Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCCCCC.C([Li])CCC.[C:24](=[O:26])=[O:25]>O1CCCC1>[Cl:8][C:7]1[C:2]([F:1])=[C:3]([C:4]([C:9]([F:12])([F:10])[F:11])=[CH:5][CH:6]=1)[C:24]([OH:26])=[O:25]
Reactant: Fc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
77.0 g of 3-fluoro-4-chlorobenzotrifluoride was dissolved in 750 ml of dried tetrahydrofuran, and to the solution, 250 ml of hexane solution of n-butyl lithium (1.6 mol/l) was added dropwise over 15 minutes at -78° C. under a nitrogen atmosphere. After stirring the solution at -78° C. for 2 hours. 50 g of dry ice was gradually added to the solution at the same temperature. After elevating the temperature of the solution up to room temperature, 500 ml of ice water was added to the solution to separate the resulting solution. While cooling down the aqueous layer, the layer was adjusted to a pH value of 1 with concentrated hydrochloric acid. The aqueous layer was then extracted with ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the oily residue obtained was crystalized with n-hexane, followed by a filtration and then dried to obtain 88.4 g of the title compound(mp. 92-93° C.).
Reaction SMILES: N1([C:6](=[S:31])[O:7][CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])C=CN=C1.CO.[O:34]1CCOC[CH2:35]1>C(Cl)(Cl)Cl>[CH3:35][O:34][C:6]([O:7][CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[S:31]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(OC(=S)n1ccnc1)c1ccccc1
Reactant: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=S)OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
4.3 g. (10mM) of α[(1H-imidazol-1-yl)thioxomethoxy]-benzeneacetic acid, diphenylmethyl ester together with 0.35 g. of methanol in 30 ml. of dioxane and one drop of a 10% sodium imidazole-dioxane solution, are held at 40° for 5 hours. After drawing off the solvent, the oily residue is dissolved in chloroform and washed three times, each time with 30 ml. of water. After drawing off the solvent, 2.3 g. of α-[(methoxycarbonothioyl)oxy] benzeneacetic acid, diphenylmethyl ester are obtained from the dried chloroform solution in the form of a pale yellow oil which crystallizes after 24 hours. Recrystallization from cyclohexane/petroleum ether yields 1.6 g. of white crystals, m.p. 74°.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.[I:22]I.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[I:22][CH:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:12]
Reactant: II
Reactant: O=C1CCCc2ccccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2ccccc2CCC1I
Temperature: 30 °C
Yield: 57.5 %

Procedure:
A suspension of 1.8 Kg (11.17mol) of 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L of methylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane was heated at reflux for 10 minutes, then cooled to 30° C. and treated with 8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated at reflux for 2.5 hours, then cooled to room temperature. Aqueous sodium sulfite containing 4.926 Kg of sodium sulfite in 44 L of water was cooled to 0° C. and into it was poured the reaction mixture in several portions with vigorous stirring while maintaining the temperature below 10° C. The reaction vessel was rinsed with 22.33 L of methylene chloride and the washing transferred to the quenching mixture. The quenching mixture was stirred vigorously and the layers allowed to separate. The aqueous layer was removed and reextracted with 22.33 L of methylene chloride. The combined organic layers were washed with 11 L of water and concentrated under vacuum to a final volume of approximately 5 L. The residue was treated with 55 L of toluene and concentrated under vacuum to a final volume of 10 L. The resulting slurry was isolated by filtration and the filter cake washed with an additional 5 L of toluene and dried under vacuum at ambient temperature for 24 hours to give 1.842 Kg (6.42 mol, 57%) of product. 1H NMR (200 MHz, CDCl3): δ 2.6-2.8 (m, 3H), 2.93 (m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.10-7.35 (m, 3H), 7.55 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][CH:26]=3)(=[O:31])=[O:30])[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(OS(=O)(=O)c2ccc(Br)s2)c2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.5 mmol, 0.099 g) is suspended in 5 mL of DCM, and enough DIEA is added to bring the pH to 9 as measured by pH paper. The solution is cooled to 0° C., and 5-bromo-thiophene-2-sulfonyl chloride (0.5 mmol, 0.13 g) is added. The solution is warmed to ambient temperature and is stirred 2 hrs. The solvent is removed under reduced pressure and the residue is triturated with Et2O. The resulting solid is filtered, is washed with Et2O, and is dried to afford the title compound (45 mg, 21%). 