Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:38])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 80%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]#[N:11])=[N:2]1.Br[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.CCOC(C)=O>[F:16][C:15]([F:18])([F:17])[CH2:14][CH2:13][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]#[N:11])=[N:2]1
Reactant: N#Cc1n[nH]c2ncccc12
Reactant: FC(F)(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nn(CCC(F)(F)F)c2ncccc12
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, as described in Step C of Example 158 (30 g, 208 mmol), 3-bromo-1,1,1-trifluoropropane (44.5 mL, 416 mmol) and potassium carbonate (95 g, 687 mmol) were combined in a flask with acetonitrile (300 mL) and stirred at 40° C. After 5 h, the reaction was cooled to rt and EtOAc and water were added. The layers were separated and the aqueous layer was washed two times with EtOAc. The combined organics were dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the material was used without further purification. 1H NMR (500 MHz, DMSO-d6): δ 8.77 (d, J=4.50 Hz, 1H); 8.46 (d, J=8.23 Hz, 1H); 7.51 (dd, J=8.22, 4.47 Hz, 1H); 4.86 (t, J=6.66 Hz, 2H); 3.10-2.98 (m, 2H). m/z=241.1 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C([O-])(=O)C.[Na+].[CH:13]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([CH2:33][C:34]([OH:36])=[O:35])[CH:26]=1)=O.C([BH3-])#N.[Na+]>CO.C(Cl)Cl.O>[CH3:32][O:31][C:30]1[C:25]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:13][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:26][C:27]([CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:29]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Glycine methyl ester hydrochloride (0.057 g, 0.44 mmol) and sodium acetate (0.038 g, 0.44 mmol) were combined in a flask. (2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.099 g, 0.29 mmol) in MeOH (3 mL) was added, followed by sodium cyanoborohydride (0.029 g, 0.44 mmol), and the reaction was stirred at room temperature for 3.5 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:35])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(N(C)C(=O)OC(C)(C)C)cc3)nc2c1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A solution of 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylic acid (213.5 mg, 0.46 mmol, 1.00 equiv, 99%) and K2CO3 (324.2 mg, 2.35 mmol, 5.00 equiv) in DMF (8 mL) was stirred 45 min at room temperature under an inert atmosphere. CH3I (333.7 mg, 2.35 mmol, 5.00 equiv) was added dropwise, with stirring, at 0° C. The resulting solution was stirred for 1 h at room temperature, then quenched by water. The solution was extracted with 5×10 mL of CH2Cl2, and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out, and the resulting mixture was concentrated under vacuum affording 218 mg (98%) of methyl 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C([Mg]Cl)CCC.Cl[CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[Mg].C([O:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=O)[CH:18]=1)C>C1COCC1>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:19]1[CH2:20][CH2:21][CH2:22][C:17](=[O:16])[CH:18]=1
Reactant: OCCCCCl
Reactant: CCOC1=CC(=O)CCC1
Agent: CCCC[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1C=C(CCCCO)CCC1
Reaction time: 2 h

Procedure:
Butylmagnesium chloride (2.0M, 20.0 ml) is added dropwise over 20 min to a solution of 4-chloro-1-butanol (4.05 g) and THF (40.0 ml). The resultant solution is stirred for 20 min and then is added dropwise over 20 min to a mixture of magnesium (1.46 g) and THF (5.0 ml). The resulting warm mixture is heated at reflux for 3 hr, and then cooled in an ice bath. A solution of 3-ethoxy-2-cyclohexene-1-one (5.39 ml) and THF (20.0 ml) is then added dropwise over 20 min. The resultant solution is allowed to warm to 20°-25° and stir for 2 hr. Acidic workup using ether and hydrochoric acid (1%) and purification by flash chromatography eluting with ethyl acetate/hexane (4/1) provides 3-(4-hydroxybutyl)-cyclohex-2-en-1-one as an oil, IR (neat) 3413, 2942, 1664, 1600, 1257, 1185 cm-1 ; MS (EI) m/e (relative %) 168 (25), 123 (25), 97 (40), 82 (36), 55 (44), 42 (100).
