Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH2:40]([O:42][C:43](=[O:47])[C:44](Cl)=[O:45])[CH3:41]>C(Cl)Cl>[CH2:40]([O:42][C:43](=[O:47])[C:44](=[O:45])[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[N:18][C:17]([NH:20][C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1)[CH3:41]
Reactant: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCNCC4)cc3)cn2)cn1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h
Yield: 99.9 %

Procedure:
[5-(4-Piperidin-4-yl-phenyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine hydrochloride (200 mg, 0.46 mmol) was slurried in DCM (2 mL) and to it was added N,N-diisopropylethylamine (1.320 mL, 7.6 mmol). Chloro-oxo-acetic acid ethyl ester (0.076 mL, 0.69 mmol) was added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between EtOAc and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain 229 mg of the title compound as a crude oil, which was taken to the next step without purification: MS (M+H)+ 499.2.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].Cl.[C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=C(OC4CCNCC4)C=CN=3)=CC=2)C=1)(C)(C)[CH3:41]>>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:40][CH3:41])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3cc(OC4CCNCC4)ccn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CCN1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)cc3)nc2)CC1
Yield: 94 %

Procedure:
N-(4-(3-(5-(1,3-Difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-ethylpiperidin-4-yloxy)picolinamide (65 mg, 94%) was prepared as a white powder using a procedure analogous to that described in Example 2, substituting N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride from Step 3 of this example for N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-4-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 2. LC-MS (ESI) m/z 543 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.60 (s, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=8.85 Hz, 1H), 7.81 (d, J=9.04 Hz, 2H), 7.63-7.72 (m, 1H), 7.42 (d, J=9.04 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.58 (s, 2H), 2.73 (br. s., 1H), 2.27 (br. s., 3H), 1.97-2.17 (m, 2H), 1.91 (s, 2H), 1.75 (s, 2H), 1.34 (s, 3H), 0.90-1.20 (m, 4H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C([OH:29])CCCCCCC/C=C\CCCCCCCC.N1C=CC=CC=1>CCCCCC>[C:2]([OH:9])(=[O:29])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Nicotinoyl chloride hydrochloride (17.8 g, 0.1 mol) and oleyl alcohol (26.85 g, 0.1 mol) were added into hexane (250 ml). Pyridine (15.8 g, 0.2 mol) was added to the stirred mixture over a period of 10 min, and the reaction mixture was stirred at room temperature for 24 h. Pyridine hydrochloride was removed by filtration and washed with hexane. The combined filtrate was extracted with water, dried over MgSO4 and evaporated to dryness. The residue was digested twice with acetonitrile, and the sticky residue was dried to give a clear water-like liquid which turned soap-like upon cooling (21.1 g, 56.5 mmol, 56.5%).
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCOCC1.Cl.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(S(C)(=O)=O)CC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 mL) was added 4 M HCl dioxane solution (0.5 mL) and stirred for 2 h at 0° C. The solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 mL) and slowly added methanesulfonyl chloride (2 μL, 0.030 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 1 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (3:1 n-Hexane/EtOAc) to give a colorless oil (3 mg, 82% yield): 1H NMR (300 MHz, CDCl3) 1.08˜1.87 (m, 20H); 2.36 (d, J=12.4 Hz, 1H); 2.77˜2.92 (m, 5H); 3.51˜3.54 (m, 1H); 4.10˜4.15 (m, 1H); 6.86˜6.96 (m, 2H); 7.13 (d, J=8.3 Hz, 1H).
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.S([O-])([O-])=O.[Na+].[Na+]>O>[CH:11]1[C:10]2[C:9](=[O:19])[C:8]3[C:17](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16](=[O:18])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
50 G of a crude 1-nitroanthraquinone manufactured according to Example 1 are treated, in accordance with German Offenlegungsschrift (German Published Specification) 2,206,960, with 30 g of sodium sulphite in 400 ml of water. After filtration, washing and drying, 34.6 g of 1-nitroanthraquinone of the composition indicated in Table A are obtained (= 63% of theory, relative to anthraquinone employed).
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([CH2:32][CH2:33][CH3:34])=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[O:19]2)=[CH:14][CH:13]=1)=[O:10]>C1C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:35])[C:17]([CH2:32][CH2:33][CH3:34])=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=4)[O:19]3)=[CH:14][CH:13]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CCl)ccc2c1=O
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CN3CCOCC3)ccc2c1=O
Reaction time: 4 h

