Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[N:15]12[C:21](=[O:22])[CH2:20][CH:19]1[CH2:18][C:17](=[O:23])[CH:16]2[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:23][C:17]1[CH2:18][CH:19]2[N:15]([C:21](=[O:22])[CH2:20]2)[C:16]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Azidoacetyl chloride (21 μl) is added by syringe in an ice-cold, stirring solution of triethylamine (42 μl) and benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (52 mg) in anhydrous methylene chloride (2 ml). After stirring 30 mins in the cold, the reaction mixture is diluted with methylene chloride (5 ml), washed with H2O (2 ml), pH 3 phosphate buffer (2 ml), and 5% NaHCO3 (2 ml), dried with MgSO4, filtered, and evaporated in vacuo. Chromatography of the residue on a silica gel GF plate gives benzyl 3-(α-azidoacetoxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH2:18][CH3:19])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)c(Br)c(O)c1

Procedure:
A mixture of 4-bromo-3,5-dihydroxybenzoic acid (45.0 g), concentrated sulfuric acid (5 mL), and ethanol (300 mL) was heated to reflux for 24 hours. The solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline in this order. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained solid was washed with hexane to obtain the title compound (48.3 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:30]#[N:31].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:30]#[N:31])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(Br)cnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Temperature: 25 °C
Yield: 22.7 %

