Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C2C(=CC=1)N=C(C1C=CC=CC=1O)N=C2N[C@H]1CCN(C(OC(C)(C)C)=O)C1.[CH3:32][C:33]([OH:37])([CH3:36])[C:34]#[CH:35].Br[C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[C:44]([C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=1[OH:56])[N:43]=[C:42]2[NH:57][C@H:58]1[CH2:62][CH2:61][N:60](C(OC(C)(C)C)=O)[CH2:59]1.OC1C=CC=CC=1C1N=C(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)C2C(=CC=C(C#CCO)C=2)N=1>>[F:55][C:53]1[CH:52]=[CH:51][C:50]([OH:56])=[C:49]([C:44]2[N:43]=[C:42]([NH:57][C@H:58]3[CH2:62][CH2:61][NH:60][CH2:59]3)[C:41]3[C:46](=[CH:47][CH:48]=[C:39]([C:35]#[C:34][C:33]([OH:37])([CH3:36])[CH3:32])[CH:40]=3)[N:45]=2)[CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(F)ccc3O)nc3ccc(Br)cc23)C1
Reactant: C#CC(C)(C)O
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(Br)cc23)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3ccccc3O)nc3ccc(C#CCO)cc23)C1
Product: CC(C)(O)C#Cc1ccc2nc(-c3cc(F)ccc3O)nc(N[C@H]3CCNC3)c2c1

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 59, replacing propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate with dimethyl propargyl alcohol and (S)-tert-butyl 3-(6-bromo-2-(5-fluoro-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate in Synthesis 59-A.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>C(Cl)Cl>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)=[O:37]
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)Cc1cccs1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 88.7 %

Procedure:
Compound (II) (3.1 g, 7.8 mmole), 2-thiopheneacetic acid (1.14 g, 8.0 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmole) were stirred in 50 mL of methylene chloride for 12 hrs. at ambient temperature. The reaction was diluted with methylene chloride, washed with 1N hydrochloric acid, 1N NaOH, water and brine. Purification of the residue obtained on evaporation was accomplished with silica gel chromatography using 50% ethyl acetate in hexanes as the eluent to yield 3.6 g of the title compound as a solid.
Reaction SMILES: O.[N+:2]([C:5]1[CH:11]=[CH:10][C:8]([O-:9])=[CH:7][CH:6]=1)([O-:4])=[O:3].[Na+].Cl.[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18]Cl)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][O:9][C:8]1[CH:10]=[CH:11][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
Water (8 ml) and xylene (35 ml) were added to a mixture of sodium 4-nitrophenoxide (10.5 g, 65 mmol), 2-(diethylamino)ethylchloride hydrochloride (8.6 g, 50 mmol) and potassium carbonate (10.4 g, 75 mmol) and the resulting mixture was heated at reflux for 2 hours. A Dean-Stark apparatus was then fitted and the water was removed. The organic solution was allowed to cool to ambient temperature and left to stand for 18 hours. The solution was decanted from the precipitated solid and the volatiles were removed from the decanted solution by evaporation to give the title compound (8.0 g, 52% yield) as an oil. NMR: 0.90 (t, 6H), 2.50 (q, 2H), 2.89 (t, 2H), 4.15 (t, 2H), 7.15 (d, 2H), 8.18 (d, 2H); m/z: 239 [MH]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3][OH:4].C(N(C(C)C)CC)(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:23](=[O:25])[NH:1]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(C[C@H](N)CO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2COC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred solution of (2S)-2-amino-3-(4-methylphenyl)propan-1-ol (Step A, 460 mg, 2.79 mmol) in CH2Cl2 (20 mL) at 0° C. was treated with diisopropylethylamine (2.92 mL, 16.74 mmol) and triphosgene (414 mg, 1.39 mmol) under an atmosphere of N2. The reaction stirred at 0° C. for 3 h. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-70% EtOAc/hexanes gradient) to afford (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as a white solid. LCMS=192.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.17 (d, J=8 Hz, 2H), 7.09 (d, J=7.7 Hz, 2H), 5.39 (br s, 1H), 4.48 (t, J=8.4 Hz, 1H), 4.37 (dd, J=8.6, 5.6 Hz, 1H), 4.11-4.06 (m, 1H), 2.86 (d, J=7.1 Hz, 2H), 2.36 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[S:35])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
90 mg of 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) are dissolved in 10 ml of toluene under an atmosphere of dry nitrogen. Subsequently, 144 mg of Lawesson's reagent are added and the solution is heated at 100° C. for 17 hours. Thereafter, the reaction mixture is evaporated to dryness to yield approximately 200 mg of crude material, which is purified by chromatography on basic aluminum oxide (eluent: dichloromethane) to afford 71 mg of the title compound as a light yellow, waxy solid. ESI-MS: 351.2 (MH+). TLC: Rf=0.53 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(F)cc21
Product: CS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 38 from ethyl 3-amino-2-benzoyl-6-fluoro-1H-indole-1-carboxylate (step 2) and methanesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH:16]([F:18])[CH3:17])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:23].[OH-].[Na+].[NH2:26][C:27]1[C:32]([F:33])=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH:41]([F:43])[CH3:42])[C:35]=2[F:44])[N:30]=[C:29]([C:45]([O:47]C)=[O:46])[C:28]=1[Cl:49].Cl>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([CH:16]([F:18])[CH3:17])[C:10]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH2:31][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:21])[C:3]=1[Cl:23].[NH2:26][C:27]1[C:32]([F:33])=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([CH:41]([F:43])[CH3:42])[C:35]=2[F:44])[N:30]=[C:29]([C:45]([OH:47])=[O:46])[C:28]=1[Cl:49]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2F)c(F)c(N)c1Cl
Agent: CC(F)c1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(F)c1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 23 °C
Reaction time: 20 h