Procedure:
The mixture consisting of 9.2 of this derivative, 700 cc of benzene, 20 cc of morpholine is heated to reflux of the benzene with stirring for 4 hours, then cooled. The benzene phase is washed with water several times, dried on sodium sulfate and evaporated. The residue is recrystallized in ethyl alcohol. Yield 60%. MP=196° C. NMR in CDCl3 : δ=0.9 ppm, 3H, triplet, CH3 (propyl), δ=1.2-1.9 ppm, 2H, poorly resolved multiplet, CH2CH2CH3 ; δ=2.3-2.9 ppm, 6H, complex multiplet, CH2CH2CH3 +2CH2N (morpholine); δ=3.2 ppm, 2H, singlet, COCH2N; δ=4.0 ppm, 3H, singlet, CH3, ester; δ=7.0-8.3 ppm, 7H, complex multiplet, aromatic protons; δ=9.4 ppm, 1H, broad peak, NH, (interchangeable with D2O).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:32][C:33](=[O:34])[N:35]([CH3:37])[CH3:36])=[O:13])(=[O:6])=[O:7]
Reactant: CN(C)C(=O)CO
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 14.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 2.90 mmol) dissolved in 40 mL of anhydrous dichloromethane (DCM) was reacted with 1.74 mL (3.48 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, an aliquot (ca. 1.45 mmol) of the acid chloride was reacted with 455 mg (4.41 mmol) of 2-hydroxy-N,N-dimethylacetamide (36b) and 352 μL mL of pyridine (344 mg, 4.35 mmol) in 10 mL of anhydrous dichloromethane (DCM). After work-up, the crude material was purified by silica gel column chromatography using mixtures of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=2:3→EtOAc/Hxn=1:1) to provide 200 mg (30% yield) of the title compound (36c) as an opaque, viscous oil. Rf=0.28 (EtOAc/Hxn=1:1). MS (ESI) m/z 464.2 (M+H)+, 486.1 (M+Na)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](=[O:31])[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
The above 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (88.5 mg, 0.19 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of pyrrolidine, 2.0 equivalent of HBTU and 3.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded to a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (29 mg, 33%). ES-MS calcd for C25H24N2O7 (m/e) 464.5, obsd 465.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[CH:3]=1.C(O)(=[O:13])C.C1N2CN3CN(C2)CN1C3.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:3]=1)[CH:9]=[O:13]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cc(Br)ccc1F
Temperature: 90 °C

