Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2ccc(F)cc2)nc1
Yield: 94.2 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 6-(4-fluorophenyl)nicotinate (390 mg) and aqueous sodium hydroxide solution (1N, 5.00 ml) and the reaction mixture was treated to afford the title compound (345 mg) as a pale yellow solid.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH2:37]([O:36][C:34]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:35])[CH3:38]
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added ethyl chloroformate (0.072 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=1011) and recrystalization (recrystalization solvent: ethyl acetate/hexane=1/3) afforded 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.084 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:17]([NH2:19])=[O:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (110 mg, 0.34 mmol) and ammonium acetate (270 mg, 3.4 mmol) in methanol (1.9 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled and sodium cyanoborohydride (43 mg, 0.69 mmol) was added. The reaction was heated at 65° C. for another 4 hours. The mixture was cooled, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (98 mg, 93%). LCMS calculated for C16H17ClFN2O (M+H)+: m/z=307.1. found: 306.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CCc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
The mixture of Example 86A (5.73 g, 36.5 mmol) and Dess-Martin periodinane (18.6 g, 43.8 mmol) in 200 mL of dichloromethane was stirred under N2 atmosphere for 4 hours at room temperature. Then saturated NaHCO3 (500 mL) and Na2S2O3 (100 mL) was added with stirring for another 30 minutes. The mixture was extracted with dichloromethane (3×300 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by distillation under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1.CC(=O)OCC>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Clc1ncnc2ccc(I)cc12
Agent: c1ccc2ncncc2c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Ic1ccc2ncnc(N3CCCc4ccccc43)c2c1
Yield: 81 %

Procedure:
1.30 g of 4-chloro-6-iodoquinazoline, 1.50 ml of 1,2,3,4-tetrahydroquinoline in 10 ml of dioxane are heated at 110° C. in a flask until the quinazoline has reacted completely (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with 5% citric acid. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 0-100% in 18 min.), giving 1.27 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline as yellowish solid (yield 81%, content 99%); MS-FAB (M+H+)=388.0; Rf (polar method): 2.89 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14](F)[C:11]([C:12]#[N:13])=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:22]([CH3:27])=[N:23][NH:24][C:25]=3[CH3:26])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:29][NH2:30]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[C:25]([CH3:26])=[N:24][NH:23][C:22]=3[CH3:27])[C:11]3[C:12]([NH2:13])=[N:29][NH:30][C:14]=3[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc(F)c1C#N
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(C)c1CCCNc1cc(-c2ccnc(N)n2)cc2[nH]nc(N)c12
Temperature: 90 °C
Yield: 32 %

Procedure:
To a solution of 4-(2-amino-4-pyrimidinyl)-2-{[3-(3,5-dimethyl-1H-pyrazol-4-yl)propyl]amino}-6-fluorobenzonitrile (22 mg, 0.037 mmol) in EtOH (2 mL) was added hydrazine monohydrate (1 mL). The resulting solution was stirred at 90° C. until the starting material was consumed as judged by LCMS (˜12 hours). The reaction mixture was concentrated, and the resulting yellow solid was dissolved in EtOH and precipitated with hexanes. The filtrate was decanted to afford the title compound (5 mg, 32%) as a light yellow solid. LC-MS (ES) m/z=378 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.91-1.98 (m, 2H), 2.16-2.23 (s, 6H), 2.59 (t, J=7.2 Hz, 2H), 3.24-3.31 (m, 2H), 6.60 (s, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.23 (s, 1H), 8.27 (d, J=5.30 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][C:20]([C:22]1[S:30][C:29]2[C:24](=[N:25][CH:26]=[CH:27][C:28]=2Cl)[CH:23]=1)=[O:21]>>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH:19][C:20]([C:22]1[S:30][C:29]2[C:24](=[N:25][CH:26]=[CH:27][C:28]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:23]=1)=[O:21]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCc1ccccn1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCc5ccccn5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide by a procedure analogous to Example 1C. MS: 414 (MH+); HPLC Rf: 4.34 min.; HPLC purity: 97%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH2:35]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(C(F)(F)F)c(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 5-fluoro-2-trifluoromethylbenzyl bromide as in the procedure of Example 43. MS (ESI) m/z 556.
Reaction SMILES: [OH:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:9]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CCOCC.[ClH:38]>ClCCl>[ClH:38].[OH:1][C@H:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:16])=[CH:18][CH:19]=1
Reactant: COCCN
Reactant: COC(=O)COc1ccc(OCCNCC(O)COc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COCCNC(=O)COc1ccc(OCCNC[C@H](O)COc2ccccc2)cc1