Reaction SMILES: [BH4-].[Na+].C(O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][CH:8]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C1C=CC=CC=1.C1C=CC=CC=1.CC(C)=O.O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([CH:27]([OH:35])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[O:14][CH2:15][CH2:16][O:17]2)=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCC2(c3ccc(F)cc3)OCCO2)CC1
Agent: [BH4-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: OC(c1ccc(F)cc1)C1CCN(CCCC2(c3ccc(F)cc3)OCCO2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3.78 g. (0.1 mole) of sodium borohydride in 25 ml. of anhydrous ethanol was stirred at room temperature. A solution of 8.16 g. (0.02 mole) of 2-(p-fluorophenyl)-2-{3-[4-(p-fluorobenzoyl)piperidino]propyl}-1,3-dioxolane in 10 ml. of anhydrous ethanol was slowly added dropwise so as to maintain a controlled evolution of gas. After the addition was complete the mixture was allowed to stir at room temperature for 16 hr. A large excess of water was added and the mixture was extracted several times with benzene. The benzene extracts were dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and a glass-like residue was obtained. The residue was dissolved in benzene and placed on a magnesium silicate column. Using a benzene-acetone gradient solution, the product was obtained. Recrystallization of the solid product from methanol-isooctane gave 6.5 g. (78%) of white solid melting at 114°-116° C.
Reaction SMILES: [CH2:1]([CH2:3][C:4]([O:6][C:7]1[C:28]([O:29][CH3:30])=[CH:27][C:10]([C:11]([O:13]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])=[O:5])[CH3:2]>[Pd].C(O)C.C(OCC)(=O)C.ClCCl>[CH2:1]([CH2:3][C:4]([O:6][C:7]1[C:28]([O:29][CH3:30])=[CH:27][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])=[O:5])[CH3:2]
Reactant: CCCC(=O)Oc1c(OC)cc(C(=O)OC(c2ccccc2)c2ccccc2)cc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(=O)Oc1c(OC)cc(C(=O)O)cc1OC
Reaction time: 16 h

Procedure:
Combine diphenylmethyl 4-(ethyl acetoxy)-3,5-dimethoxybenzoate (4.3 g, 9.56 mmol), 5% palladium-on-carbon (0.5 g), and ethanol/ethyl acetate/dichloromethane (200 mL/15 mL/15 mL). Hydrogenate at an initial pressure of 55 psi in a Parr apparatus. After 16 hours, filter and concentrate the filtrate to give a residue. Recrystallize the residue from diethyl ether/hexane to give the title compound: Rf=0.35 (silica gel, 6% methanol/dichloromethane).
Reaction SMILES: [BH4-].[Na+].[Li+].[Cl-].C[O:6][C:7]([CH:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O>CCO.C1COCC1>[C:19]([O:18][C:16]([N:10]1[CH:9]([CH2:7][OH:6])[CH2:13][O:12][C:11]1([CH3:15])[CH3:14])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO)COC1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of NaBH4 (2.247 g, 59.08 mmol) and LiCl (2.505 g, 59.08 mmol) in EtOH (42 mL), siring under nitrogen at 0° C., was added (35) (7.659 g, 29.54 mmol) in THF (30 mL) dropwise. This mixture was allowed to warm to room temperature and continued stirring for 48 hours. The precipitate was filtered and washed with ethanol. The washings were concentrated and extracted with EtOAc. The organic layer was then washed with brine and dried over anhydrous Na2SO4. Column chromatography on SiO2 (1:1 EtOAc/Hexanes) was utilized to purify 6.101 g (89%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](S([O-])=O)=[CH:5][CH:4]=1.[Na+].II.[C:15]([C:18]([CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[N:28]([CH3:34])[C:27]1=[O:35])=[CH:19][S:20]([O-:22])=[O:21])([OH:17])=[O:16].[Na+].C(N(CC)CC)C.S(=O)(=O)(O)O>O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:20](/[CH:19]=[C:18](\[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[N:28]([CH3:34])[C:27]1=[O:35])/[C:15]([OH:17])=[O:16])(=[O:22])=[O:21]
Reactant: CN1C(=O)N(CCCC(=CS(=O)[O-])C(=O)O)C(=O)C1(C)C
