Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
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+]
Product: Cc1ccccc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 85.1 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-methylphenylboronic acid (42 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (65 mg, 86% yield). EIMS 306.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:17]/[N+:14]([O-:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[N+](=O)[O-]
Reactant: CCCCOc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCOc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 75.7 %

Procedure:
A mixture of 4-butoxy-benzaldehyde (4.72 g, 26.5 mmol) described in Manufacturing Example 67-1-1, nitromethane (2.85 mL, 53 mmol), ammonium acetate (3.06 g, 39.8 mmol) and acetic acid (40 mL) was stirred for 13 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (4.44 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:6][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13](=[O:14])[CH:12]=1
Reactant: O=C(CO)c1ccccc1
Reactant: O=C(O)c1ccccc1F
Product: O=c1cc(-c2ccccc2F)oc2ccccc12

Procedure:
9 is prepared from 2-fluorobenzoic acid and 2-hydroxyacetophenone by the procedures of Examples 7 and 8. The crude material is purified by vacuum column (gradient elution using 10% ethyl acetate in hexane, 20% ethyl acetate in hexane, and 30% ethyl acetate in hexane). The material is then recrystallized from hexane/ethyl acetate, yielding 9 with a melting point of 98°-100° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[O:26][C:27]1[O:31][CH:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[O:26][C:27]1[O:31][CH:30]=[C:29]([C:32]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:11]=3)[CH2:6][CH2:5]2)=[O:33])[CH:28]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C(Cl)c1coc(Oc2cc(Cl)cc(Cl)c2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)c3coc(Oc4cc(Cl)cc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-3-furoyl chloride: ESMS m/e: 544.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[N:3]1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:16][CH2:15]1.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[F:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:3]2[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2CN1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 9 h
Yield: 16.5 %

Procedure:
Powdered zinc (2.97 g) is added at a temperature in the region of 20° C. to a stirred solution of (RS)-3-hydroxy-2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}isoindolinone (3.4 g) in acetic acid (21 cc). The mixture is heated to boiling for 9 hours and then cooled to a temperature in the vicinity of 20° C. After the addition of distilled water (30 cc), the solution is alkalinized to pH 7-8 with sodium bicarbonate. The organic phase is extracted with dichloromethane (4×30 cc), washed with distilled water (30 cc), dried over anhydrous magnesium sulphate, treated with vegetable charcoal, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column under a stream of argon at moderate pressure (0.5-1.5 bar) with ethyl acetate and then a mixture of ethyl acetate and methanol (98:2 by volume) as eluents. After recrystallization in ethyl acetate (40 cc), 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}isoindolinone (0.54 g), m.p. 175° C., is obtained.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])(O)[CH:8]=[CH2:9])([CH3:3])[CH3:2].[C:12](O)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(OCC)=C>[CH:1]([O:4][CH2:5][CH2:6][C:7]([CH3:11])=[CH:8][CH2:9][CH2:13][CH:12]=[O:14])([CH3:3])[CH3:2]
Reactant: C=CC(C)(O)CCOC(C)C
Reactant: CC(=O)O
Agent: C=COCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=CCCC=O)CCOC(C)C

Procedure:
15.8 g (0.1 mol) of 5-isopropoxy-3-methyl-1-penten-3-ol and 20.0 g of mercuric acetate in 180 cc of ethyl vinyl ether are maintained at reflux temperature over the course of 4 days. 0.9 cc of glacial acetic acid is added at 20° to the turbid solution. After 3 hours 150 cc of 5% potassium carbonate solution are added and the product is extracted with hexane. The hexane extract is dried with sodium sulphate and evaporated. The residue is heated to 165°-168° over the course of 11/2 hours without further purification and in an atmosphere of nitrogen; the residue is subsequently distilled at reduced pressure. The 7-isopropoxy-5-methyl-4-heptenal has a B.P. of 70°-73°/0.8 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=Cc1cccc(OCC(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)COc1cccc(CO)c1

Procedure:
A solution of 3-formylphenoxyacetic acid (5.Og.) in ethanol (50 ml.) was added to a suspension of sodium borohydride (2.11 g.) in ethanol (100 ml.) with stirring. After 2 hours the reaction was quenched with acetic acid (20%, 50 ml.) and the bulk of the solvent was evaporated. Water (50 ml.) was added and the aqueous mixture was extracted with ethyl acetate (2×100 ml.). The combined extracts were washed with saturated brine (100 ml.), dried (MgSO4) and evaporated to give 3-(hydroxymethyl)phenoxyacetic acid (4.66 g.) as an off white solid, NMR: 4.5(2H,s), 4.65 (2H,s) and 6.6-7.4 (4H,m)ppm, which was used without further purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].Cl>O1CCCC1>[N+:19]([C:16]1[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:18][C:17]=1[CH:5]([C:4](=[O:3])[CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:21])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
Sodium hydride (417 mmol) was added to a solution of ethyl 3-oxobutanoate (129 mmol) in tetrahydrofuran (350 mL). 1-Chloro-2,4-dinitrobenzene (123 mmol) was added and the resulting suspension was maintained for 24 h at rt. The pH was adjusted to 5 by the addition of 3 M hydrochloric acid and the resulting solution was extracted with diethyl ether (300 mL). The organic layer was washed with water (3×300 mL), dried (magnesium sulfate), and concentrated to provide ethyl 2-(2,4-dinitrophenyl)-3-oxobutanoate in 98% yield as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:22]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]CC1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:22]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrC1CCCCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and cycloheptylbromide as described for compound 8. Purified by chromatography (dichloromethane) and crystallized from diethyl ether. M.p. 131-133° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.CO.[OH-].[Na+]>CCOC(C)=O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:36])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 4 h
Yield: 54.9 %

