Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])C.[OH-].[Li+]>>[C:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:7]1[CH2:8][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:23])[F:21])(=[O:12])=[O:13])[CH2:10][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 253e, 1-biphenyl-2-yl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid which was used in the next step without further purification. MS (ESI): m/z=476.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:16][CH2:17][OH:18]>CC(N(C)C)=O>[OH:18][CH2:17][CH2:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: OCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(C(=O)OCCO)cc1
Temperature: 105 °C
Reaction time: 16 h

Procedure:
17.5 g (0.106 mol) of 4-dimethylamino benzoic acid was dissolved in 80 mL of dimethyl acetamide and added drop wise over 30 minutes to a suspension of 5.32 g (0.133 mol) of sodium hydride (60% in mineral oil) in 50 mL dimethyl acetamide. It became difficult to stir the suspension and an additional 30 mL of dimethyl acetamide was added. 7.2 mL (8.64 g, 0.107 mol) of 2-chloro-ethanol was added and the reaction mixture was heated to 105° C. The reaction was allowed to continue 16 hours at 105° C. The mixture was allowed to cool down to room temperature and the formed sodium chloride was removed by filtration. The solvent was removed under reduced pressure and the residue was crystallized from 400 mL of methanol/water 1/7. The crude 2-hydroxyethyl-(4-dimethylamino benzoate) was isolated by filtration and recrystallized from 200 mL of methanol/water 1/3. 15 g of 2-hydroxyethyl-(4-dimethylamino benzoate) was isolated (m.p. 88-90°).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(C(O)=O)[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4].C1C=CC(P([N:27]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[ClH:37].O1CCOCC1>CC(O)(C)C>[ClH:37].[CH3:1][O:2][C:3]([C:5]1([NH2:27])[C:7]2([CH2:9][CH2:8]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC12CC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COC(=O)C1(N)CC12CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a mixture of spiro[2.2]pentane-1,1-dicarboxylic acid methyl ester (400 mg, 2.30 mmol) in 3 mL of anhydrous t-BuOH was added 700 mg (2.50 mmol) of DPPA and 278 mg (2.70 mmol) of Et3N. The mixture was heated at reflux for 21 h and then partitioned between H2O and ether. The ether phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an oil. To this oil was added 3 mL of a 4 M HCl/dioxane solution. This acidic solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was triturated with ether to give 82 mg (20%) of 1-amino-spiro[2.2]pentane-1-carboxylic acid methyl ester hydrochloride salt as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.19 (br s, 3 H), 3.81 (s, 3 H), 2.16, (d, J=5.5 Hz, 1 H), 2.01 (d, J=5.5 Hz, 1 H), 1.49 (m, 1 H), 1.24, (m, 1 H), 1.12 (m, 2 H). LRMS of free amine: MS m/z 142 (M++1). Section 2 of Example 12 The following P1′ intermediates were prepared as described: 1. Preparation of Cyclopropylsulfonamide (Alternate Route):
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[CH:22][C:21]2=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.38 g, 0.76 mmol) in methanol (7.66 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (22 mg, 0.11 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% methanol/dichloromethane gradient) afforded (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.30 g, 86%) as a white solid: HR-ES-MS m/z calculated for C23H30N4O6 [M+H]+ 459.2238, observed 459.2237. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.36-1.64 (m, 2H), 1.66-1.81 (m, 1H), 3.20-3.32 (m, 2H), 3.77 (s, 4H), 3.86 (dd, J=13.3, 7.5 Hz, 1H), 4.04-4.11 (m, 1H), 4.14 (d, J=18.1 Hz, 1H), 4.53 (d, J=18.1 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.75 (s, 1H), 4.87 (dd, J=10.6, 4.8 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 7.53 (d, J=2.1 Hz, 1H), 10.74 (s, 1H).
Reaction SMILES: C[Si](I)(C)C.C[O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)[N:18]=2)[N:9]=1>C(Cl)(Cl)Cl>[OH:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:19]2[N:18]=[C:17]([N:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:8](=[O:7])[NH:9]3)[CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1
Reactant: COc1nn(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc12
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: O=c1[nH]n(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc12
Reaction time: 72 h