1H NMR (CDCl3, 300 MHz) δ 7.65 (1H, d, J=4.25 Hz), 7.56 (2H, m), 7.29 (1H, d, J=8.75 Hz), 7.19 (1H, d, J=4.25 Hz), 6.48 (1H, s), MS (ESI, Pos.) calcd for C13H6BrClO5S2 m/z [M+H]=420.9, found 420.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O1[CH2:15][CH2:14][NH:13]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][CH2:14][NH:13][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C1NCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1cccc(Cl)c1
Temperature: 195 °C
Yield: 74 %

Procedure:
A mixture of 3-chlorophenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 74 percent of the desired product, m.p. 121° C.-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cncc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Reaction time: 120 h
Yield: 90.3 %

Procedure:
To a solution of methyl (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylate (2.25 g) in tetrahydrofuran (20 ml) was added 1N sodium hydroxide (11 ml) at room temperature, and the mixture was stirred for 5 days. To the reaction mixture was added 1N hydrochloric acid (12 ml), and the mixture was concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with water and diethylether to give (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (1.92 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[CH2:8][N:9](C)[C:10](=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[CH2:8][NH:9][CH3:10]
Reactant: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1nc2ccn(COCC[Si](C)(C)C)c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A mixture of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-Pyrrolo[3,2-b]pyridin-5-yl)methyl(methyl)carbamate (200 mg, 0.5 mmol) in CH2Cl2 (5 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and then quenched by adding a sat'd. aq. NaHCO3 until the pH was about 8. The mixture was extracted with EtOAc (20 mL×2), and the combined extracts dried (MgSO4), filtered and concentrated under reduced pressure to afford 120 mg (70%) of (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylmethanamine as a brown oil. MS (ESI): m/z=310.3 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9](F)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([OH:38])[CH:27]=[N:28][C:29]=1[O:30][CH2:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34].COC(C)(C)C>CS(C)=O>[Cl:7][C:8]1[C:9]([O:38][C:26]2[CH:27]=[N:28][C:29]([O:30][CH2:31][C:32]([F:36])([F:37])[CH:33]([F:35])[F:34])=[C:24]([Cl:23])[CH:25]=2)=[CH:10][C:11]([F:21])=[C:12]([CH:20]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(OCC(F)(F)C(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Potassium carbonate (3.02 g, 21.85 mmol) was added portionwise to a suspension of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 2.26 g, 9.09 mmol), 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-ol (Preparation 73, 2.25 g, 8.67 mmol) in DMSO (13.5 mL). The mixture was stirred at room temperature under nitrogen for 3 hours. tert-butyl methyl ether (50.0 mL) was added and the mixture was washed with water (3×50.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was suspended with heptane (20.0 mL) and concentrated in vacuo. The resulting solid was suspended in heptane (20.0 mL) and heated to 90° C. until full dissolution. The mixture was cooled with stirring and the residual solid collected by filtration. The filtrate was concentrated in vacuo and the resulting solid was suspended in heptane (10.0 mL) and heated to 90° C. until dissolution. The mixture was again cooled with stirring and the residual solid collected by filtration. The two crops were combined to yield the title compound as a white solid (2.58 g, 5.29 mmol, 61%):
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](Cl)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:23]#[N:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]#[N:24])=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Clc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
