Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:29])[C:15]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=3)[N:19]=[CH:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[NH2:31].C(=O)([O-])[O-].[Na+].[Na+].ClCCl.CO>C(O)CC.O.ClCCl.C(O)(C)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:29])[C:15]([N:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[C:24]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([C:30](=[O:32])[NH2:31])[CH:38]=4)[CH:25]=[CH:26][CH:27]=3)[N:19]=[CH:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)n1cnc(-c2cccc(Br)c2)c1)C1CCN(Cc2ccccc2)CC1
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: CN(C(=O)n1cnc(-c2cccc(-c3cccc(C(N)=O)c3)c2)c1)C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium complex (0.076 g, 0.066 mmol) was added to a stirred dispersion of N-(1-benzylpiperidin-4-yl)-4-(3-bromophenyl)-N-methyl-1H-imidazole-1-carboxamide (0.600 g, 1.323 mmol), 3-carbamoylphenylboronic acid (0.229 g, 1.390 mmol) and a 2 M solution of sodium carbonate (0.794 mL, 1.588 mmol) in a mixture of 1-propanol (5 mL) and water (1 mL) at room temperature. The reaction mixture was allowed to stir at 90° C. for 1 h. Water was added and the organic layer was diluted with a mixture of dichloromethane/isopropanol (7:3). The organic layer was separated, dried (MgSO4), filtered and evaporated to give an orange oil. Column chromatography (silica, dichloromethane/methanol 5%) gave the product as an orange oil. The oil was triturated with a mixture of petroleum ether/ethyl acetate/ether to give the product as a beige solid (123 mg, 17%).
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)C.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>O>[C:17]([C:19](=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: CCCc1ccc(C(OCC)OCC)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(C=C(C#N)C(=O)OCC)cc1
Yield: 94 %

Procedure:
A mixture of 20.0 g (90 mmole) 4-n-propylbenzaldehyde diethylacetal, 20.4 g (180 mmole) ethyl cyanoacetate, 7.2 g (93.4 mmole) ammonium acetate and 60 ml toluene are heated at reflux for six hours, cooled and poured into water. The resulting mixture was extracted with ethyl ether, dried (MgSO4) and the volatiles evaporated in vacuo to afford 23.0 g crude yellow oil which was purified by chromatography on a silica gel column, eluting with 2:1 methylene chloride/hexane to give 20.58 g (94%) of the desired product. 1H-NMR(CDCl3)ppm(delta): 0.85-1.95 (m, 8H), 2.45-2.70 (t, 2H), 4.15-4.60 (q, 2H), 7.15-8.05 (q, 4H), 8.25 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C@:4]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+]>C1COCC1.O>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@:4]1([CH3:16])[C:3]([OH:17])=[O:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-2-methylproline methyl ester (3.20 g, 0.0131 mol) in THF (20 mL) was added 1 N NaOH (15.7 mL) at room temp. After the resulting mixture was stirred for 24 hr, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified by the addition of 1 N HCl, and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated in vacuo to afford 1.71 g(57%) N-tert-butoxycarbonyl-2-methylproline as a yellow syrup. 1H-NMR (CDCl3) δ 1.42 (s, 9H), 1.48 (s, 3H), 1.88–2.31 (m, 4H), 3.34–3.57 (m, 2H), 9.35 (br s, 1H)
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CC(O)CC>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:7]2[N:8]=[CH:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)cc21
Solvent: CCC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)cc21
Temperature: 140 °C

Procedure:
A mixture of 4,6-dichloro-1-isopropyl-1H-imidazo[4,5-c]pyridine (b) (40 mg, 0.17 mmol), tyramine (120 mg, 0.86 mmol), and 2-butanol (2 mL) was heated under microwave irradiation at 140° C. for 8 hr. The mixture was concentrated and the residue was purified by reverse-phase HPLC (C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid. MS m/z 331.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.N1C=CC=C[CH:17]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: c1ccncc1