Procedure:
Trimethylsilyliodide (0.80 mL, 5.6 mmol) was added under N2 to a suspension of trans-4-[4-(3-methoxyindazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (251 mg, 0.7 mmol) in chloroform (10 mL). The reaction mixture immediately became homogeneous, but within 1 hour a suspension formed, and the resulting mixture was stirred for 3 days. An additional aliquot of trimethylsilyliodide (2 mL, 14 mmol) was added, and the resulting mixture was heated to reflux overnight and stirred at RT for one day. The reaction mixture was then poured onto ice water and extracted with DCM. The insoluble solids were filtered and dissolved in a mixture of MeOH and DCM, the combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure onto silica gel. The residue was purified by flash chromatography (MeOH/DCM, gradient from 3:97 to 5:95) to give trans-1-[2-(4-hydroxycyclohexylamino)-pyrimidin-4-yl]-1,2-dihydroindazol-3-one (71 mg, 30% yield) as an off-white solid. MS=326 [M+H]+; MP=263.5-264.4° C.
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]([NH:16][NH2:17])=O)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>CN(C=O)C>[CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[N:27]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:17][N:16]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Reactant: COC1=NCCCCCC1
Solvent: CN(C)C=O
Product: CCCCCC12CCC(c3nnc4n3CCCCCC4)(CC1)CC2
Temperature: 130 °C

Procedure:
To 0.700 mL of the 0.3 M solution of 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide in DMF (crude, prepared as in step A above) was added 8-methoxy-2,3,4,5,6,7-hexahydroazocine (29.6 mg, 1 eq) and the reaction was heated to 130° C. overnight. After this time the solvent was removed under reduced pressure and the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TFA). The fractions containing the compound were determined by LCMS, added to 200 mL of methylene chloride, and extracted with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under diminished pressure. The residue was lyophilized from benzene to afford 3-(4-pentylbicyclo[2.2.2]oct-1-yl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (1-C); MS (ESI+)=300.3 (M+1)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:3]1=2>C(O)(C(F)(F)F)=O>[NH2:29][C:25]1([C:22]2[CH:23]=[CH:24][C:19]([C:10]3[C:11]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:20][CH:21]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3cccnc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3cccnc3)cc21
Reaction time: 0.01 h
Yield: 144.9 %

Procedure:
Tert-butyl (1-(4-(1-methyl-2-oxo-7-(pyridin-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.025 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (14 mg, 78% yield). LCMS (Method D) RT=0.546 min, M+1=387. 1H-NMR (500 MHz, CD3OD) δ 8.57-8.49 (1H, br s), 8.45-8.36 (1H, br s), 7.90 (1H, d), 7.67 (1H, s), 7.61-7.48 (2H, d), 7.48-7.36 (4H, m), 5.00 (2H, s), 3.45 (3H, s), 2.84-2.72 (2H, m), 2.65-2.54 (2H, m), 2.32-2.16 (1H, m), 2.06-1.90 (1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=2)=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([C@@](N)(CC1C=CC(C2C=CC=C(C=O)C=2)=CC=1)C(OC)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH3:30])[CH:23]=2)=[CH:20][CH:21]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(CNC)c2)cc1)NC(=O)OC(C)(C)C
Agent: COC(=O)[C@](N)(Cc1ccc(-c2cccc(C=O)c2)cc1)C(=O)OC(C)(C)C
Product: CNCc1cccc(-c2ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c1
Yield: 50 %

