Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH-].[Na+].[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][OH:20].Cl>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][O:14]1
Reactant: OCC1CCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 2-bromo-1-fluoro-4-nitro-benzene (5.0 g, 22.72 mmol) in DMSO (40 mL) was added NaOH (1.36 g, 34.09 mmol) and (tetrahydrofuran-2-yl)methanol (3.47 g, 34.09 mmol) at 0° C. The mixture was stirred at RT for 1 h, then poured into H2O (50 mL), the pH adjusted ˜7 with 1M HCl and extracted with EtOAc (2×250 mL). The combined organics were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to obtain i (6.50 g, 95%). 1HNMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.40 Hz, 1H), 8.20 (dd, J=2.40 and 9.20 Hz respectively, 1H), 6.98 (d, J=9.20 Hz, 1H), 4.36 (m, 1H), 4.16 (m, 2H) 3.97 (m, 1H) 3.86 (m, 1H) 2.07 (m 2H) and 1.95 (m, 2H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:19]=2[N:18]=[C:17]1[CH3:34]>CN(C)C=O>[CH3:34][C:17]1[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:19]=2[N:18]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCSc3ccccc3)c2c1C
Yield: 91.7 %

Procedure:
Benzenethiol (2.42 mL, 23.6 mmol) was added dropwise to a suspension of sodium hydride (0.944 g of 60%, 23.6 mmol) in anhydrous N,N-dimethylformamide (50 mL) and stirred until a clear solution was obtained. A solution of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (6.5 g, 18.2 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then it was quenched with water and extracted with ethyl acetate (300 mL). The extract was washed with water (5×75 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 7.20 g of 2,6,7-trimethyl-4-phenoxy-1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:13][CH2:12]4)[C@H:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:42][Br-]Br.[S-2].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[C@H:13]([Br:42])[CH2:12]4)[C@H:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@H]12
Agent: [Na+]
Agent: [S-2]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](C[C@@H](Br)C34OCCO4)[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A solution of 63.2 g of 3-acetoxy-7α-(5-acetoxypentyl)-17,17-ethylenedioxy-estra-1,3,5(10)-triene in 630 ml of tetrahydrofuran is mixed in portions at 0° C. with 61.7 g of pyridine hydrobromide perbromide, and it is stirred for 2 hours at 0° C. Then, a solution of 15 g of sodium sulfide in 70 ml of water is added, diluted with ethyl acetate, washed with sodium bicarbonate and common salt solution and dried on sodium sulfate and concentrated by evaporation in a vacuum. 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17,17-ethylenedioxy-estra-1,3,5(10)-triene is obtained as oil.
Reaction SMILES: OC(C1OC=CC=1)C1C=CC=CC=1.[C:14]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])[CH3:15].BrC1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1Br>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:14]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH3:29])([OH:16])[CH3:15]
Reactant: CC(=O)c1ccco1
Reactant: COc1ccccc1Br
Agent: OC(c1ccccc1)c1ccco1
Solvent: Brc1ccccc1
Product: COc1ccccc1C(C)(O)c1ccco1

Procedure:
(±)1-(2-Furyl)-1-(2-methoxyphenyl)ethanol (b.p. 115°-118° C./0.15 mm.Hg; m.p. 64°-66° C.) was prepared by the procedure hereinbefore described in (i) for the preparation of (±) 2-α-hydroxybenzylfuran but replacing the furfuraldehyde by 2-acetylfuran [described by Levine et al, J.A.C.S. 71, 1208,(1949)] and the bromobenzene by 2-methoxybromobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[CH2:13][S:14][CH3:15].[CH3:16][O-:17].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:17][CH3:16])[C:3]=1[CH2:13][S:14][CH3:15]
Reactant: COC(=O)c1ccc(Cl)c(CSC)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(CSC)c1OC
Yield: 84.5 %

Procedure:
A solution of methyl 4-chloro-2-fluoro-3-methylsulphenylmethylbenzoate (11.4 g) in tetrahydrofuran was stirred, with addition of sodium methoxide (3.5 g). After 2 hours water was added and the mixture extracted with ether, dried (magnesium sulphate) and evaporated to give methyl 4-chloro-2-methoxy-3-methylsulphenylmethylbenzoate (10.1 g), NMR (CDCl3) 2.15 (s,3H), 3.9 (3s,8H), 7.15 (d,1H), 7.65 (d,1H).
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC(C1C=CC=CC=1)C(O)=O.[S:25](=[O:29])(=[O:28])([OH:27])[OH:26].[Cl-].[Na+]>ClCCl.CO>[CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:25](=[O:27])(=[O:26])([OH:29])[OH:28]
Reactant: CN[C@H](C)[C@@H](O)c1ccccc1
Agent: COC(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 0 °C