Procedure:
A mixture of 79.5 g (0.296 mol) of 4-bromo-2-bromomethyl-1-fluorobenzene (prepared according to G. E. Stokker, A. W. Alberts et al., J. Med. Chem., 1986, 29, 170), 126 ml of acetic acid, 82.7 g (0.59 mol) of hexamethylenetetramine and 126 ml of water is heated for 2 hours at reflux. The mixture is cooled to 90° C., 99.5 ml of concentrated hydrochloric acid are added and the mixture is heated for 30 min at reflux. Cooling, extraction with ether, washing with water, washing with an aqueous NaHCO3 solution, washing with water, drying over Na2SO4, filtration and evaporation under vacuum are carried out. The residue is purified by chromatography on silica (eluent: 10/1 hexane/ethyl acetate). Yd.: 23.6 g (39%)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.O>[CH2:13]([O:20][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccnc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
2-Chloro-nicotinic acid (421) (3 g, 19.04 mmol) was dissolved in anhydrous THF (50 mL) and chilled to 0° C. on an ice bath. NaH (50 mmol, 60% suspension in mineral oil) was added portion wise to the solution over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Benzyl-alcohol (422) (2.27 g, 21 mmol) was added drop wise over a period of 10 minutes. The ice bath was removed and the mixture was warmed to room temperature over a period of 2 h. The mixture was refluxed for 16 h. LC-MS and TLC (Rf: 0.4–0.5 compared to Rf: 0.1 for compound 421 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was diluted with water (300 mL) and the pH was adjusted to ˜6 by the addition of HCl (aqueous, 1M) and the product was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. Recrystallization from EtOAc/hexane gave the desired product (423) as a white powder (2.8 g, 12.2 mmol, 64% yield). LC-MS (ESI): (exact mass: 229.07) m/e=230.2 [M+1]+ (100%), 459.3 [2M+1]+ (90%).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC1NS(=O)(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (20.74 g, 0.117 mol), phenylmethyl bromide (22.09 g, 0.129 mol), and tetrabutylammonium bromide (3.77 g, 0.012 mol) in toluene (400 ml) and DMF (50 ml) was refluxed for 40 hours, cooled, and poured over ice/water. The crude product was purified by flash chromatography to afford 11.1 g of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VII: R1 =propyl; R2 =R3 =H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>C1COCC1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCC(O)c1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
n-Hexyl magnesium bromide (2.0 M in Et2O, 27 mL, 54 mmol) was added to a solution of 4-bromobenzaldehyde (5.0 g, 27 mmol) in THF (20 mL) at 0° C. under nitrogen. After 1.5 h at 0° C., the reaction was quenched slowly with 3 N HCl (20 mL) and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with Et2O (3×150 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5%→10% EtOAc/Hex) afforded 5.6 g (76%) of 1-(4-bromophenyl)-heptan-1-ol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:23][O:24][C:25](=[O:29])[CH2:26][NH:27][CH3:28].CCN(CC)CC>CN(C=O)C>[CH3:23][O:24][C:25](=[O:29])[CH2:26][N:27]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:28]
Reactant: CNCC(=O)OC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), sarcosine methyl ester hydrochloride 0.139 g (1.0 mmol) with Et3N 1.0 mL (10.0 mmol) in DMF 2 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. 1H NMR (CD3OD, 400 MHz) δ 7.63-7.70 (m, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.07-7.11 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.62 (s, 3H), 3.45 (s, 3H); HRMS (ES) m/z calcd for C20H22N4O3 (M+H) 367.1764, found 367.1772.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C([O-])(=O)C.[Na+].[CH3:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][OH:16]>>[C:4]([O:16][CH2:15][CH2:14][N:13]([CH3:12])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCCN(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 84 g. (1.0 mole) of diketene contained in a three-necked round-bottom flask fitted with a mechanical stirrer addition funnel and reflux condenser and heated to 50° C. is added 500 mg. of sodium acetate followed by 175.2 g. (1.0 mole) of N-methyl-N-t-butyloxycarbonylethanolamine over a period of 20-30 minutes. The reaction mixture is allowed to stir at room temperature for 1 hour, after which it is distilled under reduced pressure to provide the desired product, 2-(N-methyl-N-t-butyloxycarbonylamino)ethyl acetoacetate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: COc1ccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)cc1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-methoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O4, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.99 (br s, 1H), 12.88 (br s, 1H), 8.97 (s, 1H), 8.28 (d, J=13.9 Hz, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.78-7.72 (m, 3H), 7.09-7.06 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][C:29]1[O:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:28][N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CNCc1ccco1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)Cc2ccco2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylfurfurylamine (367 mg, 3.3 mmol) is added to the filtrate and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provided the title compound. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=11 Hz, 2H), 3.79 (d, J=6 Hz, 2H), 6.32 (d, J=2 Hz, 1H), 6.21 (d, J=3 Hz, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 3.53 (s, 2H), 2.39 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([CH:36]=O)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26](=[O:39])[CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([C:36]2[NH:20][C:15]3[CH:14]=[C:13]([C:11]4[O:12][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][N:10]=4)[CH:18]=[CH:17][C:16]=3[N:19]=2)=[C:31]([Cl:38])[CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1N
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Reaction time: 72 h

Procedure:
To a 20 ml scint. vial was added 0.3783 g (1.32 mmol) 4-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine, 0.4000 g (1.32 mmol) of 3-(3,5-Dichloro-4-formyl-phenyl)-propionic acid tert-butyl ester (step A), and 6 mL of DMSO. To this dark brown solution was added 0.0321 g (0.198 mmol) of FeCl3. Allowed to stir open to air for 72 h. Extracted with EtOAc, and washed with water, brine and dried with Na2SO4. Purified on silica gel (ACN/DCM, 1:9 to 4:6) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (9H) 2.64 (t, J=7.33 Hz, 2H) 2.92 (t, J=7.26 Hz, 2H) 7.60 (s, 2H) 7.72 (d, 2H) 7.78 (d, J=8.59 Hz, 0.5H) 7.92 (d, J=8.46 Hz, 0.5H) 8.00-8.09 (m, 1H) 8.17-8.22 (m, 2H) 8.31 (s, 0.5H) 8.50 (s, 0.5H) 13.32 (d, J=11.24 Hz, 1H). MS (m/z) 571.1 M (+1), tR=1.59, Meth 10