Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:13]=2[OH:14])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(COC)OC.O>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(Br)cc1Cl)C(=O)N2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-bromo-2-chloro-6-methyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.34) (150 mg, 0.361 mmol) in dimethoxyethane (10 ml) under argon atmosphere was added tetrakis(triphenyl-phosphine)palladium(0) (25 mg, 0.022 mmol) and the mixture stirred at room temperature for 15 minutes. After further addition of water (2 ml), 4-chlorophenylboronic acid (68 mg, 0.435 mmol) and sodium carbonate (153 mg, 1.444 mmol), the mixture was heated at 80° C. for 10 hours. The reaction mixture was acidified at room temperature to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate (4×15 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with diethyl ether, stirred at room temperature, filtered and dried. Yield: 114 mg of 3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one as a pale brown solid, mp 236° C. (dec).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[BrH:15].O>C1(C)C=CC=CC=1>[Br:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCCCCCCCCCCO
Reactant: Br
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCCCCCCCCCCBr

Procedure:
To a stirred solution of dodecane-1,12-diol (8.365 g, 42.75 mmol), 48% HBr in water (9.7 ml, 85.50 mmol) and toluene (120 ml) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then concentrated, the crude compound was dissolved in DCM (150 ml), washed with water, NaHCO3 brine solution, dried over MgSO4 and concentrated. The crude product was purified by silica gel column (5% EtOAc in hexane) to obtain 12-bromododecan-1-ol as an off-white low melting solid (8.87 g, 78%).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]2[C@H:12]([OH:25])[CH2:13][CH2:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:16][C:9]2=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(N(CC)CC)C.[O:35]=[C:36]1[NH:44][C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]1[CH:45]1[CH2:50][CH2:49][N:48]([C:51](OC2C=CC([N+]([O-])=O)=CC=2)=[O:52])[CH2:47][CH2:46]1>C1COCC1>[O:35]=[C:36]1[NH:44][C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]1[CH:45]1[CH2:46][CH2:47][N:48]([C:51]([O:25][C@H:12]2[C:10]3=[N:11][C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=[C:9]3[CH2:16][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:14][CH2:13]2)=[O:52])[CH2:49][CH2:50]1
Reactant: CC(C)(C)Nc1ccc2c(n1)[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6R,9R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (69.1 mg, 0.199 mmol) with stirring bar was azeotroped by benzene. Sodium hydride (47.9 mg, 1.995 mmol) was added to the THF (3 mL) suspension of (6R,9R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (69.1 mg, 0.199 mmol) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-1-yl)piperidine-1-carboxylate compound with triethylamine (1:3) trihydrochloride (238 mg, 0.299 mmol) at rt. The reaction was stirred at room temperature overnight. The reaction was quenched by water and partitioned between ethyl acetate and water. The ethyl acetate layer was washed by water twice before dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 10% gave the desired product as a white solid. The product was further purified by prep HPLC (69.2 mg, 26%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.07 (d, J=5.19 Hz, 1H) 7.34-7.44 (m, 1H) 6.96-7.15 (m, 4H) 6.08-6.28 (m, 1H) 5.83-5.99 (m, 1H) 4.42-4.77 (m, 3H) 3.16-3.25 (m, 1H) 2.86-3.14 (m, 3H) 2.62-2.72 (m, 1H) 2.11-2.38 (m, 5H) 1.94 (d, J=11.90 Hz, 3H) 1.52-1.60 (m, 1H) 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[CH3:31])O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C(O)C>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[CH3:31])[CH:3]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(Br)c2)CC1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Yield: 63 %

Procedure:
To a flask containing 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (68 mg, 0.2 mmol, as prepared in Example 4, step (a)), 4,4,5,5-tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane (61 mg, 0.27 mmol, as prepared in the previous step) and Pd(PPh3)4 (14 mg, 6 mol %) was charged toluene (3 mL), ethanol (3 mL) and 2M Na2CO3 (4 mL). The resultant mixture was heated at 80° C. for 2 h and then poured into EtOAc (25 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel preparative thin layer chromatography (EtOAc) afforded 40 mg (63%) of the title compound as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H19N3O2S, 318.1 (M+H), found 318.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH:7]=[C:8]([CH3:19])[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[ClH:18].[CH3:19][CH:8]([CH2:7][C:6]1[CH:20]=[CH:21][CH:22]=[C:4]([NH2:1])[CH:5]=1)[C:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:10]
Reactant: [H][H]
Reactant: CC(=Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1cccc(N)c1)C(=O)Oc1ccc(Cl)cc1
Product: Cl