2-(4-Chlorophenyl) 2,2-diphenylacetonitrile was synthesized by carefully triturating 1.50 g (4.8 mmol) of 4-chlorotrityl chloride with 1.00 g (11 mmol) of copper cyanide and the resulting mixture was heated for 4 hours at 150° C. without a solvent. After cooling 50 ml of toluene was added, the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from petroleum ether (40-60° C.) to give 0.66 g (45%) of the triarylmethyl acetonitrile derivative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][C:22](=O)CC(=O)C.C([O-])(O)=O.[Na+]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]([F:12])[C:7]2[N:11]=[C:21]([CH3:22])[NH:10][C:8]=2[CH:9]=1)=[O:20]
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc2[nH]c(C)nc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4,5-Diamino-3-fluoro-2-phenylamino-benzoic acid methyl ester 6c (0.20 g, 0.73 mmol) is suspended in ethanol (3 mL) and 5 M aqueous NCl (1 mL, 5.00 mmol) is added. The reaction mixture is brought to reflux under N2 and then 2,4-pentanedione (0.150 mL, 1.45 mmol) is added. The reaction mixture is stirred at reflux for 60 minutes. The reaction mixture is cooled to room temperature and treated with saturated aqueous NaHCO3 until the pH of the reaction mixture is pH 7 and is then concentrated under reduced pressure to dryness. The residue is diluted with ethyl acetate and water, poured into a separatory funnel and the layer separated. The ethyl layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The red solid residue is triturated with diethyl ether to yield a light brown solid and red filtrate. The solid is collected and washed with diethyl ether to yield 0.20 g (91%) of the pure desired product as a light brown solid. MS ESI (+) m/z 300 (M+1) detected.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])([C:6]2[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)O)[CH2:3][CH2:2]1.[Br:19][Si](C)(C)C.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccccc1C(O)(c1cccn1C)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1C(=CCCBr)c1cccn1C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Cyclopropyl-(2-methylphenyl)-(N-methylpyrrol-2-yl)methanol (9.9 g, 0.041 mole) was dissolved in dichloromethane (250 ml) and cooled to -70° C. under nitrogen. Bromotrimethylsilane (6.4 g, 0.042 mole) in dichloromethane (250 ml) was added within 30 min. The reaction mixture was stirred at -70° C. for another 90 min. Pyridine (3.5 ml) was added and when the mixture had reached room temperature, saturated sodium bicarbonate solution (100 ml) was added. The phases were separated and the organic phase was dried (MgSO4) and evaporated leaving the title compound as an oil (10.9 g).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:9]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH3:10].C(N(CC)CC)C>O1CCOCC1>[C:1]([NH:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOc1ccc(C(=O)NN)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)NNC(=O)c1ccc(OCC)cc1
Yield: 90.7 %

Procedure:
29 g of ethoxalyl chloride are added, in the course of 30 minutes, to 36 g of 4-ethoxybenzhydrazide and 21.3 g of triethylamine in 360 ml of anhydrous dioxane, whilst keeping the temperature of the reaction medium at about 10° C. The stirring is continued (sic) for about two hours, whilst allowing the temperature to return to the ambient value. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure (20 mm Hg, 50° C.) and the residue is stirred in the presence of 200 ml of isopropyl ether and then filtered off. After drying (20° C., 1 mm Hg), 50.8 g of 1-ethoxalyl-2-(4-ethoxybenzoyl)-hydrazine, which melts at 126° C. after a first melting at 120° C., are obtained. Yield: 90.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
7-Benzyloxy-6-methoxy-quinolin-4-ol (WO2006108059) (1 g) was refluxed with POCl3 (8 ml) for 3 hours. The reaction was evaporated and dissolved into DCM (80 ml) that was washed with ice water followed by brine. The organic layer was dried with Na2SO4 and evaporated to dryness to give a dark yellow solid as 4-chloro-7-benzyloxy-6-methoxy-quinoline that was mixed with 5-aminoindole (600 mg) in isopropanol (15 ml). The mixture was refluxed for one hour and cooled to RT and the precipitate was filtered to give the product as 4-(1H-indol-5-ylamino)-7-benzyloxy-6-methoxy-quinoline (710 mg). This product was mixed with Pd/C (10%, 100 mg) in EtOH (80 ml) and hydrogenated at 50 psi for 8 hours to give a gray suspension that was evaporated to dryness as 4-(1H-indol-5-ylamino)-7-hydroxy-6-methoxy-quinoline (˜85% purity) for next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].[I-].[K+]>CO.O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1]