Procedure:
1-Benzyl-6-bromo-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine hydrochloride prepared in Example 273 was neutralized with a saturated sodium carbonate solution to obtain 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol). A solution of 1-benzyl-6-bromo-7-(4-fluoro-benzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (1.4 g, 3.18 mmol) and copper (I) cyanide (700 mg, 7.52 mmol) in anhydrous N,N-dimethylformamide (30 ml) was refluxed for 48 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble solid. Water was added to the resulting solution, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, v/v) to give 278 mg of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][N:23]1[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: CN1CCN(CCCCN)CC1
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCCCN3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available 4-(4-methylpiperazin-1-yl)butan-1-amine, the title compound was obtained, MS (Found M+1=413. 1H NMR (CD3OD, 300 Hz): 8.32-8.30 (d, 1H J=8.2 Hz), 8.30-7.85 (m, 1H), 7.58-7.57 (d, 1H), 7.47-7.44 (m, 1H), 7.34-7.32 (m, 1H), 4.00 (s, 3H), 3.92-3.89 (t, 2H, J=6 Hz), 2.54-2.51 (b, 4H), 2.41-2.29 (m, 6H), 2.25 (s, 3H), 1.85-1.77 (m, 2H), 1.60-1.53 (m, 2H).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][OH:20].[OH-].[K+].C(O)(C)C>O>[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][O:20][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CC1CCCCN1C(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC1CCCCN1C(=O)COc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
17 g (0.07 mol) of 5-chloro-3-trichloromethyl-1,2,4-thiadiazole are added to a stirred mixture which comprises 11 g (0.07 mol) of hydroxyacetic acid 2-methylpiperidide, 4.5 g (0.07 mol) of potassium hydroxide powder and 100 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 20 hours at -10° C. and then poured into water, and the product is filtered off under suction and washed with water. 18 g (72% of theory) of (3-trichloromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid 2-methyl-piperidide are obtained in the form of a white powder of melting point 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH:24]1[CH:28]=[N:27][C:26]([CH2:29][N:30]2[C:34](=[O:35])[CH2:33][S:32][C:31]2=[O:36])=[N:25]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14](/[CH:16]=[C:33]4/[C:34](=[O:35])[N:30]([CH2:29][C:26]5[N:27]=[CH:28][NH:24][N:25]=5)[C:31](=[O:36])[S:32]/4)=[CH:15][C:10]=3[N:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:21])[F:22])[CH:3]=1
Reactant: O=C1CSC(=O)N1Cc1nc[nH]n1
Reactant: O=Cc1ccc2c(c1)nnn2Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C1S/C(=C\c2ccc3c(c2)nnn3Cc2ccc(Cl)cc2C(F)(F)F)C(=O)N1Cc1nc[nH]n1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-benzotriazol-5-yl}methylidene)-3-(1H-1,2,4-triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from 1-(4-chloro-2-trifluoromethylbenzyl)-1H-benzotriazole-5-carbaldehyde (from Example 258) and 3-(1H-[1,2,4]triazol-3-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 90) following General Procedure F.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.[OH-].[Na+]>[NH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc([N+](=O)[O-])ccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1cc([N+](=O)[O-])ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
N-(4-methoxybenzyl)-4-nitropyridin-2-amine (27.8 g, 0.11 mol) and anisole (13 mL, 0.12 mol) were dissolved in trifluoroacetic acid (112 mL) and heated at 80° C. for 2 h. The reaction mixture was allowed to cool to rt and concentrated. Trituration of the resulting residue with EtOAc and hexanes produced a light yellow solid that was isolated via filtration. The filtrate was allowed to stand overnight and a second crop of crystals was obtained. The combined batches of solids were dissolved in 1N NaOH (250 mL) and extracted with EtOAc (2×250 mL). The combined organic solutions were dried over MgSO4, filtered and concentrated to give 2-amino-4-nitropyridine as an orange solid (10.2 g, 67%). LCMS: (FA) ES+ 140.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][N:33]4[C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])=[O:39])[CH2:24][CH2:25]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(piperazin-1-yl)-1H-indazole (0.051 g, 0.14 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.061 g, 0.28 mmol) in dichloromethane (1 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by the addition of dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to afford the (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.052 g, 0.088 mmol, 63%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C:7]1[C:12](/[C:13](=[CH:18]\[O:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:1]
Reactant: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(C=O)c1
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a stirred solution of (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.250 g) in dichloromethane (5 ml) at room temperature was added pyridinium dichromate (0.414 g). After stirring for 3 hours, GC analysis of an aliquot indicated the absence of starting material. Water was added and stirring continued for 10 minutes. The reaction mixture was filtered (filter washed through with water (5 ml) and dichloromethane (5 ml)) and then further diluted with dichloromethane (5 ml). The organic layer was separated and the aqueous phase further extracted with dichloromethane (×3). The combined organic layers were dried, filtered and evaporated to give a dark yellow oil. Chromatography on silica gel (eluent ether-petroleum ether, 7:3) afforded (E)-methyl 2-[2-(3-formylphenoxy)pyridin-3yl]-3-methoxypropenoate (0.136 g, 55%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH2:18][C:19](=O)[CH2:20][C:21](=[O:24])[CH2:22][CH3:23].[Na]>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:19]([CH2:18][CH3:17])[C:20]([C:21](=[O:24])[CH2:22][CH3:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)CC(=O)CC
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCC(=O)c1c(CC)nc2ccc(Br)cc2c1-c1ccccc1
Yield: 37 %

Procedure:
The title compound was prepared according to the general procedure of method A. The (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] (on 0.1-1 g scale) and 3,5-heptanedione (1.5 equiv) and sodium tetrachloroaureate(III) dihydrate (0.025 equiv) were heated in parallel in a Radley carousel under nitrogen in ethanol (10% w/w-solution of (2-Amino-5-bromo-phenyl)-phenyl-methanone) and reacted for 24 h. The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica gel in heptane/ethyl acetate (20:1). Yield: 37%. MS: m/z=368 (M).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl-]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)-amide as a yellow solid (53 mg, 41%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].N1C=CC=CC=1.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[O:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]([CH3:31])[C:28]([O:4][CH2:1][CH:2]=[CH2:3])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Reactant: C=CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.2 g allyl alcohol and 1.6 g pyridine in 50 cc methylene chloride, add 6.6 g of 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 60 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry the solution over magnesium sulfate concentrate under vacuum to give allyl 2-[4-(2-quinoxalinyloxy)phenoxy]propanoate.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][C:14]([NH:38][CH2:37][CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]2)=[CH:13][CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2ccc3oc(-c4cc5ccccc5cn4)cc(=NO)c3c2)CC1

