Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]([CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C(O)C[OH:16].O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:7]([CH:6]1[C:2]([OH:13])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:16])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OCCO
Reactant: CCCCCC(O)c1ccc(C)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCC1C(=O)C=CC1(C)O
Yield: 84 %

Procedure:
In the same apparatus as in Example 1 5-methyl-α-n-pentyl-furfuryl alcohol (40 parts), ethylene glycol (20 parts) and a buffer solution prepared from water (1200 parts) and sodium acetate (0.5 part) and adjusted to pH 5.2 with acetic acid were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream for 20 hours. The reaction mixture was cooled and extracted with toluene. The extract was concentrated to give 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 84 %.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:35][CH:36]([C:38]1[NH:39][C:40]([C:46]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:47]=2[N:48]=[C:49]([NH:57][CH2:58][C:59]([F:62])([F:61])[F:60])[C:50]([CH3:56])=[N:51]3)=[CH:41][C:42]=1[C:43](O)=[O:44])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:37][CH:36]1[C:38]2[NH:39][C:40]([C:46]3[CH:55]=[CH:54][CH:53]=[C:52]4[C:47]=3[N:48]=[C:49]([NH:57][CH2:58][C:59]([F:60])([F:61])[F:62])[C:50]([CH3:56])=[N:51]4)=[CH:41][C:42]=2[C:43](=[O:44])[NH:35]1
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NCC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)NC4=O)c2nc1NCC(F)(F)F
Yield: 42.2 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (AK Scientific, Inc., Union City, Calif.) (431 mg, 0.83 mmol) was added to a solution of 2-(1-aminoethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (293c) (274 mg, 0.64 mmol) and DIPEA (0.44 mL, 2.55 mmol) in CH2Cl2 (16 mL) and DMF (16 mL) at RT. After 30 min the reaction mixture was concentrated. The residue was diluted with EtOAc and washed sequentially with water, saturated NaHCO3 (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2), to provide rac-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (293d) (100 mg, 0.27 mmol, 42% yield) as a yellow solid. The mixture of enantiomers was subjected to chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 25% MeOH with 20 mM NH3; 75 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers. Example 293 (first eluting peak): (S)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (3 mg, 7.99 μmol, 1% yield, >99% ee) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83-11.95 (m, 1H), 7.86-7.93 (m, 1H), 7.74 (t, J=6.26 Hz, 1H), 7.68 (dd, J=8.12, 1.47 Hz, 1H), 7.64 (d, J=0.39 Hz, 1H), 7.44 (t, J=7.82 Hz, 1H), 6.85-6.92 (m, 1H), 4.52-4.66 (m, 1H), 4.16-4.33 (m, 1H), 4.09 (q, J=5.15 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.65 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −69.51 (s, 3F). m/z (ESI, +ve) 376.1 (M+H); and Example 294 (second eluting peak): (R)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (44 mg, 0.12 mmol, 18% yield, >99% ee). m/z (ESI, +ve) 376.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])C)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+].Cl.[CH3:15]O>>[CH3:1][O:2][C:3]1[CH2:4][C:5]([CH3:15])([CH:6]=[CH:7][CH:8]=1)[CH2:9][OH:11]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC1=CC=CC(C)(CO)C1
Temperature: 0 °C
Yield: 94 %

Procedure:
To m-methoxyacetophenone (100 g, 0.665 mol) in 400 mL of methanol was added with cooling sodium borohydride (30.22 g, 0.799 mol) over a period of 1 h and the mixture was stirred, poured into ice-water, and neutralized with conc. HCl. The above mixture was extracted with ether (3×400 mL), the organic layer was dried over sodium sulfate, and concentrated. The residue was then distilled (149°-151° C. @ 25 mm)(short path column) to afford 95.6 g (94%) of m-methoxy-1-methyl-benzyl alcohol as a clear oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)=[O:5].[CH2:7]([OH:11])[CH2:8][CH2:9][CH3:10]>CCOCC>[Cl:1][CH2:2][CH2:3][S:4]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5]
Reactant: O=S(Cl)CCCl
Reactant: CCCCO
Solvent: CCOCC
Product: CCCCOS(=O)CCCl

