Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[CH2:30][CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][CH2:30][C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[F:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCCc1ccccc1F
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCCc2ccccc2F)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of intermediate 59 (0.5 g, 1.36 mmol), 2-fluorophenethylamine (0.531 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.27 g of the product 91. 1H NMR (CDCl3) δ 7.40-6.85 (m, 13 H), 6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H), 3.90-3.60 (m, 2 H), 1.15 (s, 9 H); MS: m/z 460 (M++1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH2:23](C1C=C(OC)C=CC=1C(NCC)=O)C1C=CC=CC=1.P(=O)(O)(O)O>>[CH2:21]([N:10]1[C:9]([CH3:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]1=[O:20])[CH3:23]
Reactant: COc1ccc2c(=O)n(C)c(C)c(-c3cccc(F)c3)c2c1
Reactant: CCNC(=O)c1ccc(OC)cc1Cc1ccccc1
Agent: O=P(O)(O)O
Product: CCn1c(C)c(-c2ccccc2)c2cc(OC)ccc2c1=O

Procedure:
Following the procedure for 4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one (Step C), using 2-benzyl-N-ethyl-4-methoxybenzamide in place of 2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide and heating the final phosphoric acid solution to 100 C, the titled compound was synthesized.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=2)=[CH:16][C:15]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]2)=[CH:14][N:13]=1.[NH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1.C1COCC1>>[CH3:44][O:43][C:40]1[N:39]=[CH:38][C:37]([NH:36][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[CH:20][N:19]=3)=[CH:16][C:15]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27]3)=[CH:14][N:13]=2)=[CH:42][CH:41]=1
Reactant: Cc1ncnc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2F)n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2ncnc(C)n2)cn1
Reaction time: 1 h
Yield: 17.1 %

Procedure:
LiHMDS (1.0 M in THF, 557 μL, 0.557 mmol) was added to a stirred solution of 2-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-4-methyl-1,3,5-triazine (68.0 mg, 0.186 mmol) and 3-amino-6-methoxypyridine (Aldrich) (34.6 mg, 0.278 mmol) in THF (928 μL, 0.186 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with water (10 mL) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 5% MeOH in DCM) followed by washing with iPrOH to give N-(6-methoxypyridin-3-yl)-3-(4-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (15 mg, 17%) as a yellow solid. LCMS (API-ES) m/z 471 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.44 (s, 1H) 9.29 (s, 1H) 8.81 (s, 1H) 8.51 (br. s., 1H) 8.29 (br. s., 1H) 8.11 (d, J=9.19 Hz, 1H) 6.85 (d, J=9.19 Hz, 1H) 3.85 (s, 3H) 3.53 (s, 2H) 3.11 (br. s., 4H) 2.87 (s, 3H) 2.75 (s, 3H) 2.34-2.49 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[C:20]([O:26][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C(C)C)c3)c2c1C

Procedure:
Using 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.291 g, 0.623 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.768 g, 3.24 mmol) the title compound was prepared according to the procedure in Example 1, step 9. Purification on Dynamax C18 eluting with 100% CH3CN (0.1% TFA added) gave 0.09 g (22%) of the title compound as a white solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.09 (t, 12 H), 1.54 (s, 3 H), 2.45 (s, 3 H), 3.14-3.22 (m, 2 H), 7.27 (s, 2 H), 7.41-7.46 (m, 2 H), 7.50-7.53 (m, 2 H), 7.65-7.69 (m, 1 H), 8.09 (d, 1 H), 8.21-8.23 (m, 1 H). IR (KBr) 3400, 2950, 1700, 1375 and 1180 cm-1. mass spectrum (-ESI), m/z 665/667 (M-H). Anal. Calcd. for C33H31BrO6S2.1.7H2O: C, 56.76; H, 4.97 N, 0.00. Found: C, 56.73; H, 4.81 N, 0.12.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)(=O)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH3:18])=[CH:15][CH:14]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CNc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(c1ccc(Cl)cc1)c1ccnc2ccccc12
Yield: 97 %