Procedure:
2-isoquinolin-3-yl-6-[3-(4-methyl-piperazin-1-yl)-propylamino]-chromen-4-one oxime was prepared in 85% overall yield using the method described in examples 35 and 35A, starting from 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 4B) and 3-(4-methyl-piperazin-1-yl)-propylamine. The title compound was isolated as a yellow solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][O:36][CH2:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][O:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1CCCOC1)C(F)(F)F
Product: COc1cn(C(CC2CCCOC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
450 mg (purity 94%, 1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.24 ml (1.24 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 467 mg (1.69 mmol, 1.5 eq.) of tetrahydro-2H-pyran-3-ylmethyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 451 mg (purity 82%, 69% of theory)
Reaction SMILES: Br[C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14](B(O)O)=[CH:13][CH:12]=1>>[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)CC(=O)C=C(Br)C1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Product: CC1(C)CC(=O)C=C(c2cccc3c2oc2ccccc23)C1
Yield: 96 %

Procedure:
Synthesized from 3-bromo-5,5-dimethylcyclohex-2-enon and dibenzofuran-4-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (192 mg, 96%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.93 (dd, J=7.4, 1.1 Hz, 1H), 7.92 (ddd, J=7.7, 0.8, 0.6 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.51-7.43 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 6.91 (t, J=1.4 Hz, 1H), 2.85 (d, J=1.4 Hz, 2H), 2.42 (s, 2H), 1.19 (s, 6H). 13C (75 MHz, CDCl3): δ 200.3, 156.0, 153.9, 153.4, 127.7, 127.6, 125.6, 125.3, 124.3, 123.6, 123.2, 123.0, 122.0, 120.7, 112.0, 51.3, 43.0, 34.2, 28.7. HRMS (LCT Electrospray): mass calcd for (C20H18O2+Na) m/z 313.1204; measured [M+Na]+: m/z 313.1201.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([C:26]4[CH:27]=[CH:28][C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:25]=4)(=[O:37])=[O:36])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)c2ccc3ccccc3c2N1
Yield: 64.3 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-naphthalenesulfonyl chloride (32 mg, 0.14 mmol) were treated by heating 11 pyridine (3 mL). A post-treatment was performed in a conventional manner to give the title compound (31 mg, yield 64%) as white amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:13]1[C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:12]>>[CH2:24]([O:23][C:14]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH:11]=[O:12])[CH2:25][CH2:26][CH3:27]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCCCOc1c(C=O)cc(C)cc1B(O)O
Product: CCCCOc1c(C=O)cc(C)cc1-c1ccc([N+](=O)[O-])cn1

Procedure:
The title compound was synthesized in a manner analogous to Example 52(i), except for replacing 2-chloro-5-nitropyridin with 2-chloro-5-nitropyridine, and replacing 3-formyl-2-isopropoxy-5-methylphenylboronic acid with 3-formyl-2-butoxy-5-methylphenylboronic acid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>O1CCCC1.C(OCC)C.[Zn]>[F:16][C:10]([F:17])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1

Procedure:
To a solution of benzaldehyde (3.0 g, 28 mmol) in anhydrous tetrahydrofuran (80 mL) was added zinc (2.4 g, 36 mmol). The mixture was heated at 75° C. under inert atmosphere and ethyl 2-bromo-2,2-difluoroacetate (4.4 mL, 34 mmol) was slowly added. The mixture was heated under the same conditions for 2 hours. After cooling, 2N hydrochloric acid (25 mL) was added until the complete consumption of unreacted zinc. The solvent was removed under reduced pressure. The crude reaction was dissolved in ethyl ether (150 mL) and washed with brine (2×100 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.4 g, 99%) as yellow oil and was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][CH:28]([CH2:32][CH3:33])[C:29](O)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[CH:28]([CH3:27])[CH2:32][CH3:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CCC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (84 mg, 82%), MS (ISP) m/z=413.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.