Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[CH3:19][C:16]([Si:13]([CH3:14])([CH3:15])[O:20][CH2:21][CH2:22][N:23]([CH3:24])[S:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])(=[O:11])=[O:10])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.7 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (1 g, 4.70 mmol) in DCM (2 mL) was added slowly to a solution of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (980 mg, 5.17 mmol) in DCM (65 mL) and 10% sodium hydroxide solution (65 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL). The combined organics were washed with brine (80 mL), dried (MgSO4), and reduced in vacuo to give the desired compound as a colourless oil (0.7 g). 1H NMR δ (CDCl3): 0.00 (s, 6H), 0.83 (s, 9H), 2.91 (s, 3H), 3.24 (t, 2H), 3.73 (t, 2H), 6.87-6.96 (m, 2H), 7.82-7.88 (m, 1H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[K+].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cncn1
Temperature: 110 °C
Yield: 18.7 %

Procedure:
2-Chloro-5-nitroanisole (0.5 g, 2.67 mmol), potassium hydroxide (219 mg, 3.92 mmol) and 1,2,4-triazole (736 mg, 10.66 mmol) were dissolved in dimethyl sulfoxide (2.5 mL), and heated at 110° C. for 24 h. The reaction mixture was poured onto ice-water (100 mL). The solid was collected by filtration and purified by flash column chromatography CH3Cl 2% methanol to yield 110 mg of 3-Methoxy-4-(1H-1,2,4-triazol-1-yl)nitrobenzene. 3-Methoxy-4-(1H-1,2,4-triazol-1-yl)nitrobenzene (105 mg, 0.48 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (20 mg) was added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and the solvent evaporated to yield 77 mg of 265A. HPLC method A 97% pure. Mass spectrum M+H+=191.1, 1H 400 MHz NMR (CH3OD): δ8.65 (s, 1H), 8.09 (s, 1H), 7.25 (d, 1H, J=8.56), 6.52 (d, 1H, J=2.19) 6.40-6.35 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 95.3 %

Procedure:
The title compound was prepared from 36 (7.5 mg, 0.017 mmol) following general procedure A. Flash chromatography (SiO2, 5% MeOH—CH2Cl2) afforded the title compound (6.5 mg, 95%) as a white solid: 1H NMR (DMSO-d6, 600 MHz) δ 8.26 (dd, 1H, J=8.4 Hz), 8.16 (dd, 1H, J=8.4 Hz), 8.06 (t, 1H, J=7.8 Hz), 7.55-7.51 (m, 4H), 7.36-7.33 (m, 3H), 7.24 (t, 1H, J=7.2 Hz), 4.26-4.22 (m, 1H), 3.13-2.99 (m, 2H), 2.86-2.84 (m, 2H); 13C NMR (DMSO-d6, 150 MHz) δ 167.2, 166.2, 164.2, 149.9, 144.1, 141.1, 139.6, 139.2, 138.7, 130.9, 129.5, 127.9, 127.5, 127.3, 126.3, 70.2, 43.4, 33.7; HRMS-ESI-TOF m/z 402.1443 ([M+H]+, C23H19N3O4 requires 402.1448).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[F:8][C:6]1[CH:5]=[C:4]([CH:9]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:10]/[C:11](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:32]\[OH:33])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2cc(F)cc(F)c2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=447.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16](O)(=[O:18])[CH3:17].C(OC(=O)C)(=O)C>O>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])(=[O:18])[CH3:17]
Reactant: Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Yield: 76 %

