Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][CH:23]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22]2)[CH3:10])[C:5]([C:37]#[N:38])=[C:4]([CH3:39])[N:3]=1.O.NN>C(O)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]2)[CH3:10])[C:5]([C:37]#[N:38])=[C:4]([CH3:39])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC(N3C(=O)c4ccccc4C3=O)C2)c1C#N
Agent: NN
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@@H](N)C2)c1C#N
Temperature: 65 °C
Yield: 30.9 %

Procedure:
To a 25 mL pear flask was added 2-amino-4-(((S)-1-(6-(3-(1,3-dioxoisoindolin-2-yl)pyrrolidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (peak 1 of PREPARATION 13, 27 mg, 0.052 mmol) in ethanol (520 μL) to give a solution. To this solution was added hydrazine monohydrate (25 μL, 0.52 mmol). The mixture was heated to 65° C. for 3.5 hours, at which time the reaction was deemed to be complete based on MS/UPLC. The mixture was diluted with acetonitrile and was directly purified by preparative HPLC (basic mode, 25-45% ACN/water gradient). The product-containing fractions were concentration and lyophilized to give the title compound as a white solid (6.3 mg, 31%). The absolute configuration of the stereocenter on the pyrrolidine ring was not determined, but was assigned the opposite configuration of EXAMPLE 8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.32 Hz, 3H), 1.63-1.74 (m, 1H), 2.16 (dd, J=12.25, 7.20 Hz, 1H), 2.25 (s, 3H), 2.71 (dd, J=9.09, 4.80 Hz, 1H), 3.04 (td, J=8.27, 5.18 Hz, 1H), 3.60 (t, J=6.32 Hz, 1H), 3.71-3.85 (m, 3H), 5.75 (d, J=6.82 Hz, 1H), 6.42-6.51 (m, 1H), 7.18 (d, J=7.58 Hz, 1H), 7.51 (d, J=3.28 Hz, 1H), 7.68-7.78 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C20H25N9, 392. found 392.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Br:21])[CH:14]=1)[C:24]([CH3:26])([CH3:25])[CH:23]2[OH:27])=[O:22])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(Br)cc(OC)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)cc(OC)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methoxy-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.5 g, 12.4 mmol) and ytterbium(III) triflate hydrate (0.77 g, 1.24 mmol) in dry tetrahydrofuran (20 mL) at 25° C. was added isobutyraldehyde (0.89 g, 12.4 mmol) and water (0.22 mL, 12.4 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-methoxy-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.4 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO4 M+: 434.3, observed: 418.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:24](OCC)(=O)[CH:25]=[O:26].CC(C)=O>C(O)C.C1(C)C=CC=CC=1>[O:26]=[C:25]1[CH:24]=[N:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[C:7]=2[NH:8]1
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
tert-butyl 4-(2,3-diaminopyridin-4-yloxy)phenylcarbamate (0.86 g, 2.71 mmol) was dissolved in 15 ml of dry ethanol; 0.8 ml (4 mmol) of a 50% ethyl glyoxalate solution in toluene were added and the solution was stirred overnight at room temperature under Argon atmosphere. The solvent was partially evaporated, and tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate (0.430 g, 45% yield) is precipitated by addition of acetone (10 ml) and filtered off.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12](O)=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[C:3]1[S:4][C:5]([C:12]([Cl:19])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1sc(C(F)(F)F)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1sc(C(F)(F)F)nc1C(F)(F)F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a 500 mL 1-neck RBF under N2 was added 2,4-bis-trifluoromethylthiazole-5-carboxylic acid (31.5 g, 1.0 equiv., 0.119 moles) in 25 mL chloroform and 1 mL dimethylformamide (DMF). To this solution was added thionyl chloride (28.3 g, 2.0 equiv., 0.24 moles). The reaction was then heated at reflux for 6 hours. The reaction was cooled to room temperature and concentrated by rotary evaporation at 30° C. to remove solvent. Chloroform was added, 3×25 mL portions, concentrating by rotary evaporation each time, to give 29.8 g (88.4% yield) product as a brown oil.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=O)[CH2:12][CH2:11][CH2:10][CH2:9]3.B.O1CCCC1.[ClH:26].[H][H]>O1CCCC1>[ClH:26].[NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][CH2:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: [H][H]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: c1cc2c3c(c4c(nc3c1)CCCC4)NCCO2
Reaction time: 2 h
Yield: 57.5 %