Reactant: COc1ccc(S(=O)[O-])cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1S(=O)(=O)/C=C(\CCCN1C(=O)N(C)C(C)(C)C1=O)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Sodium 4-methoxyphenylsulfinate (10.0 g, 51.49 mmol) was dissolved in water (100 ml). This solution was shaken with iodine (9.8 g, 36.61 mmol) in dichloromethane (100 ml). The dichloromethane layer turned from deep pink to orange. The dichloromethane layer was dried over magnesium sulfate and filtered into a flask containing sodium 2-carboxy-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pent-1-ene-1-sulfinate (6.47 g, 25.74 mmol). The solution was stired overnight at room temperature and then cooled to 0° C. Triethylamine (11.0 ml, 77.23 mmol) was added and the solution was allowed to warm to room temperature over 2 hours. Sulfuric acid (2M, 50 ml) was added to quench the reaction. The organic phase was washed with 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (2M, 3×50 ml). The aqueous layer was washed with dichloromethane (50 ml) and the acidifed with sulfuric acid (2M) to pH 1. The product was extracted into dichloromethane (3×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporaed to give the title compound in 88% yield. This yellow oil was crystallised from MTBE/DCM 40:1 to give the title compound as a white solid (5.6 g, 51%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>CN(C=O)C>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Temperature: 50 °C
Yield: 18.5 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (1.346 g, 3.83 mmol) was heated with anhydrous potassium carbonate (2.118 g, 15.33 mmol) in dry DMF (17 ml) at 60° C. for 1 hour. Phenylmethyl 2-(2-bromoethyl)-1-piperidinecarboxylate (1.500 g, 4.60 mmol) was added and the reaction mixture heated at 50° C. overnight (20 hours). The reaction mixture was partitioned between water (250 ml) and ethyl acetate (150 ml). The aqueous was further extracted with 2×100 ml ethyl acetate. The combined organic layers were washed with 100 ml brine and passed through a hydrophobic frit to dry, then stripped to dryness (rotary evaporator). The residue was dissolved in DCM and loaded onto a 70 g silica cartridge and purified by chromatography using a gradient 0-100% ethyl acetate in dichloromethane+0-12% MeOH finish on a Flashmaster 2. Appropriate fractions were combined and evaporated in vacuo. The material was re-purified by chromatography on silica (70 g cartridge using a gradient of 0-100% ethyl acetate in dichloromethane over 40 mins. and subsequently a flush of 0-100% ethyl acetate in DCM+0-20% MeOH). Product fractions combined and evaporated in vacuo to give the title compound as a colourless oil (0.342 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:17][C:18]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:19]=1[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29]OS(C)(=O)=O)[CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.CCOC(C)=O.O>[Cl:17][C:18]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][C:19]=1[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][N:12]2[C:11]([CH3:14])=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:13]2)[CH2:25][CH2:24]1)=[O:21]
Reactant: COc1ccc(-c2cc(C)n[nH]2)cc1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cc(C)n(C[C@H]3CC[C@H](NC(=O)c4cc(C(F)(F)F)ccc4Cl)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(4-Methoxyphenyl)-3-methyl-1H-pyrazole (91 mg, 0.483 mmol) was dissolved in dry DMF (2 ml). The flask was flushed with N2 and the solution was treated with NaH (BO % in mineral oil) (19.33 mg, 0.483 mmol) and stirred at RT for ˜10 mins. Trans-methanesulfonic acid 4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexylmethyl ester (Intermediate G) (100 mg, 0.242 mmol) was added and the mixture was heated to 50° C. for 4 hours. After cooling to RT, the mixture was diluted with EtOAc/H2O (20 ml) and transferred to a separating funnel. The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to give a brown oil. Purification of the crude product by chromatography on silica eluting with EtOAc/iso-Hexane afforded the title compound as a white solid; LCMS Rt=1.39 min, [M+H]+ 506.3; Method 2 minLC—30_v002. 1H NMR (400 MHz, CDCl3) δ 7.9 (1H, s), 7.7 (1H, d), 7.6 (1H, d), 7.55 (1H, d), 6.95 (2H, d), 6.25 (1H, s), 5.95 (1H, d), 4.0 (1H, m), 3.95 (2H, d), 3.85 (3H, s), 2.3 (3H, s), 2.2 (2H, d), 2.1 (1H, m), 1.8 (2H, d), 1.25 (4H, m).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCCCCc1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: BrCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Phosphorus tribromide (17.6 ml, 186 mmol) was added dropwise to a solution of 4-phenyl-1-butanol (10.0 g, 66.6 mmol) in dioxane (200 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus tribromide (17.6 ml, 186 mmol) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature. It was cooled to 0° C. Water (130 ml) was added dropwise. The reaction mixture was stirred for 30 min at room temperature. It was diluted with ethyl acetate (200 ml) and washed with 1 N hydrochloric acid (200 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane 1:3 as eluent, to give 8.54 g of (4-bromobutyl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12](=O)[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1