Procedure:
A solution of 7-amino-6-nitro-3H-quinazolin-4-one (5.90 g, 28.6 mmol) [Leonard, N. J.; Morrice, A. G.; Sprecker, M. A.; J. Org. Chem., 1975, 40, 356-363] in a mixture of glacial acetic acid (300 mL) and acetic anhydride (100 mL) is heated under reflux for 6 h, and water (100 mL) is added. The solution is then concentrated to a small volume to give 7-acetamido-6-nitro-3H-quinazolin-4-one (5.37 g, 76%). 1H NMR (DMSO) δ10.51 (1H, brs), 8.57 (1H, s), 8.24 (1H, s), 7.97 (1H, s), 2.15 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:17])(=[O:16])[NH:14][CH3:15].[ClH:18]>COCCOCCOC>[Cl:18][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:13](=[O:17])(=[O:16])[NH:14][CH3:15])[CH:4]=1)=[O:12]
Reactant: CNS(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Reactant: Cl
Solvent: COCCOCCOC
Product: CNS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-methylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66(b) with concentrated HCl in diethyleneglycol dimethyl ether und worked up. Colorless crystals, melting point: 153° C.
Reaction SMILES: CN(C)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C([O-])(=O)C.[Na+]>ClCCCl>[C:3]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(=O)c1ccccc1
Reactant: c1cc[nH]c1
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N-dimethylbenzamide (48.0 g, 0.32 mol) in 1,2-dichloroethane (500 mL) was added oxalyl chloride (48.0 g, 0.38 mol). The reaction mixture was stirred for 24 hours at room temperature. To the reaction mixture was then added pyrrole (22.0 g, 0.33 mol). The reaction mixture was again stirred for 24 hours at room temperature. Aqueous sodium acetate (20%, 200 mL) was added to the reaction mixture and vigorous stirring was continued for 24 hours at room temperature. The organic layer was filtered through a silica gel column and concentrated under reduced pressure to yield 2-benzoylpyrrole which was used without further purification. Yield 43.0 g (80%).
Reaction SMILES: OS(O)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:23].[Br:24][C:25]1[CH:26]=[C:27]([N+]([O-])=O)[C:28]([C:31]#[N:32])=[N:29][CH:30]=1>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([F:23])[C:28]([C:31]#[N:32])=[N:29][CH:30]=1
Reactant: [F-]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: N#Cc1ncc(Br)cc1F
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a mixture of H2SO4 (0.2 ml) and TBAF solution (131 ml, 131 mmol, 1M in THF) was added DMF (40 ml) dropwise at −40° C. Then a solution of 5-bromo-3-nitro-pyridine-2-carbonitrile (10 g, 43 mmol) in DMF (130 ml) was added at −40° C. and the reaction mixture was stirred for 1 h. The reaction was then quenched by addition of 2M HCl solution at −40° C. adjusting the pH to 3. The resulting mixture was extracted twice with EtOAc and the combined organic extracts were washed twice with water, with brine, dried with Na2SO4 and evaporated in vacuo. The remaining residue was purified by chromatography (silica gel; hexane/EtOAc 90:10-80:20) to obtain the title compound as yellow solid (5.2 g, 59%).
Reaction SMILES: Cl.[CH3:2][O:3][CH:4]1[CH2:7][NH:6][CH2:5]1.CC([O-])(C)C.[K+].Br[C:15]1[CH:16]=[C:17]2[N:26]([CH3:27])[CH:25]=[CH:24][C:18]2=[N:19][C:20]=1[C@@H:21]([NH2:23])[CH3:22]>COCCOC>[CH3:2][O:3][CH:4]1[CH2:7][N:6]([C:15]2[CH:16]=[C:17]3[N:26]([CH3:27])[CH:25]=[CH:24][C:18]3=[N:19][C:20]=2[C@@H:21]([NH2:23])[CH3:22])[CH2:5]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: COC1CNC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)N)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a microwave vial containing 3-methoxyazetidine hydrochloride (500 mg, 4.05 mmol) were added KOt-Bu (1339 mg, 11.93 mmol) and DME (8 mL) under an atmosphere of nitrogen. The mixture was heated to 90° C. in a sand bath. A solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (461 mg, 1.82 mmol) in DME (8 mL) was added dropwise to the hot suspension. The mixture was stirred at 90° C. overnight. Additional KOt-Bu (1956 mg, 17.43 mmol) was added and the mixture was heated to 90° C. for 90 minutes. The reaction mixture was subsequently concentrated in vacuo. The residue was dispersed in DMSO/MeOH (1:1, 10 mL), filtered, and purified by preparative HPLC eluting with 15-40% ACN in water (with 0.035% NH4HCO3). The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (469 mg, 99%). ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[CH2:17]1[CH2:37][O:36][C:19]2([C:28]3[C:27](=[O:29])[CH:26]=[CH:25][C:24](=[O:30])[C:23]=3[CH2:22][C:21]([OH:35])([C:31]([O:33][CH3:34])=[O:32])[CH2:20]2)[O:18]1.C(OCC)C>C1(C)C(C)=CC=CC=1>[CH2:37]1[CH2:17][O:18][C:19]2([C:28]3[C:27](=[O:29])[C:26]4[C:25](=[CH:6][C:7]5[C:8]([CH:5]=4)=[CH:9][CH:10]=[CH:11][CH:12]=5)[C:24](=[O:30])[C:23]=3[CH2:22][C:21]([OH:35])([C:31]([O:33][CH3:34])=[O:32])[CH2:20]2)[O:36]1
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: COC(=O)C1(O)CC2=C(C(=O)C=CC2=O)C2(C1)OCCO2
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COC(=O)C1(O)CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)OCCO2
Yield: 74.6 %