Reactant: O=C(O)Cc1cncc(Br)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-(5-bromopyridin-3-yl)acetic acid (5.00 g, 23.14 mmol) in methanol (55 mL) at 0° C. was added thionyl chloride (2.196 mL, 30.1 mmol) slowly, pyridine (2.434 mL, 30.1 mmol) was added slowly after and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate, the organics was washed with brine, dried over magnesium sulfate, filtered and concentrated. Biotage purification (35% EtOAc/Hex) gave title compound (4.73 g, 20.6 mmol, 89% yield). 1H-NMR (CDCl3, 500 MHz) δ 8.63 (d, J=2.14 Hz, 1H), 8.47 (d, J=1.83 Hz, 1H), 7.84 (dd, J=2.14, 1.83 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 2H). Mass spec.: 230.9 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].ClCCl>C(N(CC)CC)C>[CH:23]([S:24]([NH:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25])=[CH2:22]
Reactant: Cc1c(-c2ccccc2)oc2c(CN)cccc2c1=O
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12

Procedure:
This compound can be prepared by reacting Intermediate XXIV with 2-chloroethylsulfonylchloride in an halogenated solvent (e.g., dichloromethane) in presence of triethylamine at 0°-40° C., according to A. A. Goldberg, Jr., J. Chem. Soc., 464 (1945).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.[O:29]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31]([OH:33])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:31](=[O:33])[C:30](=[O:29])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(O)C(=O)N1CCCC1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)C(=O)N1CCCC1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.100 mmol) in (DMF (2 mL) was added 2-oxo-2-(pyrrolidin-1-yl)acetic acid (57.2 mg, 0.400 mmol), diisopropyl-ethylamine (0.105 mL, 0.599 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.400 mmol) and 4-(dimethylamino)pyridine (DMAP) (1.221 mg, 9.99 μmol) and the resulting mixture was stirred at room temperature for 3 h. The crude was then purified by preparative HPLC and recrystallized from methanol to afford the title compound as a glassy white crystals (20 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.1 (1 H, s), 9.6 (1 H, brs), 7.4-7.4 (2 H, m), 7.0-7.0 (2 H, m), 4.8-4.9 (1 H, m), 4.6-4.7 (1 H, m), 4.4-4.5 (1 H, m), 3.6-3.7 (2 H, m), 3.5 (2 H, t, J=6.71 Hz), 3.3-3.4 (2 H, m), 3.0 (3 H, s), 2.5 (1 H, brs), 1.9-2.1 (9 H, m), 1.7-1.8 (2 H, m). LCMS (M+H)=512.24. HPLC purity: >95%.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]3[N:17]=[C:18]([NH:21][CH2:22][CH3:23])[N:19]=[CH:20][C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([NH:21][C:18]1[N:19]=[CH:20][C:9]2[C:8](=[O:24])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)=[CH:26][CH:25]=3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:17]=1)[CH3:23]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(Cc1ccc(N)cc1)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(NC(=O)c3cccnc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
Compound 6 (80.0 mg, 0.227 mmol) obtained in Example 6 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1.5 hours after adding nicotinoyl chloride.hydrochloride (61.0 mg, 0.340 mmol) and triethylamine (0.095 mL, 0.340 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 7) (54.3 mg, 52%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][C:31]([CH3:34])=[N:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:34][C:31]1[S:30][C:29]([NH:28][S:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][CH:4]=[C:5]3[C:16]4[C:8](=[CH:9][CH:10]=[C:11]5[C:15]=4[S:14][CH:13]=[N:12]5)[NH:7][C:6]3=[O:17])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[N:33][N:32]=1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Product: Cc1nnc(NS(=O)(=O)c2ccc(NC=C3C(=O)Nc4ccc5ncsc5c43)cc2)s1
Yield: 36 %

Procedure:
The title compound was prepared in 36% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.6 (d, 2H), 7.1 (d, 1H); ESI−MS m/z469 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N+:44]([O-:46])=[O:45])=[C:39]([CH:43]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:40](=[O:41])[C:39]3[CH:43]=[C:35]([Cl:34])[CH:36]=[CH:37][C:38]=3[N+:44]([O-:46])=[O:45])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
1.86 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1 ml of triethylamine are dissolved in 15 ml of methylene chloride, and 1.27 g of 5-chloro-2-nitrobenzoyl chloride are added thereto. The mixture is stirred at room temperature for one hour. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, successively. Then, the extract is evaporated to remove solvent, and the residue is crystallized with ethanol. 2.45 g of (+)-cis-2-(4-methoxyphenyl)-3-(5-chloro-2-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless prisms. Yield: 88.1%.
