Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH:17]=2)[N:3]=1.[C:31]([C:33]1[CH:34]=[C:35]([C:39]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1)#[CH:32].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C(F)(F)F)=O>CCN(CC)CC.CN(C=O)C.CCOC(C)=O.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Pd]>[NH:21]1[CH2:20][CH2:19][CH:18]([N:16]2[CH:17]=[C:13]([NH:12][C:4]3[N:3]=[C:2]([CH2:32][CH2:31][C:33]4[CH:34]=[C:35]([C:39]5([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]5)[CH:36]=[CH:37][CH:38]=4)[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=3)[CH:14]=[N:15]2)[CH2:23][CH2:22]1
Reactant: C#Cc1cccc(C2(C(N)=O)CC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C1(c2cccc(CCc3nc(Nc4cnn(C5CCNCC5)c4)ncc3C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate K8 (483 mg, 1.08 mmol), 1-(3-ethynylphenyl)cyclopropanecarboxamide A60 (200 mg, 1.08 mmol), PPh3 (14 mg, 0.054 mmol) and CuI (10 mg, 0.054 mmol) in Et3N (1 mL) and DMF (4 mL) was sonicated for 10 minutes, PdCl2(PPh3)2 (38 mg, 0.054 mmol) was added and the reaction mixture was irradiated in the microwave at 120° C. for 40 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a yellow oil. Further purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% MeOH in EtOAc) gave a yellow oil which was taken up in EtOAc (20 mL) and DMF (2 mL). Pd/C 10% (100 mg) was added to this solution and the mixture was stirred overnight under an atmosphere of hydrogen at room temperature. The mixture was filtered through Celite and the filter cake was washed with EtOAc (50 mL). The washings were combined and the volatiles were removed in vacuo to give a yellow oil that was adsorbed onto silica gel and purified by silica gel column chromatography (Biotope Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc). Further purification by silica column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) gave a crude material that was dissolved in DCM (20 mL). TFA (1 mL) was added to this solution and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resulting solid was sonicated for 10 minutes in sat. Na2CO3 (aq.) (25 mL). The precipitate was collected by filtration and washed with water (25 mL), toluene (50 mL) and air dried to give the title compound 53 as a yellow solid (15 mg, 32%). LCMS-A: rt 4.784 min; m/z 500.3 [M+H]+.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC1=O.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=c1ccc2ccccc2[nH]1
Product: O=C(O)c1ccc(Br)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
In one method the starting quinolinone carboxylic acid 22 building block used for the synthesis of compounds comprising Formulae (I)-(X) was prepared as described in Scheme 9. The commercially available 4-bromobenzoic acid 42 was nitrated under standard conditions using fuming nitric acid to give the 4-bromo-3-nitrobenzoic acid 43 in over 95% yield. The benzoic acid 43 was coupled with ethyl acrylate 44 in the presence of palladium acetate catalyst and ligand triphenylphosphine using triethylamine as base in DMF to afford the corresponding nitro substituted benzoic acid derivative 45 in over 90% yield. The reductive cyclization of the compound 45 under hydrogenation conditions using palladium over activated carbon as catalyst under hydrogen atmosphere at around 50 psi pressure gave the quinolinone carboxylic acid 22 in over 95% yield.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C)C1C=CN=CC=1.O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11.9 g (33.3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene, 120 ml of DMF, 5.1 ml (36.6 mmol) of triethylamine and 203 mg of 4-dimethylaminopyridine were introduced successively into a three-necked flask. A solution of 5.52 g (36.6 mmol) of tert-butyldimethylsilyl chloride was added dropwise and the mixture was stirred at room temperature for 12 hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane; 12 g (76%) of 7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-bromonaphthalene of melting point 120°-121° C. were recovered.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1.[Li+].[OH-]>O1CCOCC1.P([O-])([O-])([O-])=O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1c(Br)nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Bromo-5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.15 g, 0.31 mmol) was deprotected as outlined in General Procedure V by being dissolved in 5 ml dioxane at rt. To this solution was added all at once, 1.2 ml (1.2 mmol) of 1M aq. LiOH. The mixture stirred at ambient temperature for 0.25 h. The mixture was diluted with 15 ml of pH 7 phosphate buffer and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate (anhyd.), filtered and solvents evaporated. The residue was triturated in dichloromethane and 2-bromo-5-chloro-1-beta-D-ribopyranosyl-1H-benzimidazole was collected by vacuum filtration. The product was dried in a vacuum oven at 50° C. (0.041 g , 0.11 mmol 37%); m.p. 120° C. (foams), 150° C. (decomposes); 1H NMR (DMSO-d6) δ7.70-7.67 (m,2H), 7.24-7.22 (d, 1H, J=8.7 Hz), 5.64-5.61 (d, 1H,J=9.2 Hz), 5.16 (bs, 1H), 4.07-4.05 (overlapping dd, 1H), 3.98 (bs, 1H), 3.87-3.66 (m, 1H), 3.68-3.66 (d, 2H,J=8.5 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:6]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:8]=1.[BH4-].[Na+]>C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:8]=1)[CH:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CN(C)c1cc(C(=O)CS(C)(=O)=O)cc(N(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1