Procedure:
Resolution of (+)-(S)-O-methylmandelic acid. Heat 40.0 g. (0.241 moles) of racemic (±)-α-methyl-α-phenylacetic acid [D. G. Neilson et al J. Chem. Soc., (1962), 1519] with 40.0 g (0.242 moles) of d-ephedrine (available from Aldrich) in 180 mL of 95% ethanol under reflux on a steam bath. Cool the resulting solution to room temperature slowly and leave undisturbed overnight (16 hrs ). Filter the resulting crystallized solid and wash same with 95% ethanol (20 mL) and ethyl ether to give 35 6 g. Recrystallize (twice) the solid from 95% ethanol to give 26.5 g. of salt of d-ephedrine and (+)-α-methoxy-α-phenylacetic acid [(+)-(S)-O-methylmandelic acid], m.p. 185°-188°, [α]D21 +72.8° (c, 4 64, MeOH). Acidify 26.3 g. of the solid with 90 mL of ice-cooled sulfuric acid, with stirring to give a solution. Add sodium chloride (31 g.) and stir the resulting mixture Add 100 mL of dichloromethane to the mixture to give a voluminous precipitate (ephedrine, sulfuric acid salt). Add another 100 mL portion of dichloromethane to the mixture and filter the mixture through a glass filter Wash the solid with 100 mL of dichloromethane. Shake the filtrate and separate the organic and aqueous layers Extract the aqueous layer with 100 ml of dichloromethane. Dry the combined organic layers over anhydrous magnesium sulfate. Evaporate the solvent to give an oil which solidifies on cooling to yield 13.2 g. of the title compound as a solid: m.p. 60.5°-62.0°, [α]D22 +149° (C, 5.61, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[CH2:17][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: COC(=O)c1ccccc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Yield: 57.2 %

Procedure:
A solution of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 300 mg, 1.5 mmol) and methyl 2-bromomethyl-benzoate (370 mg, 1.6 mmol) in dimethylformamide (15 mL) was heated at ˜100° C. for 2 days. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was taken up in dichloromethane and purified on a Biotage 40S system, eluting with 0-2% methanol/dichloromethane to give 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (304 mg, 59%) as an orange oil. 1H NMR indicated that it contained minor impurities. It was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:18])([CH3:17])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26](O)[C:27]#[C:28][CH2:29][OH:30]>>[OH:30][CH2:29][C:28]#[C:27][CH2:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][S:14][C:13]([CH3:17])([CH3:18])[C@@H:12]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCO
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCO)cc2)CCSC1(C)C
Yield: 48.3 %

Procedure:
According to the procedure of Step 2 of Example 248, Mitsunobu coupling of 2.5 g (6.46 mmoL) of tert-butyl(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.667 g (7.752 mmol) of 2-butyne-1,4-diol gave 1.42 g of tert-butyl(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Br:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Br:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:27])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1cccc(-c2sc(Br)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(Br)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Bromo-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.41 min; [M+H]+=555.9.
Reaction SMILES: C([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([CH2:17][C@H:18]3[CH2:23][N:22]([S:24]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)(=[O:26])=[O:25])[CH2:21][CH2:20][N:19]3[C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[CH:10]1[CH2:11][O:12][CH2:13]2)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[S:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[S:24]([N:22]1[CH2:21][CH2:20][N:19]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)[C@@H:18]([CH2:17][N:16]2[CH:10]3[CH:9]([OH:8])[CH2:15][CH:14]2[CH2:13][O:12][CH2:11]3)[CH2:23]1)(=[O:25])=[O:26]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(O)C3)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.350 g, 0.537 mmol) and 5 mL of CH2Cl2. After cooling to 0° C., BCl3 (1M in CH2Cl2, 2.15 mL, 2.15 mmol, Sigma-Aldrich, St. Louis, Mo.) was added drop-wise. This mixture was allowed to warm to room temperature then stirred for an additional 15 min. 10 mL of MeOH was added and the mixture was concentrated onto silica gel and purified via column chromatography (0-7% MeOH in CH2Cl2) to give 8-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (endo) (0.210 g) as a mixture of four isomers. 1H NMR (400 MHz, CD3OD) δ 7.92 (d, J=4.9 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.54 (t, J=7.2 Hz, 2H), 7.28 (t, J=5.3 Hz, 1H), 7.06 (t, J=9.1 Hz, 2H), 4.43-4.62 (m, 2H), 3.39-4.24 (m, 13H), 2.66-2.98 (m, 2H), 2.55 (d, J=3.91 Hz, 1H), 1.69 (br. s., 3H). m/z (ESI, +ve ion) 562.1 (M+H)+. GK-GKRP IC50 (Binding)=0.028 μM; GK-GKRP EC50 (LC MS/MS-2)=0.031 μM.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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:12]([N:8]1[CH2:7][C:6]2[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:30][CH:29]=3)[C:11]=2[O:10][CH2:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)N1COc2c(Br)cc(-c3ccc(F)cc3)cc2C1
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: COCCOC
Solvent: O
Product: CC(C)(C)N1COc2c(cc(-c3ccc(F)cc3)cc2-c2ccc(C(F)(F)F)nc2)C1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
A mixture of 8-bromo-3-(tert-butyl)-6-(4-fluorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (2.0 g, 5.49 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.26 g, 6.59 mmol) and potassium carbonate (1.52 g, 10.98 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (317.2 mg, 0.275 mmol) was added and the reaction mixture heated at 80° C. in a sealed vial for 17 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 8% methanol (containing 1% aqueous ammonium hydroxide) in dichloromethane to give 3-(tert-butyl)-6-(4-fluorophenyl)-8-(6-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.773 g, 37% yield) as a colorless syrup.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.C1(B(O)O)C2C=CC3C(=CC=CC=3)C=2C=CC=1.[Br:39][C:40]1[CH:41]=[C:42](I)[CH:43]=[CH:44][CH:45]=1>>[Br:39][C:40]1[CH:45]=[C:44]([C:10]2[CH:11]=[CH:12][C:21]3[CH:20]=[CH:19][C:18]4[C:17]([C:8]=3[CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:43]=[CH:42][CH:41]=1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Reactant: Brc1cccc(I)c1
Agent: OB(O)c1cccc2c1ccc1ccccc12
Product: Brc1cccc(-c2ccc3ccc4ccccc4c3c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-1-boronic acid was used instead of phenanthrene-2-boronic acid; and 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O>O1CCCC1.[H][H]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: [H][H]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
72 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 28 were dissolved in 500 ml of tetrahydrofuran and hydrogenated with 15-20 bar of hydrogen over 5 g of palladium-oncharcoal (5% strength) at room temperature for 5 hours. The mixture was then filtered and the solvent was stripped off in vacuo. The yield was 60 g (93% of theory), and the boiling point was 80°-82° C. under 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.5 and -79.4 ppm. 1H-NMR: 4.68 ppm.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33](I)[C:27]=2[CH:26]=1)(=[O:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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:22]([C:25]1[S:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:27]=2[CH:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cc2c(I)cccc2s1
Reactant: CC(C)c1cc(B(O)O)c(OCC(F)(F)F)c(C(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc2c(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)(F)F)cccc2s1

