Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[N:19]1([CH2:25][CH2:26][C@@H:27]([NH2:36])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[N:19]1([CH2:25][CH2:26][C@@H:27]([NH:36][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:28][S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: N[C@H](CCN1CCOCC1)CSc1ccccc1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine and triethylamine at about 40° C. to about 50° C. to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide and isolating or not isolating the 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide; and
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29](OCC)=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.O>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: OCCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 65 °C

Procedure:
To a solution of ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate (90 mg, 0.2 mmol) in EtOH (3 mL) was added NaBH4 (76 mg, 2 mmol). The resulting mixture was heated at 65° C. for 2 h and then poured into CH2Cl2/H2O (50 mL/50 mL). The aqueous layer was extracted with CH2Cl2 (50 ml). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by silica gel column using EtOAc to 2% MeOH/EtOAc as the eluent to yield 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)ethanol.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([OH:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([OH:18])[N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)=[O:33]>O>[CH2:1]([C:5]1[N:10]([CH2:38][C:37]2[CH:36]=[CH:35][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:41][CH:40]=2)[C:9](=[O:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([OH:18])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(O)c(CC(=O)OCC)c(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(O)c(CC(=O)OCC)c(=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.8 %

Procedure:
100 mg of the product of Step D of Example 1 were introduced into 4 ml of dimethylformamide, 108 mg of potassium carbonate and 106 mg of [4-(methoxycarbonyl)-benzyl]-bromide. The mixture was stirred at ambient temperature for 6 hours, followed by pouring into water, extracting 3 times with ethyl acetate, washing with a saturated solution of sodium chloride and evaporating to dryness under reduced pressure. After chromatography on silica (eluant: methylene chloride-ethyl acetate: 6-4), 55 mg of the expected product melting at 170° C. were obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(Cl)Cl.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>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: OB(O)c1cccnc1F
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
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: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2nccnc2-c2cccnc2F)cc1)c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
To a microwave safe 30 ml tubes were charged with (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (0.500 g, 1.43 mmol), 2-fluoropyridin-3-ylboronic acid (0.241 g, 1.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.165 g, 0.143 mmol) and a 2M solution of sodium carbonate monohydrate (2.14 mL, 4.28 mmol) in 1,4-dioxane. The flasks were sealed and heated to 150° C. for 45 min in a microwave. The reaction mixture was diluted with DCM (75 mL), washed with water and brine. It was dried over magnesium sulfate, concentrated and dried in vacuo. It was suspended in DCM/MeOH and stirred. The insoluble material was collected by filtration, recrystallized overnight from boiling MeOH and hexane, then dried in a vacuum oven to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone as yellow solid. LC/MS: MS (ESI, pos. ion) m/z: 412.1 (M+1).
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[C:25]([CH3:36])=[C:26]([CH:28]([OH:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[O:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:36][C:25]1[C:24]2[C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:7][CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:20][CH:21]=[CH:22][C:23]=2[O:27][C:26]=1[C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:35]
Reactant: Cc1c(C(O)c2ccccn2)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)c2ccccn2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of {3-[2-(hydroxy-pyridin-2-yl-methyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-carbamic acid tert-butyl ester (30 mg) in chloroform (2 ml) was added manganese(IV) oxide (45 mg) at room temperature and the mixture was stirred vigorously overnight. The mixture was filtered through a pad of Celite and concentrated in vacuo. The titled compound (24 mg) was obtained as a pale yellow oil after the purification with silica gel TLC developed by the mixture of dichlormethane and methanol. FAB-MS: m/z 502 (MH+); 1H-NMR (CDCl3): δ 1.45 (9H, s), 2.10-2.15 (2H, m), 2.91 (3H, s), 3.40-3.50 (2H, m), 4.09 (2H, t, J=5.9 Hz), 4.48 (2H, broad s), 6.58 (1H, d, J=8.3 Hz), 7.10 (1H, d, J=8.3 Hz), 7.24 (1H, dd, J=5.3 Hz, 7.6 Hz), 7.34 (1H, t, J=8.3 Hz), 7.47-7.55 (2H, m), 7.87-7.98 (2H, m), 8.50-8.53 (2H, m), 8.77-8.80 (1H, m).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:13]1[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]1[O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Sn](Cl)(Cl)Cl>C(#N)C>[C:16]([O:15][C@@H:14]1[C@H:24]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:34]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:35][C@H:13]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 83.1 %

