Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2nccnc2c1

Procedure:
A mixture of quinoxaline-6-carboxylic acid (2 g, 11.49 mmol) and thionyl chloride (30 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness using a rotary evaporator to afford quinoxaline-6-carboxylic acid chloride (crude quantitative). A solution of the above acid chloride (11.49 mmol) in DCM (50 mL) and pyridine (20 mL) was mixed with N,O-dimethyl hydroxylamine HCl salt (2.24 g, 23 mmol) and stirred at room temperature for 12 hours. The reaction was quenched by adding aqueous HCl (50 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield quinoxaline-6-carboxylic acid methoxy-methyl-amide (2 g, 80%). To a solution of the above Weinreb amide (2.0 g, 9.2 mmol) in THF (30 mL) at 0° C. was added methyl magnesium bromide (3.9 mL, 11.6 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then 1 hour at room temperature, quenched by adding aqueous HCl (20 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield 6-acetylquinoxaline (1.17 g, 74%). A solution of 2-chloronicotinic acid ethyl ester (5.0 g, 27 mmol) in MeOH (25 mL) was mixed with sodium methoxide (25.6 mL, 112.5 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding water (100 mL), extracted with DCM (3×100 mL), concentrated using a rotary evaporator to afford 2-methoxynicotinic acid methyl ester (3.2 g, 71%). A solution of 6-acetylquinoxaline (0.62 g, 3.6 mmol), 2-methoxynicotinic acid methyl ester (0.64 g, 3.8 mmol), and sodium hydride (0.46 g, 11.4 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL) and AcOH (20 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was re-dissolved in DCM (5 mL) and MeOH (3 mL) and was diluted with Hexanes (50 mL). The solid was removed by filtration and the filtrate was concentrated to afford the diketo compound (0.7 g, 60%). A solution of the above diketone (0.4 g, 1.3 mmol) in AcOH (50 mL) and sulfuric acid (conc., 15 drops) was stirred at reflux for 1 hour. Most of the solvent was removed using a rotary evaporator. The residue was re-dissolved in MeOH and neutralized with potassium carbonate to pH=8. The solid residue was removed by filtration, washed with MeOH and DCM. The filtrate was extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator. The solid residue was purified by column (SiO2, Hexanes/EtOAc/MeOH=2:2:1) to afford 2-(quinoxalin-6-yl)-4H-pyrano[2,3-b]pyridin-4-one (90 mg, 24%); MS (ES) m/z: 276 (M+1); MP 272.3-274.8° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:39])(=[O:38])[C@H:31]([C@@H:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:35]([C@H:33]([C@@H:31]([C:30]([O-:39])=[O:38])[OH:32])[OH:34])([O-:37])=[O:36]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (2.20, 5.52 mmol) was suspended in methanol (100 ml). 0.83 g of D-tartaric acid was added. Mixture was heated until all material was dissolved, then left to cool to room temperature to form crystalline sunitinib D-tartrate, 2.95 g. Melting point 183-187° C. (form II)
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32]>CO.O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: O
Solvent: CO
Product: O=C(O)C[C@H](O)C(=O)O
Reaction time: 0.08 h

Procedure:
5 g of sunitinib base were suspended in 100 ml of methanol. 1.684 g of Malic acid dissolved in 15 ml of water was added at RT. A partial dissolution of the mixture was observed and after 5 minutes there was the formation of a precipitate. The suspension was filtered and washed with 50 ml methanol. Dried at 50° C. under vacuum for 16 h.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH3:7].[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1)[CH3:7]
Reactant: CC(C)c1ccc(C(N)=O)cc1
Reactant: CC=O
Reactant: c1ccsc1
Solvent: O=CO
Product: CC(C)c1ccc(C(=O)NC(C)c2cccs2)cc1