Procedure:
A solution of 4-chloroquinoline (5 mmol) and of 4-chloro-N-methylaniline (10 mmol) in glacial acetic acid (15 ml) was heated with reflux for 3 h under a stream of argon. After cooling, the solution was basified with a 10% NaOH solution until pH=10 and the resulting suspension was concentrated in a rotary evaporator and purified by means of flash chromatography (9:1, CH2Cl2:MeOH) to give the target molecule as a yellowish syrup (97%). 1H-NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.5, 1H, H-2quin); 7.70 (d, J=8.5, 1H, H-5quin); 7.65 (t, J=7.9, 1H, H-7quin); 7.38 (t, J=8.5, 1H, H-6quin); 7.35 (d, J=7.9, 1H, H-8quin); 7.17 (d, J=8.9, 2H, H-3,5anil); 7.14 (d, J=8.5, 1H, H-3quin); 6.76 (d, J=8.9, 2H, H-2,6anil); 3.45 (s, 6H, Me). 13C-NMR (100 MHz, CDCl3): δ 153.37 (C-4quin); 151.16 (C-2quin); 150.01 (C-1anil); 148.17 (C-8aquin); 135.02 (C-4anil); 130.07 (C-7quin); 129.52 (C-6quin); 129.29 (C-3,5anil); 126.26 (C-4aquin); 126.07 (C-5quin); 124.40 (C-8quin); 119.79 (C-2,6anil); 115.08 (C-3quin); 41.75 (Me). HRMS (m/z): Calculated for C16H13N2Cl [(M+H)]+ 269.0845. Found: 269.0845. Analysis for C16H13N2Cl. Calculated: C, 71.51; H, 4.88; N, 10.42%. Found: C, 71.60; H, 4.71; N, 10.33%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].N([O-])=[O:12].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: O=N[O-]
Reactant: CCc1ccc(N)cc1Br
Agent: [Na+]
Product: CCc1ccc(O)cc1Br

Procedure:
In a manner similar to that of Example 1(d), by reacting 27 g (135 mmol) of 3-bromo-4-ethylphenylamine with 11 g (162 mmol) of sodium nitrite, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 13 g (49%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Cl.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: C1=COCCC1
Reactant: O=C1CCC(CO)N1
Agent: Cl
Product: O=C1CCC(COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A 5 g quantity of 5-hydroxymethyl-2-pyrrolidinone [Journal of Organic Chemistry, 45, 816 (1980)] was dissolved in 10 ml of dihydropyran, 0.1 ml of concentrated hydrochloric acid was added to the solution, and the mixture was stirred at room temperature for 4 hours. Excessive dihydropyran was distilled off in a vacuum, and the residue was subjected to silica gel column chromatography to obtain an eluate of benzene/ethyl acetate=9/1, which gave 7.9 g of 5-(2-tetrahydropyranoxy)methyl-2-pyrrolidinone (yield 90%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3][C:2]1=[O:1]
Reactant: O=Cc1ccc2[nH]c(=O)oc2c1
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)oc(=O)n2CCCBr
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 290 mg (1.64 mmol) of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (Intermediate 7), 272.8 mg (1.96 mmol) of 3-bromo-propan-1-ol, 514 mg (1.96 mmol) of triphenylphospine and 0.855 ml (1.96 mmol) of 40% toluene solution of DEAD in 7 ml THF is stirred overnight. After concentration in vacuo the residue is chromatographically purified over silicagel eluting with hexane/ethyl ether (100/0 to 0/100), obtaining 423 mg of the title product (58% purity; 52% total yield) that is used per se in the next synthetic step.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][CH2:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:21][CH2:22][C:23]([NH:25][CH2:26][C:27]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:28])=[O:24]
Reactant: O=C(O)CNC(=O)CCl
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)CNC(=O)CCl)C(=O)OCC
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a suspension of diethyl 2-aminomalonate hydrochloride (4.2 g) in tetrahydrofuran are added triethylamine (2.1 g) and N-(chloroacetyl)glycine (3.0 g), and the mixture is cooled to 0° to 5° C. To the mixture is further added N,N'-dicyclohexylcarbodiimide (4.3 g), and the mixture is stirred at the same temperature for 2 hours and then allowed to stand at room temperature overnight. Insoluble substance is filtered off from the reaction mixture, and the filtrate is concentrated under reduced pressure. To the residue is added ethyl acetate, and the insoluble substance is filtered off. The filtrate is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetateisopropyl ether to give diethyl 2-[[N-(chloroacetyl)glycyl]amino]malonate (5.1 g), m.p. 104.5°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5](Cl)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:5]1[S:19][C:17]([CH3:18])=[N:20][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccc(F)cc1
Reactant: CC(N)=S
Product: CCOC(=O)c1sc(C)nc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 2-chloro-3-(4-fluoro-phenyl)-3-oxo-propionic acid ethyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=266.1.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:20]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1Cl
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(F)c(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g) and 2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a) (0.31 g). Yield 0.042 g.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[F:23])(=O)=O.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1>CN1C(=O)CCC1.O>[Br:22][C:19]1[CH:20]=[N:21][C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([F:23])=[C:9]([CH:14]=2)[O:8][CH2:7][CH2:6][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]2)=[N:17][CH:18]=1
Reactant: CS(=O)(=O)OCCOc1cc(Nc2ncc(Br)cn2)ccc1F
Reactant: COC(=O)C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCN(CCOc2cc(Nc3ncc(Br)cn3)ccc2F)CC1
Temperature: 90 °C