Procedure:
A suspension of 7.4 g. of 3',5'-bis(dimethylamino)-2-methylsulfonylacetophenone and 3.8 g. of sodium borohydride in 100 ml. of ethanol was stirred for 20 hours at 25° C. After the addition of 50 ml. of water, the alcohol was removed in vacuo and the remaining aqueous suspension extracted with 400 ml. of ethyl acetate. The ethyl acetate phases were washed with 50 ml. of water, dried over magnesium sulfate and evaporated to dryness in vacuo. Recrystallization of the residue from ethanol gave 3,5-bis(dimethylamino)- α -[(methylsulfonyl)-methyl]-benzyl alcohol, having a melting point of 142°-143° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:14](=[O:16])[C:23]=2[CH:24]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (41 ml, 765 mmol) was added to 2-(4-bromophenoxy)-5-methoxybenzoic acid (3750 mg, 12 mmol) at RT. The reaction mixture was stirred at 60° C. for 60 min. LCMS showed complete reaction. The reaction mixture was cooled to RT and poured slowly over stirred mixture of ice and water (100 ml). The tan precipitate was filtered and washed with water (3×30 ml), twice with 30 ml of 0.5N NaOH, and with water again. The residue was recrystallized from 40 ml THF to give the title compound. MS m/z=307.2 [M+H]+. Calc'd for C14H9BrO3: 305.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([C@H:9]([OH:12])[CH2:10]I)[C:7]=1[F:8].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[CH2:29][C:30]([NH:33][CH2:10][C@H:9]([C:6]1[CH:5]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:12])([CH3:31])[CH3:32]
Reactant: CC(C)(N)CC1Cc2ccccc2C1
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CI)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c1
Temperature: 90 °C
Yield: 49.4 %

Procedure:
To a solution of ethyl 3-{3,4-difluoro-5-[(1S)-1-hydroxy-2-iodoethyl]phenyl}propanoate (0.550 g, 1.43 mmol) in ethanol (2.8 mL) was added [2-(2,3-dihydro-1H-inden-2-yl)-1,1-dimethylethyl]amine (0.273 g, 1.44 mmol) and K2CO3 (0.218 g, 1.58 mmol). The reaction was heated at 90° C. for 17 h. Upon cooling, the reaction was filtered and concentrated. Column chromatography (0-12% CH3OH:CH2Cl2) provided 0.315 g (49%) of the title compound: MS (ESI) 446.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:7]=1[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]2.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]3[C:7]=2[C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[NH:10]3)[CH2:34][CH2:35]1
Reactant: Cc1ccc(OCCCCl)c2c1NC(=O)C2(C)C
Reactant: c1ccc2nc(CC3CCNCC3)ccc2c1
Product: Cc1ccc(OCCCN2CCC(Cc3ccc4ccccc4n3)CC2)c2c1NC(=O)C2(C)C