Procedure:
In a manner similar to the preparation of ethyl (S)-2-tert-butoxycarbonylamino-3-(3′-methylaminomethylbiphenyl-4-yl)propionate (Example 28d) using 10.2 g (26.6 mmol) of methyl (R)-2-tert-butoxycarbonyl-amino-3-(3′-formylbiphenyl-4-yl)propionate, 5.0 g of expected amine are isolated with a 50% yield.
Reaction SMILES: [Cl:1][C:2]([Cl:41])([Cl:40])[CH2:3][O:4][C:5]([C:7]1[N:12]2[C:13](=[O:24])[C@@H:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:11]2[S:10](=O)[CH:9]([NH2:26])[C:8]=1[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH3:39])=[CH:30][CH:29]=1)=[O:6].C1S(=O)(=O)CCC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(Cl)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:40][C:2]([Cl:1])([Cl:41])[CH2:3][O:4][C:5]([C:7]1[N:12]2[C:13](=[O:24])[C@@H:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:11]2[S:10][CH:9]([NH2:26])[C:8]=1[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH3:39])=[CH:30][CH:29]=1)=[O:6]
Reactant: COc1ccc(CC2=C(C(=O)OCC(Cl)(Cl)Cl)N3C(=O)[C@@H](C(=O)Cc4ccccc4)[C@H]3S(=O)C2N)c2ccccc12
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: COc1ccc(CC2=C(C(=O)OCC(Cl)(Cl)Cl)N3C(=O)[C@@H](C(=O)Cc4ccccc4)[C@H]3SC2N)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 0.317 g of 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester 1-oxide in 10 ml of a 9:1-mixture of tetramethylenesulphone and acetonitrile is treated with 0.250 g of sodium dithionite. The mixture is cooled to 0° and agitated in an ultrasonics bath, then treated with 0.275 g of acetic acid chloride. The mixture is allowed to react for 30 minutes and an equal amount of acetic acid chloride is again added. After a further 30 minutes, the reaction mixture is poured out onto a 5% aqueous sodium hydrogen carbonate solution. After extraction with diethyl ester, the combined organic extracts are washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 10 g of silica gel, elution being carried out with methylene chloride and fractions of 50 ml being taken. Fractions 3 and 4 yield the 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetyl-amino-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester, which after crystallisation from a mixture of ethyl acetate and diethyl ether melts at 164°-165°; thin-layer chromatogram (silica gel): Rf = 0.73 (system: toluene/ethyl acetate 1:1) and Rf = 0.59 (system: toluene/acetone 4:1); infrared absorption spectrum (in mineral oil): characteristic bands at 2,99μ, 5,63μ, 5,75μ, 5,99μ, 6,12μ, 6,29μ and 6,53μ.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:24](O)([CH3:26])[CH3:25])[CH:7]=[C:8]([CH2:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:12])[CH:9]=1)([CH3:3])=[CH2:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:11]([CH2:10][C:8]2[CH:9]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:5]=[C:6]([C:24]([CH3:26])=[CH2:25])[CH:7]=2)[CH3:12])=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C=C(C)c1cc(CN(C)Cc2ccc(C(C)(C)C)cc2)cc(C(C)(C)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)c1cc(CN(C)Cc2ccc(C(C)(C)C)cc2)cc(C(=C)C)c1
Temperature: 0 °C
Yield: 67.6 %

