Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15]C)[CH:5]=[CH:4][N:3]=1.Cl.[NH:18]1[CH2:21]C[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C)C(=O)C.[Cl-].[NH4+]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:18]([CH3:21])[CH3:19])[CH:7]=2)[CH:13]=1
Reactant: C1CNC1
Reactant: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc(-c2cc(Cl)ccc2O)ccn1
Temperature: 170 °C
Yield: 32.5 %

Procedure:
A mixture of 2-chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 866, 157 mg, 0.618 mmol), azetidine hydrochloride (120 mg, 1.2 mmol), and N,N-diisopropylethylamine (220 uL, 1.2 mmol) in N,N-dimethylacetamide (4.1 mL, 44 mmol) was heated 20 minutes at 170° C. under microwave irradiation. The reaction mixture was poured into water and saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The combined organic layers were washed with water then brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (12 g SiO2, hexanes to 9:1 ethyl acetate-methanol). A single peak containing the major products eluted from the column. The appropriate fractions were concentrated in vacuo. The residue was dissolved in 1 mL of dimethylsulfoxide, filtered through a plug of cotton, and purified by reverse-phase HPLC to afford 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol as a tan solid (50 mg, 33%) followed by 4-chloro-2-(2-chloropyridin-4-yl)phenol as a light pink solid (24 mg, 16%). Unexpectedly 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol was isolated as the main product and none of the intended product was isolated. This presumably occurred due to decomposition of the dimethylacetamide to provide dimethylamine which reacted preferentially to give 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol:
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1>CCO.C(O)(=O)C.[Fe]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)c(C)nc1OC(F)F
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 89.8 %

Procedure:
Alternate route. To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (1.00 g, 4.58 mmol) in EtOH (40 mL) and acetic acid (4 mL) was added iron powder (1.26 g, 22.9 mmol). The reaction mixture was heated at a vigorous reflux with the aid of a heating mantle in a flask without a stir bar. After 1.75 h, the reaction mixture was cooled to room temperature and the iron powder was removed by filtration through a pad of Celite. The filtrate was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous NaHCO3 (50 ml). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC on silica gel (20%→50% ethyl acetate in hexanes) to afford 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (774 mg, 90% yield) as a pale yellow solid identical to that prepared by Method A: mp 38.4-39.4° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=74.5 Hz, 1H), 6.82 (s, 1H), 2.26 (s, 3H), 2.14 (s, 3H); 13C NMR 100 MHz, CDCl3) δ 149.6, 137.4, 137.1, 127.4, 119.0, 115.0 (J=251.3 Hz), 19.3, 14.8; LRMS (ESI) m/e 189.0 [(M+H)+, calcd for C8H11N2OF2 189.1.]
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58]>O1CCCC1>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:58][CH2:57][CH2:56][CH:55]([CH3:59])[CH3:54])=[O:10]
Reactant: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCNC(=O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.24 g, 0.73 mmol) in dry tetrahydrofuran (10 ml) are added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.30 g, 0.80 mmol) and triethylamine (0.38 ml, 2.2 mmol) at RT. The reaction mixture is stirred for 5 min at RT followed by the addition of 3-methyl-butyl-amine (0.1 ml, 0.88 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with saturated sodium hydrogen carbonate solution (20 ml) before extraction with EtOAc (3×30 ml). The organic layer is washed with saturated ammonium chloride solution (30 ml), water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to get the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-(3-methyl-butyl)-benzamide (example 1) (0.16 g, 0.41 mmol, 56%). [M+H]+ 396.1.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[CH2:5][CH2:4]1)#[N:2].I[C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[N:39]([C:46]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:40]=[C:41]([C:42]([F:45])([F:44])[F:43])[C:34]=12.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:9]=[C:10]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]4[N:39]([C:46]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[N:40]=[C:41]([C:42]([F:44])([F:45])[F:43])[C:34]=34)[CH:11]=2)[CH2:4][CH2:5]1)#[N:2]
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Reactant: CC(C)(C)OC(=O)NCCCc1cc(B2OC(C)(C)C(C)(C)O2)cc(C2(C#N)CC2)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCc1cc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc(C2(C#N)CC2)c1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
tert-Butyl N-[3-[3-(1-cyanocyclopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate (50 mg, 0.1173 mmol) was dissolved in dioxane (2 mL) and 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazolo[5,4-b]pyridine (65.14 mg, 0.1173 mmol) was added followed by sodium carbonate (176.0 μL of 2 M, 0.3519 mmol). The reaction mixture was degassed and filled with nitrogen 5 times then Pd[P(tBu)3]2 (8.994 mg, 0.01760 mmol) was added and the reaction heated at 60° C. overnight. After cooling, water was added and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, the combined organics were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 12 g) eluting with 2.5-50% EtOAc:Petrol ether to give tert-butyl 3-(3-(1-cyanocyclopropyl)-5-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)propylcarbamate as a viscous oil (72 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2.N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 167-168° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=8.0, 0.7 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.2, 148.5, 143.3, 141.5, 137.5, 130.5, 129.8, 127.8, 127.7, 127.3, 126.5, 123.6, 116.5, 108.3, 102.4, 101.4, 92.9, 77.0, 57.8, 38.7; MS (ES+) m/z 446.2 (M+1), 448.2 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:27])[NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=1)[CH2:9][C@H:10]([O:12][CH2:13][CH3:14])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[Cl:36]CCl>>[ClH:36].[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][N:19]1[CH:20]=[CH:21][C:17]([NH:16][C:15](=[O:27])[C@@H:8]([NH2:7])[CH2:9][C@H:10]([O:12][CH2:13][CH3:14])[CH3:11])=[N:18]1
Reactant: CCO[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@H](C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(1S,3R)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butyl}-carbamic acid t-butyl ester (306 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 30 min. Solvents were evaporated and the residue was dried in vacuo. The resulting waxy material was dissolved in methanolic hydrogen chloride solution (5 mL). Solvents were evaporated and the residue was dried in vacuo. The white solid was triturated with dry diethyl ether and filtered to afford (2S,4R)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (274 mg). For the neutral free amine, LR-ES-MS m/z calculated for C14H26N4O3 [M]+298, observed [M+H]+ 299.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33](O)=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:15])[CH2:10][CH2:9]3.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:15])[CH2:10][CH2:9]3
Reactant: CCS(N)(=O)=O
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 48.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)-7-(3-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.070 g, 0.140 mmol) obtained in step 4 and ethanesulfonamide (0.076 g, 0.699 mmol), the title compound (0.040 g, 48%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C:14]([OH:16])=O.[Cl:17]C(Cl)OCC>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C:14]([Cl:17])=[O:16]
Reactant: CCOC(Cl)Cl
Reactant: O=C(O)CN1C(=O)Cc2ccccc2C1=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)CN1C(=O)Cc2ccccc2C1=O
Yield: 100.3 %