Procedure:
0.56 g. (5 mmol) of uracil, 2.52 g. (5 mmol) of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were agitated in 75 ml. of absolute acetonitrile with 0.65 g. (4 mmol) of HMDS, 0.43 g. (4 mmol) of TCS, and 1.56 g. (6 mmol) of SnCl4 for 2 hours at 24° C. The mixture was worked up as set forth in Example 1, yielding 83.1% of crystalline uridine tribenzoate.
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH:7]([CH3:16])[CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:16])[N:6]=1
Reactant: CC(NC(=O)c1ccccc1I)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of amide 3a, 9.5 g, 24.9 mmol) and P2O5 (44 g) in o-dichlorobenzene (150 mL) was refluxed for overnight. After it was cooled to room temperature, it was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 300 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×50 mL). The aqueous layer was cooled to 0° C. and made to pH>11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.68 g, 80%). mp 111-112° C. 1H NMR (CDCl3) d 2.67 (s, 3 H, CH3), 7.00-7.05 (m, 1 H, aromatic), 7.26-7.52 (m, 6 H, aromatic), 7.65 (d, J=8.1 Hz, 1 H, aromatic), 7.88 (d, J=8.1 Hz, 1 H, aromatic). 13C NMR (CDCl3) d 24.05 (q, CH3), 97.82 (s, =CI--, aromatic), 118.26 (d, aromatic), 124.45 (s, aromatic), 125.98 (d, aromatic), 126.77 (d, aromatic), 127.70 (d, aromatic), 129.43 (d, aromatic), 129.79 (d, aromatic), 129.92 (d, aromatic), 136.73 (s, aromatic), 138.78 (d, aromatic), 143.74 (s, aromatic), 150.24 (s, aromatic), 161.34 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.77; H, 3.51; N, 3.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[Br:18][C:19]1[N:24]=[C:23]([CH:25]=[O:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[Br:18][C:19]1[N:24]=[C:23]([CH:25]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[OH:26])[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2cc(-c3ccccc3)[nH]c2c1
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(C(O)c3cccc(Br)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 87.4 %

Procedure:
To a suspension of 6-methoxy-2-phenyl-1H-indole (893 mg) and 6-bromopyridine-2-carboaldehyde (744 mg) in dichloromethane (13.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.060 mL), and the mixture was stirred at room temperature for 13 hours under an argon atmosphere. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.43 g). 1H-NMR (CDCl3) δ ppm: 3.81 (3H, s), 4.71 (1H, d, J=2.6 Hz), 6.09 (1H, d, J=2.6 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz), 6.86 (1H, d, J=2.3 Hz), 7.02-7.13 (2H, m), 7.33-7.54 (5H, m), 7.64-7.72 (2H, m), 8.10 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[C:7](=[O:10])[CH2:8][CH3:9].O1CCCC1.[BH4-].[Li+]>Cl>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[O:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9]
Reactant: CCC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-one (0.68 g, 2.4 mmol) and tetrahydrofuran (5 mL) are stirred at 0° C. Lithium borohydride (0.14 g, 6.36 mmol) is added and the mixture is stirred 10 min at 0° C., and 30 min at room temperature. The mixture is diluted with 1M aqueous hydrochloric acid and washed with ethyl acetate (three 50 mL portions). The organic ishes are dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified over silica eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes ethyl acetate to afford 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol as ivory solid, 0.69 g, 100%. MS (M++1) 286.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:43][CH3:44])=[C:4]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:30][CH2:29]2)=[O:17])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].[OH-].[Na+]>ClCCl.CO>[CH3:52][S:53]([NH:1][C:2]1[C:3]([O:43][CH3:44])=[C:4]([NH:15][C:16]([C:18]2[N:19]([CH3:42])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH3:41])=[O:35])[CH2:32][CH2:33]2)=[O:17])[CH:5]=[C:6]([C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[CH:7]=1)(=[O:55])=[O:54]
Reactant: COc1c(N)cc(C(F)(F)C(F)(F)F)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)[C@@H]5CCCN5C)CC4)c3n2C)cc(C(F)(F)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
70 mg (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(3-amino-2-methoxy-5-pentafluoroethyl-phenyl)-amide are dissolved in 2 ml dichloromethane, combined with 36 μl triethylamine, and 20 μl methanesulphonic acid chloride are added dropwise to this mixture. It is stirred for 2 hours, a further 20 μl methanesulphonic acid chloride and 36 μl triethylamine are added and then it is stirred for 1.5 hours. Then 2 ml of methanol and 600 μl of 2 N sodium hydroxide solution are added. The mixture is stirred for 2 hours, the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/(methanol/ammonia in methanol (saturated) 9:1) 99:1 to 85:15).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH2:25])[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][CH2:23][CH2:24][NH:25][C:27](=[O:28])[O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[O:18][CH2:17]2)=[CH:11][CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCC[C@H]1OC[C@H](c2cccc3cc(OCC4CC4)ccc32)CO1)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.205 g (0.60 mmol) of trans-3-[5-(6-cyclopropylmethoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propylamine is added, in small portions and at ambient temperature, to a solution of 0.110 ml (0.78 mmol) of 4-chlorophenyl chloroformate and 0.205 ml (1.2 mmol) of N,N-diisopropylethylamine in 6 ml of dichloromethane. The mixture is stirred at ambient temperature for 16 hours, then washing is carried out with 5 ml of a saturated sodium bicarbonate solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.176 g of a white solid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:16].Cl>O.C(=S)=S>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[C:6]([C:15](=[O:16])[CH3:14])[CH:7]=1
Reactant: CSc1ccc(F)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CSc1ccc(F)cc1C(C)=O
Yield: 58 %