Procedure:
2-Chloroethanesulfinyl chloride (16.2 w), prepared as in Example I was dissolved in dry ether (130 v) and the solution was cooled to -15°. Normal butanol was added dropwise under a nitrogen atmosphere to the cooled solution. Upon completion of the addition period the reaction mixture was allowed to warm to ambient temperatures and the solvent was removed by distillation in a vacuum to yield a colorless liquid, butyl 2-chloroethanesulfinate (18.5 w).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[ClH:9].[Cl:9][C:4]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1ncccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccnc2Cl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of 3-(bromomethyl)-2-chloropyridine (1.0 g, 4.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (570 mg, 4.0 mmol), and triethylamine (1.4 mL, 10.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with EtOH (15 mL), diethyl ether (3×15 mL), water (3×30 mL), and hexanes (3×15 mL). The solid material was dried in vacuo, affording the 2-{[(2-chloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (400 mg, 31% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2].[OH-].[Na+].O>CO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:24]1[NH:29][C:28](=[O:30])[C:27]2=[C:31]([CH3:39])[N:32]=[C:33]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[N:26]2[N:25]=1)[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(OCC)c(-c3nn4c(C5CCCC5)nc(C)c4c(=O)[nH]3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1ccc(S(=O)(=O)N2CCC(C(=O)O)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
180 mg (0.323 mmol) of the ester from Example 8 and 50 mg (1.29 mmol) of sodium hydroxide are stirred at room temperature in 20 ml of methanol/water 3:1 for minutes, 10 ml of water are added and the mixture is extracted once with dichloromethane. The aqueous phase is acidified using 2 n HCl and extracted twice with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and evaporated. The residue is recrystallized from diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([Mg]Br)=[CH:21][CH3:22].[Cl-:25].[NH4+]>O1CCCC1>[ClH:25].[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:13]3[NH:14][C:21]([CH3:22])=[C:20]([CH3:19])[C:12]=3[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccncc1OCc1ccc(F)cc1
Reactant: [Cl-]
Reactant: CC=C(C)[Mg]Br
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(OCc3ccc(F)cc3)cncc2c1C
Product: Cl
Temperature: -20 °C
Reaction time: 5 h
Yield: 13.5 %

Procedure:
3-(4-Fluorobenzyloxy)-4-nitropyridine (6.6 g, 26.59 mmol) prepared in Preparation 1 was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 80 ml) was added at −78° C. to the solution, which was then stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1 (v/v)) and then concentrated to remove the solvent. The resulting residue was dissolved in 10 ml of ethyl acetate and saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (910 mg, 13.5%).
Reaction SMILES: ClC(Cl)C.[NH2:5][CH2:6][C@@H:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][N:9]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH2:8]1.[C:31]([C:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[S:36][CH:35]=1)(=O)[CH3:32].[BH4-].[Na+]>CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[S:36]1[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:34]([CH:31]([NH:5][CH2:6][C@@H:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][N:9]([C:18]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=3)=[O:19])[CH2:8]2)[CH3:32])=[CH:35]1
Reactant: CC(=O)c1csc2ccccc12
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN)[C@@H](c3ccccc3)C2)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CNC(C)c3csc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
A 1.0 ml dichloroethane solution of 119 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-(aminomethyl)-4-phenylpyrrolidine-1-carboxylate and 62 mg of 3-acetylbenzothiophene was mixed with 0.12 ml of tetraisopropoxy titanium and stirred for 2 hours. The reaction solution was diluted with 1.0 ml of methanol, mixed with 38 mg of sodium borohydride, further stirred for 1 hour and then concentrated under a reduced pressure, and the thus obtained was purified by a silica gel chromatography (chloroform-methanol) to obtain 95 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[1-(1-benzothien-3-yl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a yellow amorphous substance. EP: 515.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]1COCC1>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:14][C:15]4[CH:21]=[CH:29][C:19]([CH2:20][CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:18][C:16]=4[N:17]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Reactant: C1CCOC1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CCN3CCOCC3)ccc2[nH]1)NC1CC1
Reaction time: 8 h