Procedure:
In 250 ml of ethanol were suspended 28.5 g of the p-chlorophenyl m-nitro-α-methylcinnamate thus obtained and 3.0 g of 10% palladium-carbon, and gaseous hydrogen was introduced into the resulting suspension with stirring. About 8.5 liters of hydrogen was absorbed in 2 hours. After the reaction, the palladium catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 200 ml of ethyl ether, and gaseous hydrogen chloride was introduced into the resulting solution to obtain p-chlorophenyl α-methyl-β-(m-aminophenyl)-propionate hydrochloride in the form of colorless crystals. Yield: 23.0 g (78.5%); melting point: 85°-95° C.; IR (cm-1): 3500-2500, 1748, 1492.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[CH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[CH:26]=1)=[N+]=[N-].O>C1COCC1.C(OCC)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH:23]([NH2:20])[CH2:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(CC(N=[N+]=[N-])c2cccc(Cl)c2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CC(N)c2cccc(Cl)c2)on1
Temperature: 50 °C

Procedure:
Triphenylphosphine (137 g, 0.522 mol, 1.19 eq) was added to a solution of 5-(2-azido-2-(3-chlorophenyl)ethyl)-3-methylisoxazole (Preparation 48, 115 g, 0.437 mol, 1 eq) in THF (1 L) under nitrogen atmosphere. The reaction mixture was stirred for 1 hr after which water (45 mL) was added and it was heated at 50° C. overnight. The reaction mixture was concentrated, the crude oil so obtained was dissolved in 1 L ethyl acetate and cooled to 0° C. It was extracted with 6M HCl (3×500 mL). The aqueous phase was saturated by sodium chloride and basified with 6M sodium hydroxide to pH-10 (2 L) and was extracted with ethyl acetate (2 L). Organics were washed by brine, dried and concentrated to yield a liquid, which solidifies upon refrigeration. The title compound was obtained as white solid (30 g, 0.127 mol, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[S:31][C:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=4)[N:20]=[C:21]([CH3:22])[C:16]=3[C:6]=2[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:9]=1)[CH3:2].[OH2:32].C[N+]1([O-])CC[O:37]CC1>CC(C)=O>[OH:32][CH:29]([C:26]1[CH:27]=[CH:28][C:23]([C:19]2[N:20]=[C:21]([CH3:22])[C:16]3[C:6]4[N:7]=[C:8]([N:10]5[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]5)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[S:31][C:17]=3[N:18]=2)=[CH:24][CH:25]=1)[CH2:30][OH:37]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Reactant: O
Solvent: CC(C)=O
Product: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(C(O)CO)cc3)nc(C)c12
Reaction time: 24 h