Procedure:
To a solution of 2-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid (150 mg, 0.684 mmol) in CHCl3 (3 ml), (dichloromethoxy)ethane (1 ml, 0.684 mmol) was added, and the mixture refluxed for 3 hours. The solvent was evaporated under reduced pressure, the crude taken up with CHCl3, and the solvent evaporated again to give the title compound (163 mg, quantitative yield).
Reaction SMILES: FC1(F)O[C:5]2[CH:7]=[CH:8][C:9]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:10][C:4]=2O1.BrC1C=CC([S:28][C:29]([F:32])([F:31])[F:30])=CC=1>>[CH3:17][C:14]1([CH3:16])[C:13]([CH3:18])([CH3:19])[O:12][B:11]([C:9]2[CH:10]=[CH:4][C:5]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:7][CH:8]=2)[O:15]1
Reactant: FC(F)(F)Sc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)OC(F)(F)O3)OC1(C)C
Product: CC1(C)OB(c2ccc(SC(F)(F)F)cc2)OC1(C)C

Procedure:
The title compound was prepared using methods analogous to those described for Intermediate 2 substituting 1-bromo-4-trifluoromethylsulfanyl-benzene as a starting material.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:10][N:11]([CH2:13]N(C)C)[CH3:12]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CN(C)C
Reactant: CCCCc1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCc1nccn1CN(C)C
Yield: 103 %