Procedure:
Compound 142 (0.28 g; 7.66×10−1 mmol) and phosphorus oxychloride (0.59 g; 3.83 mmol) was added dropwise to pyridine (15 ml), and the mixture was refluxed for 2 hours. The mixture was brought to room temperature, and poured into ice/water. The pH of the mixture was adjusted to weak alkaline by use of sodium carbonate, followed by extraction with chloroform (50 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 0.18 g of the target compound (yield: 67.6%).
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][O:7][C:8]1([O:28][CH3:29])[CH2:25][CH2:24][C:23]2[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=O)[CH2:16][CH2:15]4)[C@H:12]([CH3:27])[CH2:11][C:10]=2[CH2:9]1>C(O)COCCO>[CH3:29][O:28][C:8]1([O:7][CH3:6])[CH2:25][CH2:24][C:23]2[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[CH2:17][CH2:16][CH2:15]4)[C@H:12]([CH3:27])[CH2:11][C:10]=2[CH2:9]1
Reactant: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COC1(OC)CCC2=C(C[C@@H](C)[C@@H]3[C@@H]2CC[C@]2(C)CCC[C@@H]32)C1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
Potassium hydroxide (1.5 g, 27 mmol) and hydrazine monohydrate (3 ml, 62 mmol) were added to a suspension of (7α)-3,3-dimethoxy-7-methylestr-5(10)-en-17-one (1 g, 3 mmol) in 17 mL diethyleneglycol at room temperature under a nitrogen atmosphere. The reaction mixture was heated for 1 hour at 130° C. followed by 1 hour and 15 minutes at 230° C. A Dean-Stark trap was used to remove the water and the excess of hydrazine. The reaction mixture was cooled down to room temperature and water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated to dryness to give the crude product (7α)-3,3-dimethoxy-7-methylestr-5(10)-ene, which was converted into (7α,16α,17β)-7,16-dimethyl-3-methylene-17-(1-propynyl)estr-5(10)-en-17-ol according to the procedures described above, mp 57° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.OS(O)(=O)=O.[N+:16]([O-])([O-:18])=[O:17].[K+].[NH4+].[OH-]>>[F:1][C:2]1[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: COc1cc(F)c([N+](=O)[O-])cc1N
Yield: 77.4 %

Procedure:
4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to concentrated H2SO4 (15 mL) which was cooled in a ice/water bath, and where the temperature was kept below 15° C. during the addition. The mixture was stirred until all the solid that formed had dissolved. KNO3 (0.815 mL, 17.00 mmol) was added portionwise such that the temperature was maintained below 10° C. The mixture was stirred overnight and then poured onto ice/water. The mixture was basified with concentrated NH4OH. The resulting solid was filtered off and then dissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated onto silica. Purification by FCC, eluting with 50-0% heptane in CH2Cl2 gave the title compound (2.450 g, 77%) as a yellow crystalline solid; 1H NMR: 3.91 (3H, s), 5.21 (2H, s), 7.03 (1H, d), 7.35 (1H, d); m/z: ES+ MH+ 187.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Product: Fc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 43.2 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (92 mg, 43%). MS (ISP) 427.0 [(M+H)+]; mp 262° C.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]([C:17]([F:20])([F:19])[F:18])[O:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26]Cl>>[Cl:26][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:14][CH:13]([C:17]([F:19])([F:20])[F:18])[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]2
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(N3CCCCC3)cc2OC1C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(Cl)c(N3CCCCC3)cc2OC1C(F)(F)F

Procedure:
The ester of Example 143 Step 1 (0.38 g, 1.06 mmol) was treated with Cl2 following the method of Example 103 Step 3 to give ethyl 6-chloro-7-piperidin-1-yl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.16 g, 0.41 mmol). The product structure was consistent with 1H, 19F and 13C NMR analyses.
Reaction SMILES: CO[C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NCC1[NH:45][N:44]=[N:43][N:42]=1>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]1[NH:45][N:44]=[N:43][N:42]=1)=[O:37]
Reactant: NCc1nnn[nH]1
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Product: O=C(NCc1nnn[nH]1)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 58 %

Procedure:
The title compound was prepared in analogy to Example 38, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 5-(aminomethyl)-tetrazole (commercially available, CAS RN 31602-63-8) to provide 0.078 g (58%) of the title compound as a light yellow solid. MS (ESI): m/z=565.126 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2ccc(Cl)cc2Cl)cs1)c1cc(Cl)ccc1O
Yield: 8 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,4-dichlorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19]>CN(C=O)C>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:3]([C:2](=[O:1])[CH2:6][CH3:7])[C:4]#[N:5]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 3-oxopentanenitrile (500 mg, 5.2 mmol) in DMF (10 mL) was added NaH (248 mg, 6.2 mmol) and stirred at 0° C. for 1 h. Then 1-(bromomethyl)-2,3-dichlorobenzene (1.23 g, 5.2 mmol) was added to the mixture and warmed to room temperature, stirred for 20 h. The mixture was concentrated under reduced pressure to give the crude titled product (1.2 g, 92%), which was used for next step without further purification.