Procedure:
2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl methanesulfonate 46b (0.24 mmol) and methyl piperidine-4-carboxylate (0.48 mmol) are dissolved in NMP (2 mL) and heated to 90° C. for 3 h. The reaction mixture is cooled to rt and diluted with water and extracted with EtOAc (2×30 mL). The organic layer is washed with water, brine, dried over sodium sulfate, and concentrated to dryness. The crude product is purified by short SiO2 chromatography using DCM:hexane=9:1 as eluant to yield methyl 1-(2-(5-(5-bromopyrimidin-2-ylamino)-2-fluorophenoxy)ethyl)piperidine-4-carboxylate 47 as light brown solid. MS (m/z) (M+1)+: 454.1.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:38][C:39]([OH:41])=[O:40])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCC(=O)O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 57 (158 mg, 0.31 mmol) in anhydrous DMF (5 mL) were added tert-butyl bromoacetate (460 μL, 10 equiv) and anhydrous K2CO3 (425 mg, 10 equiv). The suspension was heated at 80° C. under nitrogen for 16 h. After cooling, resulting solids were removed by filtration. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel, eluting with MeOH-DCM (5:95) to give the product, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Br:8].[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=O>FC(F)(F)CO>[Br:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]2[N:9]([CH2:11][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]3)[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1cc(Br)c(Br)cc1N
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(C3CCN(C(=O)OC(C)(C)C)CC3)nc3cc(Br)c(Br)cc32)CC1

Procedure:
4,5-dibromobenzene-1,2-diamine (100 mg, 0.38 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (160 mg, 0.76 mmol) were stirred for 1 hour in 2,2,2trifluoroethanol. Then Solvent was evaporated and product was purified on silica gel using EA/hex (1/1). Yield: 20 mg. m/z 657.1, rt. 4.2 min.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:16]=1)=O)(C)(C)C>O1CCOCC1.ClCCl>[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:22])[CH2:18][CH:19]([CH3:20])[CH3:21])=[N:15][CH:16]=1
Reactant: CC(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CC(=O)c1ccc(CN)cn1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Add 4N hydrogen chloride in dioxane (0.5 mL) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(3-methyl-butyryl)-pyridine (60 mg, 0.2 mmol) in anhydrous dichloromethane (2 mL) and stir the solution overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. Extract the aqueous phase with dichloromethane (2×15 mL) and EtOAc (2×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound (37 mg, 95%) that was used without any further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc(Cl)cc3Cl)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2,4-dichlorophenyl isocyanate: ESMS m/e: 533.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: Cn1ncc2cc(CN)ccc21
Product: Cc1cc(Br)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-methylbenzene-1-sulfonyl chloride and (1-methyl-1H-indazol-5-yl)methanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13]O[C:11](=[O:14])[C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:33][NH2:34]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:13][N:34]([CH3:33])[C:11](=[O:14])[C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1
Reactant: CN
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)N(C)C2)cc1
Yield: 29 %