Procedure:
4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinic acid. A 2 molar (M) solution of aqueous sodium hydroxide (NaOH; 580 μL, 1.2 mmol, 4.0 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinate (110 mg, 0.29 mmol, 1.0 equiv) in methyl alcohol (1.9 mL) at 23° C. The resulting homogeneous pale yellow solution was stirred at 23° C. for 20 h. The reaction mixture was adjusted to approximately pH=4 via dropwise addition of concentrated hydrochloric acid (HCl) and concentrated via rotary evaporation. The residue was slurried in water and vacuum filtered to afford the desired product, 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-5-fluoropicolinic acid as a white powder (55 mg, 50%): IR (thin film) 3319 (m), 3193 (w), 2983 (w), 1719 (m), 1629 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 7.58 (t, J=9 Hz, 1H), 7.49 (d, J=9 Hz, 1H), 6.99 (br s, 2H), 6.15 (dq, J=44, 7 Hz, 1H), 1.71 (dd, J=23, 7 Hz, 3H); ESIMS m/z 365 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[I-].[Mg+2].[I-].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[CH:19]1[C:23](=[O:24])[CH:22]=[CH:21][C:20]1=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]2[O:4][CH:5]([CH:6]=1)[CH:21]1[CH:22]2[C:23](=[O:24])[CH:19]([C:12]2[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][C:13]=2[CH3:18])[C:20]1=[O:25]
Reactant: Brc1ccoc1
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Product: Cc1cc(C)c(C2C(=O)C3C4C=C(Br)C(O4)C3C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Bromofuran (5.2 g, 56 mmol) and magnesium iodide (1.5 g, 5.6 mmol) are added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (4.0 g, 18.7 mmol) and the mixture is stirred at room temperature for 2 days; small quantities of dichloromethane are added when required to aid stirring. The reaction mixture is allowed to stand at room temperature for 17 hours, then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS, 2RS,6SR,7SR)-8-bromo-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([O:12]C)[CH:3]=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CC(=O)O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(Cl)cc1O

Procedure:
4-chloro-2-methoxy-benzeneacetic acid (1.4 g), HBr (25 ml), acetic acid (5 ml) were refluxed for 48 h then evaporated under reduced pressure. The residue was azeotroped with toluene and triturated with diethyl ether and isohexane. Yield 0.56 g.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:26])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:37]1([N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[C:10](=[O:26])[CH2:11][CH2:12]4)[CH2:25][CH2:24]2)[CH2:39][CH2:38]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CCc2cc(OC3CCN(C4CC4)CC3)ccc2N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A suspension of 1-(4-fluorophenyl)-6-(piperidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one hydrochloride prepared in Example 7-(3) (0.30 g), triethylamine (0.080 g), [(1-ethoxycyclopropyl)-oxy]trimethylsilane (0.69 g), acetic acid (0.48 g) and molecular sieves 3A (1.0 g) in methanol (10 mL) was stirred at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (0.25 g) and stirring at the same temperature for 16 hours. The reaction mixture was warmed to 95° C., heated under reflux for 7 hours, and then cooled to room temperature, followed by filtration to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform→chloroform/methanol=4/1) and preparative TLC (on a single plate of 2 mm thickness, developing solvent: chloroform/methanol=9/1) to give the titled compound (0.11 g, 37%) as a colorless amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]([C:23]1[N:27]([CH3:28])[C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([C:23]1[N:27]([CH3:28])[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC2CC2)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 23.8 %

Procedure:
According to general procedure B, 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide (224 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide (56 mg, 24%) was provided after purification. MS (ESI) m/z 399. HPLC purity 99.1% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=[C:22]([CH:25]=1)[CH:23]=O.[Na]>ClC(Cl)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][CH2:23][C:22]2[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=2[O:26][CH2:27][CH2:28][O:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=2)(=[O:32])=[O:31])[CH:7]=1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Reactant: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(C=O)c1
Agent: [Na]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 71 %