Procedure:
Thiophene (25 mmol), acetaldehyde (20 mmol) and 4-isopropylbenzamide (10 mmol) were stirred in formic acid (10 ml) under the following condition to obtain N-[1-(2-thienyl)ethyl]-4-isopropylbenzamide:
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=1>C(O)C.O.[OH-].[Na+]>[CH2:13]([CH:12]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=1)[C:3]([OH:17])=[O:2])[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)c1cc(C(=O)OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Temperature: 70 °C
Yield: 85.3 %

Procedure:
A solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid methyl ester (50 g, 0.211 mol) in ethanol (250 mL), water (50 mL) and 32% aq. NaOH (50 mL) is stirred at 80° C. for 1 h. The mixture is concentrated and the residue is dissolved in water (200 mL) and extracted with TBME. The org. phase is separated and washed once with water (200 mL). The TBME phase is discarded. The combined aq. phases are acidified by adding 25% aq. HCl and then extracted with EA (400+200 mL). The combined org. extracts are concentrated. Water (550 mL) is added to the remaining residue. The mixture is heated to 70° C., cooled to rt and the precipitate that forms is collected and dried to give the title compound (40.2 g) as a white solid; LC-MS: tR=0.95 min, [M+1]+=224.04; 1H NMR (D6-DMSO): δ 0.73 (t, J=7.3 Hz, 6H), 1.59-1.72 (m, 4H), 2.52-2.58 (m, 1H), 3.88 (s, 3H), 7.00 (d, J=1.0 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(#N)C>CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: N#Cc1ccccc1N
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of acetonitrile followed by agitation at room temperature for 5 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 2.2 g of 1-(2-cyanophenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(Cl)(Cl)Cl>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 51 %

Procedure:
A solution of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (16.2 g) in acetic acid (200 ml) is dropwise added to a suspension of iron powder (14 g) in a 5% aqueous acetic acid (30 ml) at 90°-100° C. and refluxed for 1 hour. After being allowed to cool, chloroform is added to the resultant mixture, followed by filtration. The organic layer is separated from the filtrate, washed with a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue is recrystallized from a mixture of ether and petroleum ether to give 7.5 g of N-(3-amino-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 144.5°-146.5° C.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>C(Cl)Cl>[C:27]1([CH2:26][NH:33][CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 20 h
Yield: 99.9 %

Procedure:
1,4-Cyclohexanedione ethylene ketal (5.00 g, 32.0 mmol, 1 eq.), sodium triacetoxyborohydride (8.14 g, 38.4 mmol, 1.2 eq.) and benzylamine (3.50 mL, 32.0 mmol, 1 eq.) were mixed in methylene chloride (100 mL) at room temperature. Stirred for 20 hours. Added 50 mL of 1.0 N NaOH. Stirred for 10 minutes. Extracted 3 times with methylene chloride (50 mL). The organic layers were combined, dried over sodium sulfate and stripped to give N-(phenylmethyl)-1,4-Dioxaspiro[4.5]decan-8-amine (7.91 g) of a light amber oil as product. Yield=100%. LCMS detects (M+H)+=248.26.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][Cl:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:7]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.07 [M+H]+ No Ionization.
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and Cul (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1COCC1.C(Cl)Cl>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: CSCS(C)=O
Reactant: N#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
1.830 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of THF, and to the solution 415 mg of sodium hydride was added under cooling with ice, followed by 90 minutes' stirring at room temperature. Thereafter 1.520 g of benzonitrile was added. The system was stirred for 1.5 hours at room temperature and for 16 hours at 50°C., followed by the addition of 2 ml of water and 70 ml of methylene chloride, and for one hour stirring at room temperature. The reaction mixture was dried with Glauber's salt, and filtrated. The filtrate was concentrated under reduced pressure and the resulting yellow solid was crystallized from ethylene chloride-carbon tetrachloride and a minor amount of cyclohexane. Thus 2.391 g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene was obtained. The isolation yield was 77.1%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Yield: 74.7 %