Procedure:
A stirred solution of 4-(4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (500 mg, 1.18 mmol) in 2N methanolic MeNH2 (50 mL) was refluxed for 3 h. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 4N HCl in dioxane The reaction mixture was refluxed for 16 h, then basified with aqueous NaHCO3 solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-methoxyphenyl)-1-methyl-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (150 mg, 29%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.39 (m, 1H), 8.04-7.98 (m, 2H), 7.82-7.56 (m, 3H), 7.18-7.09 (m, 4H), 7.04 (d, J=7.2 Hz, 2H), 6.82 (d, J=7.2 Hz, 2H), 5.39 (s, 2H), 4.38 (s, 2H), 3.78 (s, 3H), 2.99 (s, 3H). MS: M+H: m/z=437.1; M+Na: m/z=459.2; M+K: m/z=475.2 and HPLC: 87%, (Condition-B).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)=[O:8])[CH3:5]>C(O)C.O>[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:3][CH2:1][CH3:2])[N:10]=1)=[O:8])[CH3:5]
Reactant: CCN
Reactant: CCNC(=O)c1cccc(Br)n1
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1cccc(NCC)n1

Procedure:
prepared by reaction of ethylamine with 6-bromo-pyridine-2-carboxylic acid ethylamide; in contrast to the general procedure the reaction was carried out by heating a solution of the starting materials in ethanol/water for 72 h at 100° C. in an autoclave
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1(C)[CH2:16][CH2:15][CH2:14]1)[N:8]([CH:18]1[CH2:20][CH2:19]1)[C:7]2=[O:21].[CH3:23][C@@H:24]1[C:28]2[NH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][C:27]=2[C:26](=[O:41])[NH:25]1>>[CH:18]1([N:8]2[C:7](=[O:21])[C:6]3[C:11](=[C:2]([C:30]4[NH:29][C:28]5[C@@H:24]([CH3:23])[NH:25][C:26](=[O:41])[C:27]=5[CH:31]=4)[C:3]([F:22])=[CH:4][CH:5]=3)[N:10]=[C:9]2[NH:12][C:13]2([CH3:16])[CH2:14][CH2:15]2)[CH2:19][CH2:20]1
Reactant: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CCC1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3c(F)ccc4c(=O)n(C5CC5)c(NC5(C)CC5)nc34)[nH]c21
Yield: 51.7 %

Procedure:
(R)-3-Cyclopropyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (78 mg, 50% yield) as a light yellow solid was prepared according to the procedure described for Example 495, using 8-bromo-3-cyclopropyl-7-fluoro-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (498a; 137 mg, 0.37 mmol) and boronic ester 705 (147 mg, 0.45 mmol) as starting material. MS (ESI, pos. ion) m/z: 422 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (1H, s), 7.86 (1H, dd, J=8.8, 6.3 Hz), 7.66 (1H, s), 6.98-7.14 (2H, m), 6.51 (1H, d, J=1.8 Hz), 4.57 (1H, q, J=6.6 Hz), 2.72-2.84 (1H, m), 2.35-2.44 (2H, m), 2.06 (2H, dt, J=12.3, 6.1 Hz), 1.78-1.91 (2H, m), 1.59 (3H, s), 1.39 (3H, d, J=6.7 Hz), 1.16-1.31 (2H, m), 0.75-0.83 (2H, m).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[NH:39]1[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:39]4[CH2:47][CH2:46][CH:42]([C:43]([OH:45])=[O:44])[CH2:41][CH2:40]4)[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: O=C(O)C1CCNCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1OC(=O)C(=CN2CCC(C(=O)O)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added isonipecotic acid (60 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 561 (M+H).