Reactant: COc1ccc2[nH]cc(C(=O)CCC(=O)N3CCc4c(oc5ccccc45)C3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 1 h

Procedure:
A suspension of 40.2 g of 2-[4-(5-methoxy-3-indolyl)-1,4-dioxobutyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine [obtainable from 4-(5-methoxy-3-indolyl)-4-oxobutyric acid and 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine] in 3 l of hot absolute THF is added dropwise, with stirring, to a suspension of 23.4 g of LiAlH4 in 1100 ml of absolute THF, and the mixture is boiled for 1 hour, cooled, and decomposition is carried out with water and sodium hydroxide solution, and the usual working up is carried out. 2-[4-(5-methoxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained, Rf 0.5 (ethyl acetate).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:48](=[O:49])[C:47]2[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:51])[C:40]1=[O:52].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[Cl:23][C:24]1[C:25]([N:39]2[C:48](=[O:49])[C:47]3[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=3)[N:41]([CH3:51])[C:40]2=[O:52])=[CH:26][CH:27]=[CH:28][C:29]=1[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22]
Reactant: Cn1c(=O)n(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2Cl)c(=O)c2cccc(F)c21
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c(=O)n(-c2cccc(-c3c(F)cc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2Cl)c(=O)c2cccc(F)c21
Temperature: 60 °C
Yield: 30.9 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (40 mg, 0.110 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (47 mg, 0.110 mmol), Cs2CO3 (107 mg, 0.329 mmol), dioxane (8 mL) and water (2 mL) was bubbled with nitrogen for 10 min. The mixture was treated with PdCl2(dppf) DCM adduct (7.2 mg, 8.76 μmol), and heated at 60° C. overnight. The cooled mixture was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with MeOH-DCM (gradient from 0-5%), to give 4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (20 mg, 31% yield). Mass spectrum m/z 569 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). 19F NMR (400 MHz, chloroform-d) δ −121.34, −127.34.
Reaction SMILES: [OH-].[Na+].[N+]([CH:6]([CH:8]1[CH:15]2[CH:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][CH:9]1[CH3:17])[CH3:7])([O-])=O.S(=O)(=O)(O)[OH:19].[N+](=C)([O-])[O-]>CO.O.C(O)(=O)C>[C:6]([CH:8]1[CH:15]2[CH:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][CH:9]1[CH3:17])(=[O:19])[CH3:7]
Reactant: CC1CC2OC(=O)CC2C1C(C)[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: C=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1C(C)CC2OC(=O)CC21

Procedure:
A solution of sodium hydroxide (22 g, 0.55 mole) in methanol (275 mL) was cooled to 0° and added all at once to a cold (0° ) solution of crude, racemic (3aR,4S,5R,6aS)-4-(1-nitroethyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (91.5 g, 0.43 mole) in methanol (350 mL). The resulting solution was stirred without further cooling for 11/2 hours during which time a solution of concentrated sulfuric acid (65 mL, 1.22 mole) in methanol (350 mL) was prepared by slow addition of the acid to the methanol while stirring and cooling in a dry ice/acetone bath. Both solutions were chilled to (-35°) and the nitronate anion solution as added all at once to acid solution. This mixture was kept for 11/2 hours during which the color changed from yellow to a pale blue-green. Approximately 500 mL of methanol was stripped off under reduced pressure using a 35° bath and a solution of acetic acid (50 mL) in water (300 mL) was added. Stripping was continued for 11/4 hours (40° bath) during which the remaining solvent was removed. The Product was extracted with ethyl acetate. The extract was washed with NaHCO3 solution and with brine, dried over sodium sulfate, and stripped of solvent. The racemic (3aR,4S,5R,6aS)-4-acetylhexahydro-5-methyl-2H-cyclopenta[b]furan-2-one thus obtained was 70.8 g (90.5%) of amber-colored oil. The yield based on racemic 3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester was 77.8%. A sample for analysis was vacuum distilled giving a colorless liquid. Anal. Found: C. 65.78: H, 7.91.