Reaction SMILES: BrBr.[OH-:3].[Na+].C[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11]2)=[O:7]>O.O1CCOCC1>[C:21]1([S:18]([NH:17][CH:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([C:6]([OH:7])=[O:3])[CH:9]=3)[CH2:13]2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.5 g (0.0795 mol) of bromine are added at -10° C. to a solution of 8.5 g (0.214 mol) of sodium hydroxide in 85 ml of water, and a solution of 5 g (0.015 mol) of 2-benzenesulphonamido-indan-5-yl methyl ketone in 20 ml of dioxan is then added with vigorous stirring. The mixture is stirred for 2 hours at room temperature, the excess bromine is destroyed by adding sodium bisulphite, the alkaline phase is washed with ether and acidified with hydrochloric acid, and the reaction product is extracted with methylene chloride. Evaporation leaves as residue 5.3 g of a resinous substance, which is recrystallised from glacial acetic acid and then from methanol/water.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[N:27]=[C:26]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][CH:37]=4)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]5)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:17]=[CH:16][CH:15]=4)[N:27]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(4-methylpiperazin-1-yl)acetamide. (33 mg, 33%)
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1.[P:52](Cl)([O:57]CC)([O:54][CH2:55][CH3:56])=[S:53].C1(C)C=CC=CC=1.CCOC(C)=O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:55]([O:54][P:52]([O-:57])([O:47][CH2:46][CH3:48])=[S:53])[CH3:56].[CH3:1][CH2:2][C@@H:3]1[O:26][C:24](=[O:25])[CH2:23][C@@H:22]2[C:11](=[CH:12][C@@H:13]3[C@H:21]2[CH:20]=[CH:19][C@H:18]2[C@H:14]3[CH2:15][C@H:16]([O:27][C@@H:28]3[O:33][C@@H:32]([CH3:34])[C@H:31]([O:35][CH3:36])[C@@H:30]([O:37][CH3:38])[C@H:29]3[OH:39])[CH2:17]2)[C:9](=[O:10])[C@H:8]([CH3:40])[C@@H:7]([O:41][C@@H:42]2[O:47][C@H:46]([CH3:48])[C@@H:45]([N:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOP(=S)(Cl)OCC
Agent: CC[C@H]1CCC[C@H](O[C@H]2CC[C@H](N(C)C)[C@@H](C)O2)[C@@H](C)C(=O)C2=C[C@@H]3[C@@H](C=C[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]5O)C[C@@H]34)[C@@H]2CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP([O-])(=S)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound Spinosyn H (261 mg, 0.364 mmol) was dissolved in dry pyridine (3 ml). DMAP (60 mg) was added, followed by diethyl chlorothiophosphate (152 mg, 125 μl, 0.80 mmol). The reaction mixture was stirred at RT under nitrogen. After 12 hrs. toluene (50 ml) and EtOAc (50 ml) were added. The solution was extracted with brine, then with 5% aq. NaHCO3. The organic layer was dried over and Na2SO4 and concentrated in vacuo. The residue was purified over a flash SiO2 column (30 g/EtOAc) to give compound 2'R)-(diethyl)thiophosphate of Spinosyn H; 84 mg, 27%) CI MS m/z 870 (M+1); 1H-NMR (CDCl3) δ 6.74 (1H, bs), 4.80 (1H, m), 4.22 (4H, 2× CH2, m), 1.30 (6H, 2× CH3, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([O:28][C:29]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([O:28][C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:37][CH:38]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:20][CH2:18][CH3:19])[N:3]=1
Reactant: CCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(ethylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, ethylamine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]2[CH2:30][C:29](C(O)=O)([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.CS(C)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2)[CH2:26][C@H:27]1[CH2:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28]1
Reactant: O=C(O)C1(C(=O)O)CC(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)[C@H]1C[C@H](Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
3-((3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-cyclobutane-1,1-dicarboxylic acid (0.360 g, 0.716 mmol) was treated with 4 mL DMSO, fitted with a water cooled reflux condenser, and heated to 160° C. After 4 h, the reaction mixture was cooled to rt. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water once, satd NaCl once and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a light yellow solid, as an approximately 2:1 mixture of isomers. Separation by SFC (Gradient with Chiralpak IC (21×250 mm, 5 micron), pure methanol with CO2 70 mL/min) gave (trans)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzyl)cyclobutanecarboxylic acid as a white solid. MS (ESI) m/z: calculated: 458.2; Observed: 459.1 (M++1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.O>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[NH:10][CH:11]=1
Reactant: BrBr
Reactant: Clc1cnc2[nH]ccc2c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1cnc2[nH]cc(Br)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of bromine (3.5 ml) in chloroform (40 ml) was added dropwise to an ice-cold solution of the 5-chloro-1H-pyrrolo[2,3-b]pyridine (3) (10 g, 65 mM) in chloroform (260 ml). The reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was then hydrolysed with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration, and the aqueous was extracted with dichloromethane. The organic was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (10.5 g, 69%). 1H NMR (DMSO-d6) 7.8 (1H, s), 7.9 (1H, s), 8.3 (1H, s)
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:4]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=1)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.CCO.[BH4-].[Na+]>CS(C)=O.C(Cl)Cl.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][CH2:1][C:3]3[C:8]([C:9]([F:12])([F:10])[F:11])=[CH:7][C:6]([C:13]([F:14])([F:15])[F:16])=[CH:5][C:4]=3[C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=3)=[CH:42][CH:41]=2)=[CH:38][CH:39]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(5-(2-formyl-3,5-bis(trifluoromethyl)phenyl)picolinamido)propanoate (76 mg, 0.16 mmol) and 4′-chloro-[1,1′-biphenyl]-4-amine (40 mg, 0.20 mmol) in DMSO (0.16 mL) was stirred at 100° C. After 30 min EtOH (0.16 mL) was added and the resulting homogeneous solution was stirred at 100° C. After 1 h the resulting homogeneous solution was cooled to room temperature, and NaBH4 (20 mg, 0.53 mmol), EtOH (1 mL), and DMSO (0.5 mL) were added and the resulting mixture was stirred. After 30 min, additional NaBH4 (20 mg, 0.53 mmol) was added and the resulting homogeneous solution was stirred. After 20 min the resulting mixture was diluted with DCM (5 mL) and 1 M NaH2PO4 (4 mL) was carefully added. Water was added and the aqueous phase was extracted with DCM. The combined organic layers were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.