Reactant: Cc1ccnc(O)c1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccn(CCCCCl)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
A mixture of 2-hydroxy-4-methylpyridine (1.50 g, 13.75 mmol) and potassium carbonate (1.90 g, 13.75 mmol) in 13 ml of methanol were stirred at room temperature for 15 minutes and then 1-bromo-4-chlorobutane (3.54 g, 20.62 mmol) and a spatula tip of potassium iodide were added thereto. The reaction mixture was heated to reflux for 6 hours and then stirred at room temperature for 12 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted with dichloromethane. Drying of the organic phase and removal of the desiccant by filtration was followed by concentration of the organic phase in vacuo. Flash chromatography of resulting residue on silica gel (eluent: CH2Cl2/CH3OH: 98:2) afforded 2.0 g of 1-(4-chlorobutyl)-4-methylpyridin-2(1H)-one.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)=[O:18])[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:18])[NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@H:23]([O:30][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([N:40]5[CH2:45][CH2:44][CH:43]([CH2:46][O:47][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:42][CH2:41]5)=[N:38][N:39]=4)[CH:36]=3)[CH2:22][CH2:21]2)[N:13]([CH3:15])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(CO)CC4)n3c2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(COS(C)(=O)=O)CC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Methanesulfonyl chloride (8.8 μL, 0.13 mmol) was added to a solution of Intermediate 14g (50 mg, 0.08 mmol) and DIPEA (46 μL, 0.26 mmol) in DCM (1.5 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound (57 mg, 100%). LCMS (Method 3): Rt: 3.21 min, m/z 651 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=O)[C:7]([C:15]([O:17]CC)=[O:16])=[CH:8][N:9]2[CH2:13][CH3:14])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(CC)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCN1C=C(C(=O)O)Cc2cnc(Cl)c(Cl)c21
Temperature: 0 °C

Procedure:
6.2 g (0.0196 mol) of ethyl 7,8-dichloro-1-ethyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 26 ml of acetic acid, 26 ml of water and 2.6 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>CCCCCCC>[CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH2:18]2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: Cc1ccc(-c2nc(CO[C@H]3CCC[C@@H](OCc4cccc(C)c4C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
from tert-butyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-cyclohexyloxymethyl]benzoate: 200 g (396 mmol) of tert-butyl methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoate are dissolved in n-heptane. 300 g (2.6 mol) of trifluoroacetic acid are added. The reaction is stirred at RT for 24 hours and subsequently concentrated fully by evaporation. The residue is taken up in 1.0 l of diisopropyl ether and washed four time with 500 ml each time of water. Subsequently, 1.0 l of water is added and a basic pH is established by addition of sodium hydroxide solution (4 M). After phase separation, the aqueous phase is washed twice with 400 ml each time of diisopropyl ether. After addition of 1.6 l of diisopropyl ether, the mixture is acidified with hydrochloric acid (2 M). After phase separation, the organic phase is washed four times with 500 ml each time of water and subsequently concentrated to about a third of the volume. 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoic acid precipitates out as a crystalline solid and is filtered off. After drying under reduced pressure, 2-methyl-6-[(1R,3S)-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyloxymethyl]benzoic acid is obtained in 66% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[I:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[I:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccccc1I
Product: O=C(O)Cc1ccccc1Nc1ccccc1I

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-iodoaniline to yield 2-[(2-iodophenyl)amino]phenylacetic acid.