Procedure:
3-{4-[1-(4′-tert-butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (30 mg) is taken into MeOH (10 mL), followed by the addition of 5N NaOH (1 mL). The reaction is stirred for 4 h, diluted with EtOAc, washed with aqueous HCl, and brine. The organic portion is dried over MgSO4, and concentrated to afford 16 mg of the titled compound. MS (ES): 487.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1
Reactant: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2cc(F)ccc2n1
Temperature: 25 °C

Procedure:
A stirred solution of ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.2 g, 5.08 mmol) in phosphorus oxychloride (15 mL) was heated at 105° C. for 6 h. After cooling to rt, the reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in anhydrous toluene. The toluene was concentrated under reduced pressure. The residue was dissolved in a small volume of DCM and it was passed through a short pad of silica gel eluting with DCM. Ethyl 4-chloro-6-fluoroquinazoline-2-carboxylate was obtained as a solid (1.3 g, 100%). LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]([OH:15])=[O:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CO>[C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([OH:16])=[CH:18][CH:19]=3)[C:9]([C:13]([OH:15])=[O:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1=NN(c2ccccc2)C(=O)C1
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
204 g (1 mole) of 1-phenyl-3-carboxy-2-pyrazolin-5-one and 122 g (1 mole) of p-hydroxybenzaldehyde were dissolved in 1000 ml of methanol. After a few minutes of refluxing the dye started crystallizing and after 1 h of boiling the reaction mixture was cooled to room temperature. The dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:32])[CH:21]=[C:22]([CH2:26][CH3:27])[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:28]([F:30])([F:29])[F:31]
Reactant: CCc1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: CCc1cn(C)c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c2)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To a suspension of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(5-ethyl-4-oxo-1,4-dihydro-2-pyrimidinyl)thio]methyl}benzonitrile (120 mg, 0.258 mmol) and DIPEA (0.090 ml, 0.515 mmol) in DCM (2 mL) was added MeI (0.02416 ml, 0.386 mmol). The mixture was stirred at room temperature for 2 h. The reaction was then quenched with water, extracted with EA. The combined organic layers were dried with Na2SO4, filtered, concentrated and purified via reverse phase flash chromatography to afford the title compound (40 mg, 32.4% yield). LCMS: rt=3.44 min, [M+H+]=480
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:3]=1.[BH4-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)O
Yield: 62.9 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-propanon-1-yl)oxybenzamide (1.28 g, 3.7 mmoles) and sodium borohydride (80 mg, 2.1 mmoles) in absolute ethanol (15 ml) was refluxed for 30 minutes, followed by addition of another 50 mg (1.3 mmole) of sodium borohydride and reflux for 10 minutes. The mixture was acidified with 2N HCl and concentrated in vacuo. The residue was partitioned between water and ether, and the ether layer was discarded. The aqueous layer was made basic with N2CO3 and the solid filtered off to give 0.80 g (77%) of the title compound mp 149°-150°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.48 (bs, 1H); 8.16 (s, 1H); 6.28 (s, 1H); 4.4-3.4 (m, 7H); 2.64 (m, 6H); 1.26 (d, J=7.5Hz, 3H); 1.08 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>O1CCCC1>[OH:12][CH2:11][C:3]1[CH:2]=[N:1][CH:6]=[C:5]([CH:4]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cncc(CO)c1
Temperature: 0 °C
Yield: 26 %