Procedure:
A mixture of 4-fluorothioanisole (19c) (4 g, 28.13 mmol), anhydrous aluminium chloride (8.40 g, 63.02 mmol) and carbon disulphide (89 ml) was heated at reflux under argon atmosphere, and acetic arhydride (2.65 ml, 28.07 mmol) was added dropwise in 2 h. After refluxing for 24h, the solution was poured into crushed ice, water (62.48 ml) and concentrated hydrochloric acid (2.68 ml). The organic phase was separated and water extracted with dichloromethane (3×30 ml), the organic layers were washed with brine, dried and concentrated. The oily residue was chromatographed (50% petroleum ether 40-60° in dichloromethane) to afford 20c (2.98 g) as a colourless crystalline solid, mp 82.0-84.3° C. (58% yield). 1H NMR (CDCl3) δ7.49-7.43 (dd, 1H, J=9.23, 2.44 Hz); 7.29-7.11 (m, 2H); 2.57 (s, 3H); 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17]Br)[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24]>>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][P:21]([O:22][CH2:23][CH3:24])([CH3:20])=[O:25])[C:14](=[O:19])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(C)OCC
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCBr
Product: CCOP(C)(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 120 °C
Yield: 81.1 %

Procedure:
5.30 g (16.1 mmol) of (4S)-3-benzyloxycarbonyl-4-(2-bromomethyl)-1,3-oxazolidin-5-one (from Example 5) are mixed with 4.40 g (32.3 mmol) of diethyl methanephosphonite and the mixture is heated under argon for 6 hours at 120° C. The excess diethyl methanephosphonite is distilled off in high vacuum and the residue is purified by chromatography on silica gel (mobile phase: dichloromethane/acetonitrile). 4.64 g (81.1% of theory) of (4S)-3-benzyloxycarbonyl-4-{2-[ethoxy(methyl)phosphinyl]ethyl}-1,3-oxazolidin-5-one are obtained as a colorless oil. Analytical data:
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+].FC(F)(F)C(O)=O.N>ClCCl.O>[N:21]([C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3])=[N+:22]=[N-:23]
Reactant: CC(C)(O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(N=[N+]=[N-])c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (135 mg, 0.50 mmol) and sodium azide (71.5 mg, 1.1 mmol) in dichloromethane (1 ml) is added a solution of trifluoroacetic acid (316 μl, 4.1 mmol) in dichloromethane (0.6 ml) dropwise under external cooling with ice. The reaction mixture is stirred for 3 days at room temperature. Water (5 ml) and 25% aqueous ammonia (0.5 ml) are added. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to afford 2-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white solid; HPLC/MS 1.98 min (C), [M+H] 295.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([O:22]C)=[CH:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.Cl.[OH-].[NH4+].C>CO.ClCCl>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([CH2:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1)=[O:22]
Reactant: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Yield: 84.9 %

Procedure:
In this Example, 8,14-dihydro-thebaine (6.00 g, 19.14 mmol) was mixed with 24 ml of approx. 6 N Hydrochloric acid (144 mmol, prepared by mixing concentrated hydrochloric acid (12 ml) with DI water (12 ml)) at room temperature with stirring. The homogeneous light yellow colored solution was stirred for 4 hours. Thin Layer chromatography on silica gel plates 90:10:1 (dichloromethane:methanol: concentrated ammonium hydroxide) indicated that the reaction was complete. Decolorizing charcoal (Darco, 0.3 g) was added to the mixture and the reaction stirred for 20 minutes and then filtered. The charcoal was washed with DI water (2×5 ml). The combined acidic phases were cooled to <5° C. and the pH was adjusted to 9.64 with concentrated (28.0-30.0%) ammonium hydroxide solution (approx. 20 ml). The solid was filtered and washed with 2×10 ml of DI water. The product was dried at 60° C. under 22″ Hg vacuum until constant weight to give hydrocodone as a white amorphous said (4.87 g, 84.9% yield, 96.2 wt % by assay).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.[OH-].[Na+].[NH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=2)=[O:11])[CH:2]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1cccnc1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[O:13][C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[O:5][CH2:4]1>CC(C)=O>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[O:13][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: OC1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
3.6 g (95 mmol) of NaBH4 are added to a solution of 50 g (25 mmol) of 1,4-cyclohexanedione monoethylene ketal and the mixture is stirred until the reaction is complete. For working up, 30 ml of acetone are added and stirring is continued for 30 minutes. The mixture is subsequently evaporated to dryness and the residue is taken up in 200 ml of ether, the organic phase is washed with aqueous NH4Cl solution and water, and the organic phase is dried over MgSO4. The solvent is subsequently evaporated on a rotary evaporator and the residue is dried.