Procedure:
0.20 g (0.46 mmol) 4-ethoxy-9-methyl-2-piperazin-1-yl-7-(4-vinylphenyl)-thieno[2,3-d:4,5-d′]dipyrimidine and 0.16 g (1.39 mmol) N-methylmorpholine-N-oxide-monohydrate were dissolved in 50 ml acetone. Then, 0.3 ml (4% aqueous) OSO4 solution was added and stirring was carried out at room temperature for 24 h. Thereafter, 100 ml 1 M NaCO3 solution were added and extraction with dichloromethane was carried out. Following flash chromatographic purification (chloroform/methanol, 8.5:1.5) 100 mg (46%) of the title compound is obtained. ESI-MS [m/z]: 466, melting point: >300° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[OH:14][CH2:15][C:16](O)=O>>[CH3:1][N:2]1[C:3]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[N:6]3)[N:13]=[C:16]1[CH2:15][OH:14]
Reactant: O=C(O)CO
Reactant: CNc1ccc2nccnc2c1N
Product: Cn1c(CO)nc2c3nccnc3ccc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of N6-methylquinoxaline-5,6-diamine (1.14 g, 6.4 mmol) and 2-hydroxyacetic acid (486 mg, 6.4 mmol) was stirred at 110° C. for 2 h. Then the mixture was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give (3-methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol as a yellow solid (880 mg, yield 39%). ESI MS: m/z 215.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[N:28]1([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH:1]1([CH:4]([OH:16])[CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:31]3[CH2:32][CH2:33][N:28]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:43])[F:44])[CH2:29][CH2:30]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCC(O)C1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(NCC(O)C1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide (58 mg, 0.24 mmol) in 10 mL of DMF was added 1,8-diazabicylco[5.4.0]undec-7-ene (0.109 g), piperazin-1-yl-(2-trifluoromethylphenyl)methanone (86.7 mg, 0.33 mmol) and Bu4NI (4 mg, 0.01 mmol). The mixture was heated at 80° C. overnight. Water was added and the mixture was extracted with ethyl acetate (2×15 mL). The organic extract was washed with diluted HCl, followed by bicarbonate solution and brine, then dried over Na2SO4 and concentrated. The residue was dissolved in small amount of dichloromethane and purified by column chromatography eluted with ethyl acetate to yield the product as a white solid (35.5 mg, 32% yield). 1H NMR (300 MHz, CDCl3) δ 8.24, 8.02, 7.73, 7.58, 7.34, 6.98, 4.04, 3.85, 3.52, 3.33, 3.10, 2.60-2.41, 0.95, 0.52, 0.32. MS (ES+) m/z 464.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:24][O:23][C:14]1[CH:15]=[C:16]([O:19][CH2:20][O:21][CH3:22])[CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH3:28])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:25])([CH3:26])[CH:6]=[C:5]2[CH3:27]
Reactant: COCOc1ccc(-c2ccc3c(c2CCl)C(C)=CC(C)(C)N3)c(OC)c1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2, 262 mg, 0.675 mmol), 2-methoxyaniline (84 μL, 0.74 mmol) and potassium carbonate (151 mg, 1.09 mmol) was suspended in anhydrous N,N-dimethylformamide (4 mL) and the suspension was stirred at 80° C. overnight. After cooling down, ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and separated. The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (196 mg) as a yellow amorphous product. (Yield 61%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.CN(C=O)C.[CH3:35][C:36]([NH2:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[C:36]([NH:39][C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:12]=2)[CH:24]=[CH:23][CH:22]=1)=[O:20])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) was slurried into DMF (0.7 mL) and TEA (0.1 mL). To this slurry was added 2-methylpropan-2-amine (11.27 mg, 0.154 mmol) and then HATU (59 mg, 0.15 mmol) (solution became yellow). The reaction was stirred at rt overnight (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammonium acetate buffer) to yield 6-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (19.6 mg, 0.042 mmol, 41% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.90 (dd, J=9.2, 1.8 Hz, 1H), 7.88-7.85 (m, 1H), 7.84-7.82 (m, 1H), 7.81-7.78 (m, 2H), 7.77 (br d, J=9.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.69 (s, 3H), 1.52 (s, 9H). LC-MS retention time 1.39 min; m/z 443 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 mM where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]5[O:34][CH2:35][O:36][C:28]=45)=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:37][CH3:38])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[ClH:33].[ClH:33].[Cl:33][C:32]1[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:17]([O:37][CH3:38])[CH:18]=3)[N:23]=[CH:22][N:21]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCNCC1
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 11, 7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxyquinazoline was reacted with trifluoroacetic acid. The material so obtained was triturated under a 6M solution of hydrogen chloride in diethyl ether. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 1.5–1.65 (m, 2H), 2.0 (d, 2H), 2.2 (m, 1H), 2.95 (m, 2H), 3.2–3.4 (m, 2H), 4.02 (s, 3H), 4.12 (d, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.42 (s, 1H), 8.22 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 443 and 445.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)C=C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:35])[C:10]=2[N:9]=[CH:8]1)[CH:2]=[CH2:3]
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: C=CCN
Product: C=CCn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 10.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), allylamine (86 mg, 0.92 mmol), and acetic acid (0.1 ml) were used to give 11.7 mg (0.04 mmol, 10.2% yield) of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([NH2:21])=[C:16]([Cl:22])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:21]/[C:17]1[C:18]([Cl:20])=[CH:19][C:14]([Br:13])=[CH:15][C:16]=1[Cl:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 4-bromo-2,6-dichlorophenylamine (14.4 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol). The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound (quantitative yield). This was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1OC1C.CCN(CC)CC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCCCc1ccccc1
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (18 g, 0.077 mol) and 1-bromo-7-phenyl heptane [Example 1a] (15 g, 0.059 mol) in HMPA (45 ml) at 130° C., was added, dropwise, during 1 h, a solution of propylene oxide (18 ml) and Et3N (1 ml). After six more hours, second portions of propylene oxide (4 ml) and Et3N (1 ml) were added and heating was continued for 4 h. The cooled mixture was extracted successively with pet ether, Et2O and Me2CO. The residue returned 2.5 g of starting material (i.e., 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline). The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated to a viscous oil. This material was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. Concentration of the eluates and crystallization of the residue from pet ether (Darco) gave 12 g, (50%) of 6-methoxy-4-methyl-8-nitro-5-(7-phenyl heptoxy) quinoline as yellow crystals, mp 53°-54° C.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:9]=[C:8]([S:16]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:17])=[O:18])[C:7]=1[OH:20]
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Reactant: C1CCNC1
Product: CC(C)(C)c1cc(CN)c(O)c(S(=O)(=O)N2CCCC2)c1
Product: Cl

Procedure:
This compound is prepared analogously to Examples 11 c and 11 d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and pyrrolidine.