Procedure:
A sample of crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea free base was dissolved in THF and then concentrated in vacuo to a minimum volume (˜4 volumes). To the solution was added water dropwise (2-4 volumes) until the solution became turbid. A small amount of THF was added to re-establish solution clarity and the mixture left to stand overnight to give a crystalline material which was air-dried to give 1-cyclopropyl-3-[3-(5-morpholin-4-ylethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea free base dihydrate.
Reaction SMILES: C[C:2](C)([O-:4])[CH3:3].[K+].CCC[CH2:10][CH2:11][CH3:12].C1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH2:15]([O:16][C:17]([O:4][CH2:2][CH3:3])=[C:11]([CH3:10])[CH3:12])[CH3:14]
Reactant: CCCCCC
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(OCC)=C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of preparation 41(b) (2.3 g, 0.02 mol) in THF (50 mL) was added potassium t-butoxide (2.3 g, 0.02 mol). The mixture was stirred at room temperature for 1 hour, then hexane (20 mL) was added. The mixture was filtered through celite, the filtrate was concentrated in vacuo, and the residue was distilled at 50 mmHg to afford 2.1 g of 1,1-diethoxy-2,2-dimethylethylene (Formula V: R3 =R4 =CH3 ; R5 =R6 =OC2H5).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-:3])=[O:2].C(O)(=[O:15])C>[O-2].[Cr+6].[O-2].[O-2]>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:15])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Agent: [Cr+6]
Agent: [O-2]
Product: O=C1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of chromium(VI) oxide (36.7 g, 367.7 mmol) in acetic acid (400 mL) was added slowly to a solution of 4-nitroindane (20 g, 122.6 mmol) in glacial acetic acid (500 mL). Extra acetic acid (200 mL) was used to transfer all the chromium(VI)oxide. The reaction was stirred vigorously at room temperature for about 5 hours and was then quenched with water (200 mL). Most of the acetic acid was removed under high vacuum and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using first hexane/ethyl acetate (20:1) as eluent to remove unreacted starting material and then hexane/ethyl acetate (10:1) to provide the desired product. MS (ESI): m/z 176 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccc(F)cc1F
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)cc2C1=O

Procedure:
The compound of example 9 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2,4-difluorophenyl isocyanate. The compound of example 9 was used directly without isolation for the preparation of compound of example 10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:24]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[OH:32])[CH2:25]1>>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][C:26]2([CH2:24][CH2:25]2)[C@H:27]([OH:32])[CH2:28]1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2ccccc2)CCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccccc2)CCC1=O

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-(7-oxo-4-phenyl-[1,4]diazepan-1-yl)-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 50% as light yellow foam. MS: 416.3 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4.[CH3:31][S:32][CH2:33]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:31][S:32][CH2:33][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[N:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14]4
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To Sodium hydride (763 mg of 60% dispersion in mineral oil, 19.1 mmol) in HMPA (15 mL) was added a solution of (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (6.00 g, 15.9 mmol) from Example 1 in HMPA (50 mL) at room temperature. The reaction mixture was stirred for 30 min and then chloromethyl methyl sulfide (1.60 mL, 19.1 mmol) was added dropwise. The reaction mixture was stirred vigorously at room temperature overnight. The product was extracted with EtOAc (500 mL). The EtOAc layer was washed with saturated NaHCO3 solution and dried over MgSO4, filtered and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (1.78 g, 26%) as a yellow gum.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([O:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:13]>>[CH2:12]([O:14][CH:15]([O:20][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9])[C:16]([F:19])([F:18])[F:17])[CH3:13]
Reactant: CCOC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CCOC(Oc1cc(F)ccc1N)C(F)(F)F

Procedure:
Was prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and 1-ethoxy-2,2,2-trifluoro-ethanol.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=O)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][C:17]1[C:18]([O:32][CH3:33])=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:21]1[CH:20]=[C:19]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([O:32][CH3:33])=[C:17]([NH:16][C:13]([C:10]2[S:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=3[CH:11]=2)=[O:15])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(O)c1cc2c([N+](=O)[O-])cccc2s1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1c(NC(=O)c2cc3c([N+](=O)[O-])cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.4 %