Procedure:
In a manner similar to that described in Example 1, 4-(3-chloropropoxy)-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one (268 mg) and 4-(2-quinolylmethyl)piperidine (226 mg) were processed, to thereby obtain the title compound as white powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>C(O)(C(F)(F)F)=O.[Pt](=O)=O>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: FC(F)(F)COc1cnc2ccccc2c1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cnc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)quinoline (1.13 g, 5.0 mmol) and platinum (IV) oxide (50 mg) in TFA (8 mL) was stirred at room temperature for 12 hours under hydrogen atmosphere (1 atm). Then the mixture was filtered off through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1-7:1) to give 495 mg (43% yield) of the title compound as a colorless oil:
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[Cl:24][C:25]1[CH:48]=[CH:47][CH:46]=[CH:45][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32]2[C:33]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40][C:34]=3[NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1>>[Cl:24][C:25]1[CH:48]=[CH:47][CH:46]=[CH:45][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32]2[C@@H:33]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40][C@@H:34]3[NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: Clc1ccccc1OCCCc1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: Clc1ccccc1OCCCc1cccc2c1[C@@H]1CCNCC[C@@H]1N2

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-[3-(2-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CDCl3) δ 1.99-2.20, 2.27, 2.78, 2.93-3.05, 3.51, 4.11, 6.48, 6.62, 6.92, 7.03, 7.19, 7.38, 7.40. HRMS (FAB) calcd for C21H25ClN2O1 (MH+) 357.1733, found 357.1749.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ccc1Cl
Yield: 84 %

Procedure:
Prepared according to the method described in Example 22 from 2,5-dichlorobenzoic acid (0.319 g), 1-adamantanemethylamine (0.25 g), 4-dimethylaminopyridine (0.20 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.321 g) in dichloromethane (30 ml). The crude product was purified by silica gel chromatography eluting with dichloromethane to give the title compound as a white solid (0.43 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:29](=[O:31])[CH3:30])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(CNc2ccc(Cl)cc2)c[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccc(Cl)cc2)c[nH]1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) (0.2868 g, 1.03 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (2.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1971 mL, 1.13 mmol) was added, then acetyl chloride (0.0805 mL, 1.13 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (90 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 2:1 Hexanes:Ethyl acetate) to obtain pure 4-[(acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (189, 0.2701 g, 82%) as a sticky white solid. 1H (CD3OD, 400 MHz): δ 11.25 (1H, broad s), 7.35 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz), 6.76 (1H, s), 6.69 (1H, s), 4.68 (2H, s), 4.22 (2H, q, J=7.1 Hz), 1.81 (3H, s), 1.29 (3H, t, J=7.1 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.17, 162.50, 142.39, 134.87, 130.94, 130.70, 124.46 & 124.30, 123.94, 121.91 & 121.88, 116.64, 61.13, 46.43, 22.70, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.70, 14.75; CH2 carbons: 61.13, 46.43; CH carbons: 130.94, 130.70, 124.46 & 124.30, 116.64 ppm. HPLC: 9.247 min.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN1C(=O)CCC1>[CH3:11][C:10]1[C:3]2[C:4]([NH:5][CH:6]=[N:7][C:2]=2[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[N:8][CH:9]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (136 mg), N-4-piperidinylbenzamide (249 mg, 1.217 mmol) and DIPEA (0.354 mL, 2.029 mmol) in NMP (1 mL) was heated in the microwave at 150° C. for 20 minutes. EtOAc (10 mL) was added to the mixture and a precipitate formed which was filtered off—this was shown to be remaining piperidinylbenzamide starting material. The filtrate was diluted with further EtOAc (10 mL) and washed with water (3×15 mL). On the third washing a precipitate formed—this was filtered off and found to be mainly desired product. The filtrate was dried (phase separator) and concentrated to give further solid. Both solids were purified by MDAP and the clean fractions combined and concentrated in vacuo before drying in a drying pistol to give E17 (117 mg); 1H NMR (d6-DMSO) δ 11.54 (1H, brs), 8.48 (1H, d), 8.21 (1H, s), 7.86 (2H, d), 7.52 (1H, t), 7.45 (2H, t), 7.08 (1H, s), 4.13-3.98 (3H, m), 3.04 (2H, t), 2.33 (3H, s), 1.93 (2H, dd), 1.72 (2H, ddd), MS(ES+) 336 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OC(C)=O