Procedure:
1,3,9,10,11,12-Hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.00 g) was suspended in dry tetrahydrofuran (100 ml) and 1M borane/tetrahydrofuran (16.0 ml) was added. After 2 hrs, an additional 30 ml of 1M borane/tetrahydrofuran was added, and the reaction mixture was stirred overnight. The reaction mixture was poured into 5% hydrochloric acid and stirred unit hydrogen evolution ceased. The organic layer was separated and the aqueous phase was washed once with ethyl acetate. The aqueous phase was basified with 10% sodium hydroxide solution and precipitate was collected. The precipitate was treated with methanol/ether/hydrogen chloride. Recrystallized from methanol/ether gave 2.50 g (57.5%) of product, mp 300° C. (dec).
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].N1C=CC=CC=1.Cl[C:47](=O)[C:48]([O:50][CH3:51])=[O:49]>ClC(Cl)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[N:1]=[C:47]([C:48]([O:50][CH3:51])=[O:49])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: COC(=O)C(=O)Cl
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O>[Cu]>[C:23]1([N:20]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:6]=[CH:5][C:4]([C:8]3[CH:13]=[CH:12][C:11]([N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]4[CH:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=5)[CH:13]=[CH:12][CH:11]=4)=[CH:10][CH:9]=3)=[CH:3][CH:2]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Ic1cccc(-c2ccccc2)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cccc(N(c3ccccc3)c3ccc(-c4ccc(N(c5ccccc5)c5cccc(-c6ccccc6)c5)cc4)cc3)c2)cc1
Yield: 78.89 %

Procedure:
300-ml reactor was charged with 10 q (0.0298 mol) of N,N'-diphenylbenzidie, 25 g (0.0893 mol) of m-iodobiphenyl, 12.3 g (0.0891 mol) of potassium carbonate, 2.6 g of copper powder, and 150 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the solvent was distilled off from the filtrate. The still residue was purified through a silica gel column with a 5/1 mixture of n-hexane and ethyl acetate, obtaining 15 g of N,N'-diphenyl-N,N'-di(3-biphenylyl)benzidine of primary purity grade (yield 78.89%. It was further purified by recrystallization from toluene and train sublimation, obtaining 10.6 g of a 99.9% pure product (yield 55.6%). Further purification by sublimation yielded a 99,99% pure product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](N)=[N:9][CH:10]=1)=[O:4].Cl.C(Cl)[Cl:14].N([O-])=O.[Na+]>CCCCCC.[Cl-].[Cl-].[Zn+2]>[Cl:14][C:8]1[N:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=1
Reactant: ClCCl
Reactant: COC(=O)c1cnc(N)nc1
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: CCCCCC
Product: COC(=O)c1cnc(Cl)nc1
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
Compound 207 (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CH2Cl2 (60 mL). After cooling, ZnCl2 (18.6 g, 0.138 mol) was added at 15-20° C. The mixture was stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10° C. The reaction was continued for ˜2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL*2). The combined organic extracts were concentrated to afford crude product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60° C. for 30 minutes and filtered. The filtrate was concentrated to afford the title compound R-2-2 (3.5 g, 44.4%) as an off-white solid. LCMS (m/z): 214.1[M+42]+. 1HNMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 9.15 (s, 2H).
Reaction SMILES: [Br:1]Br.[CH3:3][Si:4]([C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)([CH3:6])[CH3:5]>O1CCCC1.O>[Br:1][CH:16]([CH3:17])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][Si:4]([CH3:5])([CH3:6])[CH3:3])=[CH:14][CH:13]=1)=[O:18]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (8.4 g) is slowly added to 1-(4-trimethylsilanylethynylphenyl)propan-1-one (10.0 g) in 100 ml of tetrahydrofuran at 0° C. and subsequently stirred at room temperature for 2 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 19:1 as eluent to obtain 2-bromo-1-(4-trimethylsilanylethynylphenyl)propan-1-one as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:4].Cl.[CH3:30][O:31][C:32](=[O:35])[CH2:33][NH2:34].C(N(CC)CC)C>COC(O)C>[CH3:30][O:31][C:32]([CH2:33][NH:34][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:4])=[O:35]
Reactant: COC(=O)CN
Reactant: CCOC(=O)c1cc2c(NC(=O)CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: COC(C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(NC(=O)CNCC(=O)OC)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 100 °C

Procedure:
Ethyl 4-chloroacetamido-N-(3,4-dichlorobenzyl)indole-2-carboxylate (0.4 g), glycine methyl ester hydrochloride (0.57 g) and triethylamine (1.25 ml) were dissolved in methoxyethanol (4.0 ml) and the reaction heated at 100° C. for 6 hours. The reaction was cooled and partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated and the residue purified by chromatography using toluene:ethyl acetate (1:1) as eluent to give the product, ethyl 4-[(N-(methoxycarbonylmethyl)glycyl)amino]-N-(3,4-dichlorobenzyl)indole-2-carboxylate, as a pale yellow solid (0.17 g, 38%); NMR d (CD3SOCD3) 1.28 (t, 3H), 3.44 (s, 2H), 3.50 (s, 2H), 3.63 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.88 (dd, 1H), 7.10-7.30 (m, 4H), 7.50 (d, 1H), 7.69 (s, 1H), 7.80 (dd, 1H), 10.00 (brs, 1H); M/z (+) 494, 492 (M+).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:5])#[N:2].C[O-].[Na+]>CO>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:3]([C:1]#[N:2])[C:4]1=[O:5]
Reactant: COc1ccc(CN(C(=O)CC#N)c2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2c(=O)c(C#N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Temperature: 25 °C