Procedure:
1.67 g of dimethyl pyridine-3,5-dicarboxylate was dissolved in 30 ml of anhydrous tetrahydrofuran, and with stirring under ice cooling, 162 mg of lithium aluminium hydride was added. The mixture was stirred at this temperature for 30 minutes. The reaction mixture was poured into ice water, and ethyl ether was added to extract it. The extract was worked up in a customary manner to give crude methyl 5-hydroxymethylnicotinate. The crude product was dissolved in 20 ml of methylene chloride, and 2.2 g of pyridinium chlorochromate was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water. The organic layer was separated, worked up in a customary manner, and purified by silica gel column chromatography Wakogel C-200, 80 g; eluting solvent: chloroform/methanol=20/1) to give 0.37 g (yield 26%) of
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:29][CH:30]1[CH2:33][NH:32][CH2:31]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH:30]([OH:29])[CH2:31]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CNC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(CN2CC(O)C2)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxy-1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 1d, 72 mg, 0.17 mmol) in DMF (2 mL) is added 3-hydroxyazetidine hydrochloride (56 mg, 0.51 mmol). The reaction mixture is stirred for 30 min at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson, Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: COS(OC)(=O)=O.[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.[C:20]1(C)C=CC=CC=1.[OH-].[Na+]>O>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([CH3:20])[CH:19]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc(-c2c[nH]cn2)c1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cn1cnc(-c2cccc(Br)c2)c1
Temperature: 100 °C
Yield: 33 %

Procedure:
Using the method of Hazeldine et al., J. Chem. Soc., 125, 1431-41 (1924) a mixture of dimethylsulphate (145 μl, 1.53 mmol) and 4-m-bromophenyl imidazole (341 mg; 1.54 mmol) was stirred under N2 until the reaction mixture became extremely viscous. Toluene (150 μl) was added, and the mixture was heated at 100° C. for 1 hour. After cooling to ambient temperature, H2O (5 ml) was added, and the reaction mixture was brought to pH 9 with NaOH solution. It was then extracted with CH2Cl2 (2×10 ml). The organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo to give 262 mg crude product mixed with starting material. Purification using preparative TLC on 2-1000μ Si Gel GF plates (eluting with 5% MeOH in CH2Cl2 and extracting with 10% MeOH in CH2Cl2) provided the product, 4-m-bromophenyl-1-methylimidazole (121 mg, 33% yield) as the least polar band.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (13 g, 36 mmol) in DCM (100 mL) was added pyridine (8.5 g, 107 mmol). The mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (9.1 g, 43 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt over night. Then the reaction was washed with water (100 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (12 g, 62.2% yield, two batches combined). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95-11.05 (br, 1H), 8.54 (d, J=5.2 Hz, 1H), 7.67-7.79 (m, 1H), 7.45-7.50 (m, 2H), 7.22-7.37 (m, 3H), 7.10 (d, J=5.2 Hz, 1H), 1.42 (s, 9H). MS (ES+): 539 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([CH3:44])([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26](NC(CC1CCCCC1)C(=O)C(=O)CCC)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5]>CO>[C:4]([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([OH:1])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])([CH3:44])([CH3:3])[CH3:5]
Reactant: [OH-]
Reactant: CCCC(=O)C(=O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
Sodium hydroxide (1N; 12 ml, 12 mmol) was added to a 40 ml methanol solution of (S)-<α-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanoic acid, methyl ester (3.92 g, 10 mmol) and a chromatography check after one hour revealed total disappearance of starting material. The solvents were removed on rotary evaporator. The resulting white solid was suspended in 10 ml of water and 50 ml of ethyl acetate, acidified to pH=3.5 using 1N hydrochloric acid and the two layers separated. The aqueous layer was reextracted with ethyl acetate (3×30 ml), combined organic extracts dried over sodium sulfate and concentrated to give 3.54 g of the title E compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21](C(OC(C)(C)C)=O)[C:20]([C:32]2[C:33](=[O:42])[NH:34][C:35]4[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:19]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>CS(C)=O.O>[N:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([C:32]2[C:33](=[O:42])[NH:34][C:35]4[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:19]3)=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:48]([OH:50])([C:47]([F:52])([F:51])[F:46])=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3c(c2)cc(-c2cc4ccccc4[nH]c2=O)n3C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1)N1CCNCC1

Procedure:
A solution of tert-butyl 5-{[4-(tert-butoxycarbonyl)-1-piperazinyl]carbonyl}-2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-indole-1-carboxylate (6-2, 213 mg, 0.373 mmol, 1 equiv) in a 1:1 mixture of CH2Cl2 and trifluoroacetic acid (40 mL) was treated with 3 drops of DMSO and H2O, and the resulting mixture was heated at reflux for 45 minutes. The solution was concentrated, and the residue was dried by azeotropic removal of water using a 90:10 mixture of toluene and methanol (100 mL). It was then purified by reverse phase chromatography (H2O/CH3CN gradient with 0.1% TFA present) to provide 3-[5-(1-piperazinylcarbonyl)-1H-indol-2-yl]-2(1H)-quinolinone (6-3) as a TFA salt (brown solid). 1H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 11.83 (s, 1H), 8.59 (s, 1H), 7.75 (d, 1H, J=7.9 Hz), 7.74 (s, 1H), 7.59 (d, 1H, J=8.3 Hz), 7.54 (t, 1H, J=7.6 Hz), 7.42 (s, 1H), 7.39 (d, 1H, J=8.3 Hz), 7.25 (m, 2H), 3.86–3.15 (br m, 8H).