Procedure:
(-)-Methyl 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0 g) (the same starting material as in Example 2) and 2-methoxyethylamine (30 ml) were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane (200 ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride (39.2 g), m.p. 171°-3° C.; αD =-10.7° (c=1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, 7.9%; required for C22H31ClN2O6 : C, 58.1; H, 6.9; N, 6.2; Cl 7.8%: NMR (DMSO-d6) 3.1(m,1H, CHCH2NH); 3.24(s, 3H,OCH3); 3.24-3.45(m,7H,CHCH2NHCH2 ; NHCH2CH2OCH3); 4.0(m,2H, ArOCH2CHOH); 4.2-4.35(m,3H,CHOH; CH2CH2OAr); 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,1H, CONHCH2); 9.16 and 9.35 (broad peaks, 2H, NH2+).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([O:18]CC3C=CC=CC=3)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
In methanol was suspended 151 g (452 mmol) of phenyl-methyl 1-[N-(morpholine-4-carbonyl)amino]cyclohexane-carboxylate, 15 g of 5% palladium-active carbon was added to the suspension and the mixture was stirred under hydrogen stream at room temperature overnight. After removing the catalyst by filtration, the catalyst was washed three times with a mixed solvent of chloroform-methanol, and the organic layers were combined and the solvent was distilled off under reduced pressure to obtain 112 g (Yield: 100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>C(O)(=O)C>[F:25][C:24]([F:26])([F:27])[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:6]3[CH:5]=[N:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]3[N:1]=[CH:14][CH:15]=2)[CH:19]=1
Reactant: CCOC(=O)c1nc[nH]c1N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 1.55 g. of ethyl 5-aminoimidazole-4-carboxylate and 2.43 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid is refluxed for 6 hours. On cooling the product crystallized from solution, m.p. 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.C(O)C.Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1O)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1O)C2

Procedure:
To 7-(5-chloro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one were added aminoguanidine hydrochloride (0.53 g), ethanol (30 ml), concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-hydroxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 167) (1.1 g) as colorless crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[C@H:20]([C@H:21]([OH:33])[C@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CC[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@H](Cc1cc(F)cc(F)c1)[C@@H](O)[C@@H]1CO[C@@H](CCC(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add acetic anhydride (25 μL, 0.264 mmol) to a solution of 5-(R)-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (107 mg, 0.240 mmol) and triethylamine (37 μL, 0.267 mmol) in tetrahydrofuran (5 mL) and stir at room temperature for 18 hours. Concentrate and purify (silica gel chromatography, eluting with 80:20 ethyl acetate:dichloromethane), to separate the two title compounds 5-(R)-[2-(S)-acetylamino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (0.141 g, 59%) and 5-(S)-[2-(R)-acetylamino-3-(3,5-difluorophenyl)-1-(R)-hydroxypropyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester (25.1 mg, 22%).
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH:37]=[CH:36][C:35]=2[CH:34]=1.O>O1CCCC1>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH:36]=[CH:37]3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A solution of 715 mg of difluoromethyldiphenylphosphine oxide in 36 ml of tetrahydrofuran is slowly mixed with 1.42 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraen-17-one in 10 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is added to water, extracted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraene is obtained as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11](C#N)=[C:10](N2CCN(C(C3SC=CC=3)=O)CC2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+]>CN(C=O)C>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Compound 116 (364 mg, 1 mmol) in DMF was added to a stirred suspension of NaH (60% in mineral oil, 44 mg, 1.1 mmol) in DMF at room temperature under argon atmosphere. The solution was stirred at room temperature for 1 h and the corresponding alkyl halide was added via syringe. The solution was further stirred at room temperature for 3 to 48 h (TLC control). The reaction was worked up as described in General Procedure C.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]#[CH:26]>>[O:27]([CH2:24][C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CCOc1ccccc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(COc3ccccc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and phenyl prop-2-yn-1-yl ether. MS (+ESI) m/z: 403.2.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)([F:4])[CH3:3].Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][CH:10]([CH:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(C)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (1.91 g, 14.0 mmol) in diethyl ether (50 ml), sodium borohydride (1.06 g, 28.1 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (2.556 g, 7.015 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was for 2 hrs. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 19.7 %

Procedure:
At 0° C., a solution of N-methyl-2-(2-nitrophenyl)acetamide (7.00 g, 36.05 mmol) in tetrahydrofuran (410 ml) was added dropwise to a suspension of sodium borohydride (1.63 g, 43.25 mmol) in tetrahydrofuran (110 ml). A solution of iodine (4.57 g, 18.02 mmol) in tetrahydrofuran (150 ml) was added dropwise. The reaction mixture was warmed to reflux for 16 h. It was cooled to 0° C. Methanol (310 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in 20% aqueous sodium hydoxide solution (300 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (160 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.28 g of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: Cc1cc(Cl)ccc1C(CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(Cl)cc1C

Procedure:
In analogy to example 74, step 4, from 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-propanoic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a colorless oil, MS (ESI+): m/z=398.03 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(COCc2ccc(F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.062 g) as a light yellow gum (0.087 g). MS (ESI−): 419.0. ([M−H]−)