 mL). The extracts were combined, washed with brine and evaporated. The residue was recrystallized from ethyl acetate to provide 1.5 g yellow needles. Analysis: Calculated: C, 66.4; H, 6.3; N, 15.5; Found: C, 66.6; H, 6.4; N, 16.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][NH:10][C:11](=[O:14])[CH2:12][O:15]2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCC(O)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1COC(c2ccc(Br)cc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide (2.0 g, 6.8 mmol) in THF (20 mL) was added potassium t-butoxide (0.46 g, 8.2 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.6 g, 92% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl3): δ7.46 (d, 2H), 7.20 (d, 2H), 6.56 (s, 1H), 4.67 (m, 1H), 4.35 (d, 1H), 4.24 (d, 1H), 3.40 (m, 2H):
Reaction SMILES: [CH2:1]([C:9]#N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][OH:17]>C(=S)=S>[OH:17][CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][N:11]=[C:9]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC#N
Reactant: NCCNCCO
Solvent: S=C=S
Product: CCCCCCCCC1=NCCN1CCO
Yield: 58.3 %

Procedure:
13.02 g (93.51 mmoles) of octyl cyanide was treated with 12.327 g (118.36 mmoles) of 2-(2-aminoethylamino)ethanol in presence of 0.5 ml of carbon disulfide at 125° C. for 24 hrs. and worked up as outlined under Example 23. Distillation of the residue at 167°-169° C./0.5 mm gave 12.332 g (62.7%) of product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=4[CH:13]=3)[CH:10]=2)[CH:5]=[C:4]([C:26]([OH:28])=[O:27])[CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>C1COCC1.O.CN(C)C=O>[CH3:31][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:18]([CH3:22])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:24])([CH3:25])[C:14]=4[CH:13]=3)[CH:10]=2)[CH:5]=[C:4]([C:26]([OH:28])=[O:27])[CH:3]=1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)O)cc2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
0.8 g (2.1 mmoles) of the acid obtained in Example 2, dissolved in 10 ml of THF, are added drop by drop to a suspension of sodium hydride (0.113 g; 4.7 mmoles) in 10 ml of THF. After stirring for two hours at room temperature, 10 ml of dimethylformamide and 0.90 g (6.3 mmoles) of methyl iodide are added. After stirring for one hour, the mixture is poured into water and brought to pH 1 (concentrated hydrochloric acid). Following extraction by ether, the organic phase is decanted, then dried and evaporated. The solid thus formed is recrystallized in a mixture of diisopropyl ether (50%) and cyclohexane (50%). In this manner is obtained 0.60 g (74%) of 4-methoxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid which melts at 242° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:28].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CF
Temperature: 80 °C
Reaction time: 19 h

Procedure:
91.1 To a stirred solution of 150 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (example 17.2) at r.t. in 3.3 ml DMF under an argon atmosphere was added 1.71 ml tetrabutylammonium fluoride solution (1 M in THF). The mixture was heated to 80° C. and stirring at that temperature was continued for 19 h. The mixture was cooled to r.t., diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 1:1) to give 44 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-fluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white amorphous solid. MS 361.0 ([M−H]−)