Procedure:
To stirred solution of 9.1 g (45 mmol) 1b, 15.8 g (45 mmol) 5a and one drop of glacial acid in 60 ml dichloroethane (pH=5) were added 14.8 g (70 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 5 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 5b was obtained in 71% yield (17.2 g, 32.0 mmol) as yellow oil. The crude product 5b was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:32])[CH2:9][NH:10][CH2:11][C@H:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[O:13]2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:32])[CH2:9][NH:10][CH2:11][C@H:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=4)[CH:18]=3)[O:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2ccc(N)nc2)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc([C@@H](O)CNC[C@H]2CCc3cc(-c4ccc(C(=O)O)cc4)ccc3O2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a solution of methyl 4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 381, 40 mg, 0.1 mmol) in THF (2 mL) and methanol (2 mL) was added 2 M aq. lithium hydroxide (0.5 mL, 1 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Prep. HPLC of the residue afforded 10.8 mg (28%) of the desired product. The product had: 1H NMR (CDCl3, δ): 7.96 (d, J=8.2 Hz, 2 H), 7.90 (d, J=2.2 Hz, 1 H), 7.49-7.56 (m, 3 H), 7.32-7.39 (m, 2 H), 6.82 (d, J=9.0 Hz, 1 H), 6.59 (d, J=8.6 Hz, 1 H), 4.70 (dd, J=8.3, 4.4 Hz, 1 H), 4.14-4.23 (m, 1 H), 2.75-3.02 (m, 6 H), 1.99-2.10 (m, 1 H), 1.70-1.85 (m, 1 H); mass spectroscopy gave m/z=420.2 [M+H]+ (calc'd exact mass for C24H25N3O4=419.2).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[C:15]2[C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:8]=1)(=O)=O.B([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[N:49]=[N:50][N:51]([C:53]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C=O)C.O.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>[C:25]1([C:23]2[N:24]=[C:20]([C:15]3[C@H:14]([CH2:13][C:9]4[CH:8]=[CH:7][CH:12]=[C:11]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=5[C:48]5[N:49]=[N:50][N:51]([C:53]([C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)([C:60]6[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=6)[C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[N:52]=5)[CH:10]=4)[CH2:19][CH2:18][CH2:17][CH:16]=3)[O:21][C:22]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1-c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=S(=O)(Oc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)C(F)(F)F
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: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)[C@H](Cc2cccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl trifluoromethanesulfonate (1.17 g) in dichloromethane (100 ml) were added 5-(2-boronophenyl)-2-(triphenylmethyl)-2H-tetrazole (1.16 g), tetrakis(triphenylphosphine)palladium (600 mg), and K2CO3 (630 mg) in a mixture of DMF and water. After being stirred for 8 hours at 100° C., the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (S)-2-(4,5-diphenyloxazol-2-yl)-1-{3-{2-[2-(triphenyl-methyl)tetrazol-5-yl]phenyl}benzyl}-2-cyclohexene (0.83 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@:21]42[O:26][C@H:20]4[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[ClH:28].C(=O)(O)[O-].[Na+]>CCOCC>[C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@:21]2([Cl:28])[C@@H:20]([OH:26])[CH2:19][C@@:18]2([CH3:27])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)C[C@@H]4O[C@@]432)C1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)C[C@H](O)[C@@]32Cl)C1
Reaction time: 0.07 h

Procedure:
3α-Acetoxy-9β,11β-epoxy-5α-pregnan-20-one (500 mg.) was dissolved in ether and the ether evaporated to leave a gummy residue. Hydrochloric acid (11.6N; 5ml.) was added and the reaction stirred for 4 min., it was then poured into aqueous sodium bicarbonate solution and the solid filtered off, washed with water and dried. Crystallisation from methyl acetate-petrol gave the title compound (250 mg.), m.p. 175°-179°. Recrystallisation from aqueous acetone gave a sample m.p. 177°-179°, [α]D + 97°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[CH:40]=O.[Na]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:40][C:31]3[CH:32]=[CH:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:30]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=Cc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc4ccccc4n3)CC1)O2
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3, was stirred for 10 minutes, then extracted with DCM and treated with quinoline-2-carbaldehyde (96 mg, 0.61 mmol) and sodium triacethoxyborohydride (159 mg, 0.750 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (196 mg) as a yellow solid. The ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (190 mg) as an orange solid (hydrochloride salt). The acid was suspended in DCM (5 ml), TEA (0.16 ml, 1.16 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(quinolin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (162 mg) as a yellow solid. The compound was then was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.4 ml, 1.6 mmol) as described in Example 55, Step D, giving a yellow solid (145 mg, di-hydrochloride salt)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]1[CH:26]=[C:27]([C:35](O)=[O:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:27]2[C:28]3[O:33][CH2:32][O:31][CH2:30][C:29]=3[CH:34]=[C:25]([F:24])[CH:26]=2)=[O:36])=[O:10])[N:12]=1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)cc3c2OCOC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=508.4.