Procedure:
A solution of 200 mg of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 100 mg of methyl rac-4,4-ethylenedioxy-1,2,3,4,5,8-hexahydro-2-hydroxy-5,8-dioxonaphthalene-2-carboxylate in 10 ml of xylene was stirred and heated under reflux for 1.5 hours under an atmosphere of nitrogen. The solution was evaporated to give a bright yellow crystalline residue. Trituration of this residue with diethyl ether gave 100 mg (74.5%) of methyl rac-4,4-ethylenedioxy-1,2,3,4,5,12-hexahydro-2-hydroxy-5,12-dioxonaphthacene-2-carboxylate in the form of yellow crystals of melting point 207°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:25])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 207, step 2, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 332, step 2) was coupled with 2-(methylsulfonyl)ethanamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=515.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH2:21])[CH:10]=2)[CH2:4][CH2:3]1.Br[C:23]1[CH:28]=[N:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:21][C:23]3[N:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=3)[CH:10]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1cnc(Br)cn1
Reactant: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CN1CCC(Nc2cc(Nc3cnc(C#N)cn3)ncc2-c2ccccc2)CC1
Temperature: 90 °C
Yield: 17.3 %

Procedure:
A solution of N4-(1-methylpiperidin-4-yl)-5-phenylpyridine-2,4-diamine (0.050 g, 0.17 mmol), 2-bromo-5-cyanopyrazine (0.022 g, 0.12 mmol), BINAP (0.003 g, 0.01 mmol), sodium tert-butoxide (0.016 g, 0.16 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.005 g, 0.01 mmol) in toluene (0.7 mL) was stirred at r.t. under nitrogen for 10 min before being heated under microwave irradiation for 30 min at 90° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (0.5 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was purified by preparative thin layer chromatography eluting with methanol/dichloromethane (1/9) to give the desired compound as a yellow solid (0.008 g, 17%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:31])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: O=C(NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Yield: 67.4 %