Procedure:
12.4 g of butylimidazole and 20.4 g of bis-(dimethylamino)methane were refluxed in 100 ml of tetrahydrofuran for 24 hours. The solvent was evaporated to give 18.64 g of product. The yield was quantitative. Other data concerning the product was:
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: CC(=O)O
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)propanamide (74 mg, 0.222 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (63 mg). MS 352.3 (M+H); UV 206.6, 223.0, 245.6, 295.3, 351.1 nm; t 0.360 min.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.C([O:8][C:9](=O)[C:10](Br)=[C:11](Br)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.Cl>CO.O1CCOCC1.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[O:1][N:4]=[C:9]([OH:8])[CH:10]=2)=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Oc1cc(-c2ccc(Cl)cc2)on1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
Sodium hydroxide (151 g) was dissolved in methanol (600 ml), and an aqueous hydroxylamine hydrochloride (45 g) solution (50 ml) was added dropwise thereto under stirring at 0° C., and then a solution of α,β-dibromo-4-chlorocinnamic acid ethyl ester (200 g) in dioxane (200 ml) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 4 hours and further refluxed for 5 hours. The reaction mixture was cooled to 5° C., and the pH of the mixture was adjusted to a value of 2 with conc. hydrochloric acid. Then, the reaction mixture was added to water (5 L). Precipitate was separated from the mixture by filtration and washed with water (2 L) and then with ethanol (1 L) to obtain 90 g of the title compound (85%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCN(CC)CC>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:29]2[CH2:30][CH2:31][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccsc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115 %

Procedure:
To a solution of 0.13 g (0.48 mmol) of 1-benzyl-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine and 0.13 g (0.67 mmol) of 4-phenylpiperidine in 2 mL of dichloroethane and 0.1 mL of Et3N at rt was added 0.21 g (0.96 mmol) of sodium triacetoxyborohydride. After stirring for 3 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.23 g of the title compound. 1H NMR CDCl3) δ7.21-7.44 (m, 11H), 7.07-7.13 (m, 2H), 3.74 (d, 1H, J=12.8 Hz), 3.67 (d, 1H, J=13.1 Hz). Mass Spectrum (CI) m/e=417 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][C@@H:10]([CH3:24])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(Cl)(Cl)(Cl)Cl.[O-2].[Ca+2].[I:32]I>CO.[Cl-].[Ca+2].[Cl-].C1COCC1>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][C@@H:10]([CH3:24])[C@@H:11]2[C:12](=[O:14])[CH2:13][I:32])[CH2:3]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: II
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI

Procedure:
A mixture of 3α-hydroxy-16α-methyl-5α-pregnan-20-one (21 g) methanol (80 ml), carbon tetrachloride (40 ml), THF (120 ml), calcium oxide (25 g) and calcium chloride in methanol (10%, 3 ml) is stirred at 25°-30°. A solution of iodine (20 g) in calcium chloride (10%, 70 ml) is added to the steroid mixture over 1 hr. The mixture is stirred an additional 2 hr at 30°, filtered through a pad of filter aid, and the filtrate concentrated under reduced pressure to an oil. The oil is dissolved in methylene chloride and flash chromatographed over silica gel (100 g) eluting with methylene chloride/ethyl acetate (4/1). The appropriate fractions are pooled, concentrated and the residue triturated with ether to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]I)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCNC2
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Product: Nc1sc2c(c1C(=O)c1ccc(Cl)cc1)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Yield: 72 %

Procedure:
The same procedure as Example 17 was used except an equivalent amount of 2-amino-3-(4-chloro-benzoyl) 4,5,6,7-tetrahydrothieno[2,3-c]pyridine was used in place of 2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2 mmol), and an equivalent amount of p-nitrophenylethyl iodide was used in place of methyl iodide (3 mmol). (m.p. 150-152° C.; 72% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:13]1([C:16](=[O:23])[CH2:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:15][CH2:14]1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[C:17]([C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:23])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Product: O=C(C(=Cc1cccc(C(F)(F)F)c1)C(=O)C1CC1)C1CC1

Procedure:
The procedure described in Example 19 was repeated by using 2.15 ml 3-trifluoromethylbenzaldehyde and 2.42 g 1,3-dicyclopropyl-1,3-propanedione. Yield 2.71 g, mp 56°-58° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:29][CH3:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)c(F)c1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)c(F)c3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
1-(5-Amino-2,3,4-trifluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) and a 40% methylamine solution (88 mg) were added to pyridine (1 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue. Solids were collected by filtration and washed with diethyl ether to obtain the title compound (55 mg) as a yellow powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (2.53 g, 6.92 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.277 g, 6.92 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.424 mL, 6.92 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.516 g, 65.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.14 (m, 4H), 2.55-2.65 (m, 1H), 2.72-2.81 (m, 1H), 2.93-3.03 (m, 1H), 3.08-3.19 (m, 1H), 3.61 (s, 3H), 3.95-4.05 (m, 1H), 4.20-4.30 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.02-7.09 (m, 2H). MS m/z 335 (M+H)+