Procedure:
To a stirred solution of the 2-methoxy-4-nitrophenyl acetate prepared in Part A (99.2 mg, 0.47 mmol) in EtOAc (4.5 mL) was added palladium on carbon (33.0 mg, 5% dry basis, Degussa type: 50% water content). The suspension was hydrogenated (1 atm, balloon) for 3 h, filtered through Celite and the filter cake was rinsed with MeOH (5×10 mL). Evaporation of the combined filtrates gave the desired aniline (84.8 mg, quant.) as a brown oil: MS (electrospray, + ions) m/z 182 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:12])[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:10]=[N:11][C:6]=2[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:3]=1
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(N)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Yield: 37.8 %

Procedure:
In a dry 25 mL round bottom flask, 5-methyl-7-(3-nitro-phenyl)-benzo[1,2,4]triazin-3-ylamine (0.223 g, 0.7935 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.396 g, 1.19 mmol, 1.5 equiv), cesium carbonate (0.776 g, 2.38 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.092 g, 0.159 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.073 g, 0.079 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (10 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 5 hours, then filtered hot and the solvents were evaporated. Silica gel column purification provided desired product as a yellow powder (0.16 g, 39% yield). MS (ESI+): m/z=582.1
Reaction SMILES: CC(O[C:6](=[O:18])[N:7]([CH3:17])[CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2C(O)=O)=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:17][N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[C:6]([C:40]1[N:41]=[C:42]([CH3:44])[S:43][C:39]=1[C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)=[O:18]
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N(C)CCNC(=O)C(F)(F)F)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
An ice-cooled solution of methyl-[2-(2,2,2-trifluoro-ethanoylamino)-ethyl]-carbamic acid dimethyl-ethyl ester, D3 (3.61 g, 13.4 mmol) in dichloromethane (80 ml) was treated with trifluoroacetic acid (20 ml). After stirring at room temperature for 5 h the mixture was poured cautiously onto solid K2CO3 (excess)/ice. The product was extracted with dichloromethane (4×) then 10% methanol-dichloromethane (5×). The combined organics were dried (MgSO4) and the solvent removed in vacuo. The resulting yellow gum (380 mg) was added to a stirring solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (530 mg, 2.2 mmol), N,N-diisopropylethylamine (1.17 ml, 6.7 mmol) and HATU (851 mg, 2.2 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h, then partitioned between ethyl acetate and water. The organic phase was washed with water (2×), brine, dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, 20–100% ethyl acetate-pentane) afforded the title compound as a colourless gum (443 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[C:12](O)(=[O:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[O:19])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: O=C(O)c1ccncc1
Reactant: CCOP(=O)(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOP(=O)(CCNC(=O)c1ccncc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
A mixture of diethyl 2-aminoethylphosphonate (12.5 g), isonicotinic acid (10.2 g), 1-hydroxybenzotriazole (11.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.83 g) and dichloromethane (190 ml) was stirred at room temperature for 15 hours. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol-chloroform) to give 7.94 g of N-(2-diethoxyphosphorylethyl)-4-pyridinecarboxamide as an oil.