Procedure:
To solution of 2-cyano-N-(2,4-dimethoxybenzyl)-N-[2-(3-fluorobenzoyl)-4-methoxyphenyl]acetamide (56.0 mg, 0.121 mmol) in 1 mL of methanol was added sodium methoxide solution in methanol (0.083 mL of 4.37 M, 0.363 mmol). The solution was heated to reflux for 5 minutes, then cooled to room temperature. The reaction was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chomatography through SiO2 (30-50% EtOAc/hexane) to provide the titled product as a yellow foam. 1H-NMR (500 MHz, CDCl3) δ 7.56-7.60 (m, 1H), 7.39 (d, J=9.5 Hz, 1H), 7.25-7.31 (m, 2H), 7.17-7.21 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 6.74 (br s, 1H), 6.52 (br s, 1H), 6.38 (br d, J=8.5 Hz, 1H), 5.54 (s, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) ppm. HRMS (ES) exact mass calculated for C26H22FN2O4 (M+H+): 445.1558. Found 445.1574.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:12]([NH:20][C:21](=[O:22])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN=C=O
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)OCc1ccccc1[N+](=O)[O-]
Yield: 62.1 %

Procedure:
100 mL toluene, 10 g 2-nitrobenzyl alcohol, and 11.4 g octyl isocyanate were placed in a 200-mL roundbottom flask, heated at reflux under nitrogen for 2 hours, and then cooled. The reaction solution was washed with water several times and the resulting toluene solution was then dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was removed from the filtrate on a rotary evaporator. The resulting solid was recrystallized twice from hexane, yielding 12.5 g o-nitrobenzyl n-octylcarbamate as light yellow needle-like crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]=[O:21])[CH:6]=[CH:5]2.[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24].C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]([OH:21])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CC(C)C[Mg]Br
Reactant: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C=O)nc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C(O)CC(C)C)nc12
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of diethyl 6-bromo-2-formyl-8-quinolylphosphonate (293 mg, 0.78 mmol) in toluene (6 mL) at −10° C. was added a 2M solution of isobutylmagnesium bromide in THF (1.59 mL, 3.12 mmol). The mixture was stirred at −10° C. to −5° C. for 2 h. Aqueous NH4CL was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 179 mg (53%) of the title compound
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])/[CH:10]=[CH:12]/[N:13]([CH3:15])[CH3:14]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(F)cc1F
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield from 1-(2,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.90 (3H, s), 3.11(3H, s), 5.59-5.62 (1H, m), 6.77-6.83 (1H, m), 6.88-6.93 (m, 1H), 7.75-7.83 (2H, m).
Reaction SMILES: ClC1C(N)=C2C(C(OC)=CC=N2)=CC=1.[NH2:15][C:16]1[C:17]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=O)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2.[CH3:35][NH:36][S:37](Cl)(=[O:39])=[O:38].[BH4-].[Na+]>N1C=CC=CC=1>[CH3:35][N:36]1[S:37](=[O:39])(=[O:38])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][N:24]=3)[CH:19]=[CH:18][C:17]=2[CH:26]1[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)c2ccc3cccnc3c2N)cc1
Reactant: CNS(=O)(=O)Cl
Agent: COc1ccnc2c(N)c(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)cc1
Yield: 5.1 %

Procedure:
In a similar fashion using route 27 general procedure (Intermediate 70), (8-amino-quinolin-7-yl)-p-tolyl-methanone (Intermediate 368) (180 mg, 0.69 mmol), N-methylsulamoyl chloride (Intermediate 213) (267 mg, 2.06 mmol) and NaBH4 (26 mg, 0.69 mmol) in pyridine (10 ml) gave the title compound (12 mg, 5%) after purification by column chromatography with heptane/EtOAc (80:20-50:50) as the eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17]Cl)[CH3:14]>CN(C=O)C>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:14]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 20 h

Procedure:
To a cold solution of 41.8 g of 4-nitrophenol in 250 ml of DMF was added 16.0 g of a 57% dispersion of sodium hydride in mineral oil, followed by 46.0 g of 2-diethylaminoethyl chloride. After 20 hours, the mixture was filtered, freed of solvent by evaporation under reduced pressure, the residue dissolved in ether and washed with water. Extraction with 2N hydrochloric acid and basification of the extract gave N,N-diethyl-2-(4-nitrophenoxy)ethanamine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH2:45][CH3:46])=[C:34]([NH2:47])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:48])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[CH2:45][CH3:46])=[C:34]([NH:47][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1N
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC1CCCCC1Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a solution of 0.24 g of thiophen-2-yl-acetic acid in 40 ml of dry DMF 0.11 g of HOAT, 0.36 g of EDC and 0.5 ml of DIPEA were added at 0° C. After 30 min 0.41 g of 3-Amino-4-(2-ethyl-cyclohexylamino)-benzoic acid methyl ester were added, followed by the addition of 0.5 ml of DIPEA and the reaction was stirred at rt for 48 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 0.60 g (97%) of 4-(2-Ethyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH:30]1[CH2:33][CH:32]([S:34](Cl)(=[O:36])=[O:35])[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:31]2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCO2
Yield: 31.2 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.53 g, 1.0 mmol) in pyridine (4 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (0.179 mg, 1.2 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 195 mg of the product (23.8% yield).