Procedure:
4-Nitro-benzo[b]thiophene-2-carboxylic acid (369 mg, 1.65 mmol) and N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (500 mg, 1.84 mmol) were dissolved in 25 mL DMF and stirred at room temperature. After about 10 min, EDC (317 mg, 1.65 mmol) and HOBt (224 mg, 1.65 mmol) were added and the brown solution was stirred at room temperature 12 h. After stirring 12 h, the reaction was partitioned between EtOAc (150 mL) and water (50 mL). The layers were separated and the organic portion was washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford a brown solid. Column chromatography on silica gel afforded 4-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a pale yellow solid (200 mg, 25%).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].[OH-].[Na+]>>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[NH:20][CH2:17][CH2:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNC(=O)N(c1ccccc1)c1ccccc1

Procedure:
By way of illustration, one mole of diphenylamine is reacted with a 10% molar excess of phosgene in a suitable solvent such as monochlorobenzene, to yield diphenylcarbamyl chloride. The carbamyl chloride thus produced is reacted further with n-propyl amine in stoichiometric amounts, in the presence of a mole of caustic soda. Diphenyl propyl urea (DPPU) is formed in essentially stoichiometric amounts. The DPPU formed may be either separated from the solvent or, if desired, supplied as a solution in its reaction solvent. DPPU pyrolyzes at 210°-220° C. to yield n-propyl isocyanate of 99% purity and greater than 90% yield. The diphenylamine remaining may be returned easily in tankcars or tankwagons for reprocessing.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[Si]([O:13][CH:14]1[CH2:23][C:22]([F:25])([F:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=2)[C:15]1=[O:27])(C(C)(C)C)(C)C.F>N1C=CC=CC=1>[F:25][C:22]1([F:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=2)[C:15]([CH:1]([CH3:5])[CH3:2])([OH:27])[CH:14]([OH:13])[CH2:23]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(F)(F)c2cc(F)ccc2C1=O
Reactant: C1CCOC1
Agent: F
Solvent: c1ccncc1
Product: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Temperature: 25 °C
Yield: 69 %

Procedure:
A THF solution (8 mL) of 2-((tert-butyldimethylsilyl)oxy)-4,4,6-trifluoro-3,4-dihydronaphthalen-1(2H)-one 54 (0.585 g, 1.77 mmol) was cooled to 0° C. and a solution of hydrogen fluoride in pyridine (70%, 200 μL) was added dropwise. The reaction was allowed to warm to ambient temperature over 12 h at which point the reaction was quenched with an aqueous solution of saturated sodium bicarbonate, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product as a colorless oil (0.263 g, 1.22 mmol, 69% yield). 1H NMR (400 MHz, CDCl3) δ: 8.14 (dd, J=8, 4 Hz, 1H), 7.48 (dt, J=8, 4 Hz, 1H), 7.36 (m, 1H), 4.67 (ddd, J=12, 8, 4 Hz, 1H), 3.66 (s, 1H), 3.17 (m, 1H), 2.54 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:15])([F:14])/[C:10](/Br)=[N:11]/[OH:12].[CH2:16]([OH:19])[C:17]#[CH:18]>C1(C)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[C:10]1[CH:18]=[C:17]([CH2:16][OH:19])[O:12][N:11]=1
Reactant: O/N=C(\Br)C(F)(F)F
Reactant: C#CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.3 %

Procedure:
A solution of triethylamine (5.35 ml, 38.6 mmol) in toluene (15 ml) was added dropwise over 10 minutes to a solution of (Z)-2,2,2-trifluoro-N-hydroxyacetimidoyl bromide (71) (5.35 g, 19.3 mmol) and prop-2-yn-1-ol (72) (3.25 g, 57.9 mmol, TCI_JP) in toluene (37.5 ml) and stirred for 10 hours at room temperature. The reaction was quenched with H2O (30 ml), extracted with ethyl acetate (50 ml), washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product of (3-(trifluoromethyl)isoxazol-5-yl)methanol (73) (1.88 g, yield 47%) as a brown oil.