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-(2,2,2-trifluoroethoxy)-phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo-benzo[b]thiophene and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3,5-di-iso-propylphenyl]-benzo[b]thiophene.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH:17]([Br:19])[CH3:18].C1(=O)NC(=O)C2=CC=CC=C12>CC(C)=O>[Br:19][CH:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)CCCBr
Agent: [K]
Solvent: CC(C)=O
Product: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Temperature: 15 °C
Yield: 97.6 %

Procedure:
A one liter, four necked round bottom flask equipped with a mechanical stirrer, thermowatch and condenser was charged with acetone (500 ml), potassium phthalimide (92.5 g, 0.5 moles) and 1,4-dibromopentane (153 g, 0.665 moles). The resulting mixture was refluxed for 24 hours (HPLC showed 2.5% unreacted phthalimide), then cooled to 15° C. Solid sodium bromide was removed by suction filtration and one wash of the cake with acetone (50 ml). The solvent was removed using a rotary evaporator to give 187.2 g of a crude viscous yellow oil. Excess 1,4-dibromopentane (34.5 g) was removed by vacuum distillation at 35-40° C./0.3 mm of pressure, leaving 144.6 g (97.7%) of a yellow viscous oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:22])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20])=[O:8])(=O)C.[OH-].[NH4+].Cl>O>[SH:4][CH2:5][CH:6]([CH3:22])[C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N1c2ccccc2CCC1C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(CS)C(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(±) 1-(3-Acetylthio-2-methyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid (26 g), concentrated ammonium hydroxide (55 ml), and water (110 ml) were combined and stirred at room temperature under nitrogen for six hours. After this time, concentrated hydrochloric acid was added while cooling with an ice bath until pH 2. The reaction mixture was extracted with ether (150 ml) and the extract dried over sodium sulfate, and evaporated to an oil. This residue, (±)-1,2,3,4-tetrahydro-1-(3-mercapto-2-methyl-1-oxopropyl)-2-quinolinecarboxylic acid, was crystallized from toluene; yield 4.5 g, m.p. 98°-101°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([N:17]3[CH2:18][CH2:19][CH:14]([C:7]4[C:8](=[O:13])[NH:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)[CH2:15][CH2:16]3)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)N5CCc6cc(F)ccc65)ncn4)CC3)cc2c1

Procedure:
25 mg (70 μmol) 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one, 20 mg (70 μmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 50 μL (0.29 mmol) DIPEA were stirred in 2 mL DMF overnight at RT. Then the reaction mixture was diluted with DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2cccc3[nH]c(=O)ccc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 48 mg (0.3 mmol) of 5-aminoquinolone and 0.1 ml of titanium tetraethoxide are reacted to give 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]-amino}quinolin-2(1H)-one. 130 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 and preparative HPLC yield 11 mg of product.