Procedure:
To a degassed solution of [4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamic acid benzyl ester 25 (0.19 g, 0.43 mmol) in ethanol (4 mL) was added 10% palladium on activated carbon (0.1 g, 50% wet). The mixture was hydrogenated overnight at atmospheric hydrogen. The catalyst was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20–5:1:0.1–1 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 26 (0.09 g, 72%) as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.56 (m, 4H), 2.56 (t, 2H), 2.65 (t, 1H), 3.29 (m, 1H), 3.55 (m, 4H), 3.72 (m, 4H), 4.90 (s, 2H), 6.86 (d, 2H), 7.09 (d, 2H). m/z (ESI): 311 [C16H26N2O4+H]+.
Reaction SMILES: [C:1](OC(=NC1CCCCC1)NC1CCCCC1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:24][N:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([CH2:28][C:29]([O:31][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=NC1CCCCC1)NC1CCCCC1
Reactant: O=C(O)Cc1ccnc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccnc(Cl)c1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
Compound 2-tert-butyl-1,3-dicyclohexylisourea (650 mg, 2.30 mmol) was added to a solution of 2-(2-chloropyridin-4-yl)acetic acid (200 mg, 1.16 mmol) in DCM (5 ml) at room temperature. The reaction mixture was stirred for 24 h, filtered, washed with DCM (5 ml) and saturated sodium bicarbonate solution (10 ml). The solvent was evaporated in vacuum to afford 200 mg (77%) of tert-butyl 2-(2-chloropyridin-4-yl)acetate as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:13]2=[O:35].[CH3:36][NH:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:36][N:37]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:13]3=[O:35])[CH:4]=1)[CH3:38]
Reactant: COc1cccc(-c2nc3ccc(-c4cc(C=O)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cccc(-c2nc3ccc(-c4cc(CN(C)C)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-[6-(2-fluoro-5-formylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (19 mg, 0.04 mmol) in dichloroethane (2 mL) and acetic acid (0.05 mL) was added dimethylamine (2M in acetonitrile, 0.50 mL, 1.0 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was then added as a solid with stirring at room temperature for 24 h. The solvent was removed in vacuo, the residue partitioned between ethyl acetate and a 1 N NaOH (aq.), the organic layer was washed with brine, dried (MgSO4) and the solvent evaporated. The resulting residue was subjected to preparative HPLC purification to provide 2-[6-(5-dimethylaminomethyl-2-fluorophenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6a) (10 mg, 0.02 mmol, 50%).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:9]2[CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[CH:8]2[CH2:7][CH:6]([C:20]([OH:22])=[O:21])[CH2:5]1)[NH:13][CH:12]=3.[C:23]1(C)[CH:28]=[CH:27]C(S(OC(CC)CC)(=O)=O)=[CH:25][CH:24]=1>CS(C)=O>[CH2:24]([CH:23]([N:13]1[C:14]2[C:19]3[C:11]([CH2:10][C@@H:9]4[C@@H:8]([C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([C:20]([OH:22])=[O:21])[CH2:5][N:4]4[CH3:3])=[CH:12]1)[CH2:28][CH3:27])[CH3:25]
Reactant: CCC(CC)OS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCC(CC)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
A 500 ml, three-neck round bottom flask was charged with 11.72 g (180.0 mmol) of 86% pure powdered potassium hydroxide, 10.0 g (33.9 mmol) of 92% pure 9,10-dihydrolysergic acid and 150 ml of DMSO. The mixture was stirred at room temperature for 15 minutes, and 10.3 g (42.6 mmol) of p-toluenesulfonic acid, 1-ethylpropyl ester was added. The mixture was stirred at room temperature for 19 hours, and 1000 ml of ice water was added. The mixture was washed twice with 250 ml aliquots of ethyl acetate, and the pH of the aqueous layer was adjusted to 5 with glacial acetic acid. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The solid was dried under vacuum to provide 7.94 g of 1-(1-ethylpropyl)-6-methylergoline-8carboxylic acid. A second crop of material was obtained to provide 0.9 g of product. The purity of the first crop was 96.7%, and the purity of the second crop was 96%. Total yield 72.1%. The identity of the product was determined by thin layer chromatography as compared to an authentic reference standard.
Reaction SMILES: C1(S(O[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)(=O)=O)C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[CH:23]2.CCCCCC>C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[CH:12]=[C:13]([CH3:18])[CH:14]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1cc(C)cc(OS(=O)(=O)c2ccccc2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(Nc2ccc3[nH]ccc3c2)c1
Yield: 74.5 %

Procedure:
Following the general procedure, 3,5-dimethylphenyl benzenesulfonate (131 mg, 0.5 mmol) was coupled with 5-aminoindole (100 mg, 0.75 mmol) with the reaction time of 4 h. Chromatography on silica gel column with 6:1 hexane:ethyl acetate gave 88 mg (74%) of 5-(3,5-dimethylphenylamino)indole as a pale brown solid; and 16 mg (14%) of 1-(3,5-dimethylphenyl)-5-aminoindole as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:22][CH:21]2[CH2:30][C:31]([O:33]CC)=[O:32]>>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:24][CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:14])[F:13])[CH2:27][CH2:28]1)[CH2:22][CH:21]2[CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.83, min, m/z=468, 466
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14](=O)[CH3:15])=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:17][C:18]([NH2:20])=[S:19]>CCO.CCOC(C)=O>[CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14]2[S:19][C:18]([NH2:20])=[N:17][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(C(C)=O)s1
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(-c2cnc(N)s2)s1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of (5-acetyl-thiophen-2-yl)-phosphonic acid diethyl ester (1.13 g, 4.31 mmol) in EtOH (80 ml) was added CuBr2 (959 mg, 8.62 mmol). The reaction mixture was then refluxed for 3 hr, diluted with EtOAc, quenched by adding sat. NaHCO3. After layers were separated, the org. layer was collected and the aqueous layer was further extracted with EtOAc once. Combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was then dissolved in EtOH/EtOAc (4 ml/16 ml) and treated with thiourea (394 mg, 5.17 mmol). The reaction mixture was then heated to reflux for 1 hr, cooled to r.t., and concentrated down. The residue was partitioned between EtOAc and water. The organic layer was collected, dried over MgSO4, filtrated, concentrated, and purified by Biotage to give the final compound (218 mg, 15.9%). 1H NMR (300 MHz, DMSO-d6): δ 7.50 (m, 2H), 7.23 (s, 2H), 7.10 (s, 1H), 4.02 (m, 4H), 1.21 (m, 6H). LC-MS m/z=263.4 [C7H7N2O3PS2+H]+.