Procedure:
A mixture of 0.073 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 112 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of trimethylsilyldiazomethane in CH2Cl2 (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6aminonicotinate as a yellow solid. Title compound was prepared from this crude methyl 6-aminonicotinate in 17% yield according to a procedure similar to that described in Preparation 6.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17]CC3C=CC=CC=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1

Procedure:
To a solution of 1-Benzyl-4-benzyloxy-2-methyl-1H-indole (2) (35 g, 0.107 mole) in methanol (1 L) and ethyl acetate (500 mL), Pd/C (10%, 17 g) was added. Hydrogen was bubbled through the mixture at room pressure and temperature for 6 h. The reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (6:1 Hex:EtOAc) to afford intermediate (3) as an orange solid. Yield: 22 g (60%)
Reaction SMILES: C(O)[CH2:2][CH2:3][CH2:4][OH:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-:12].[Na+]>>[CH2:7]([O:5][CH2:4][CH:3]1[O:12][CH2:2]1)[CH:9]1[O:11][CH2:10]1
Reactant: ClCC1CO1
Reactant: [OH-]
Reactant: OCCCCO
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
In a 750 ml sulfonation flask equipped with thermometer, reflux condenser, N2 inlet and metering device, 90.12 g (1.0 mol) of 1,4-butanediol are added to catalyst B and the reaction mixture is heated to 100° C. With efficient stirring, 160.7 ml (2.05 mol) of epichlorohydrin are added over 1 h and the mixture is allowed to react for 1 h. Afterwards the reaction mixture is cooled to 50° C. and to the solution are added 16 g (0.2 mol) of a 50% aqueous solution of NaOH over 5 min. Then 76 g (1.9 mol) of pulverised NaOH are added by increments over 45 min and the suspension is stirred for 30 min. The reaction mixture is filtered, washed with 100 ml of toluene and the phases are separated. The organic phase is dried over MgSO4, filtered and the filtrate is freed from solvent on a rotary evaporator (bath temperature 70° C.), giving 199.0 g (98% of theory) of colourless diglycidyl ether of 1,4-butanediol having the following properties: epoxy value: 8.64 eq/kg (87% of theory); total chlorine content: 3.4%; concentration of hydrolisable chlorine: 620 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.[OH:21]C(C(C)=C)C(OCC)=O.Cl.[C:32]1([CH3:38])C=CC=C[CH:33]=1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.C([N+](CC)(CC)CC)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:21])[C:17](=[C:32]([CH3:38])[CH3:33])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OCC
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.7 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (1.16 g, 11.2 mmol) and tetraethylammonium p-toluenesulfonate (151 mg, 0.50 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3.5 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.76 g, yield 49.7%).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([O:30]COC)=[CH:26][CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4 (2.89 g, 6.09 mmol) in MeOH (40 ml) was added 4N HCl in 1,4-dioxane (15.2 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual solid was triturated with AcOEt to give 5 (89%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCCCCCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a solution of ethyl 7-bromoheptanoate (10.0 g, 42.17 mmol) in toluene (280 mL) was added solid triphenylphosphine (11.06 g, 42.17 mmol). The solution was refluxed over 24 hours under nitrogen atmosphere and then cooled to room temperature. The supernatant was transferred into a different flask and an excess of triphenylphosphine (5.53 g, 21.09 mmol) was added. The solution was refluxed over 3 days and cooled to room temperature without stirring to favor sedimentation. The supernatant again removed by decantation and the resulting colorless oil was dried over high vacuum affording the title compound 176 (18.24 g) in 87% yield. 1H NMR: (300 MHz, CDCl3) δ: 7.96-7.62 (m, 9H), 7.37-7.08 (m, 6H), 4.11-4.00 (m, 2H), 3.86-3.70 (m, 2H), 2.37-2.32 (m, 4H), 2.28-2.19 (m, 2H), 1.72-1.46 (m, 6H), 1.31-1.25 (m, 2H), 1.22-1.15 (m, 3H). MS (ESI)=419 (Phosphonium Ion).