Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][O:39][CH3:38])[CH2:48][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCOC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(3-methoxy-propyl)-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C37H48Cl2N5O3 [(M+H)+] 680.3129, observed 680.3133.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:26](=[O:27])[NH:25][C:24]([C:28](O)=[O:29])=[C:23]([CH3:31])[CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:28]([C:24]1[NH:25][C:26](=[O:27])[C:21]([Br:20])=[CH:22][C:23]=1[CH3:31])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNCc1ccccc1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g, 12.9 mmol) in dimethylformamide (50 mL), 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3, 3.6 g, 12.9 mmol), HBTU (6.4 g, 16.9 mmol) and N,N-diisopropylethylamine (2.2 g, 16.9 mmol) were added at room temperature. The mixture was stirred for 16 h. TLC showed completion of reaction. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy) propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as yellow liquid. Yield: 3.0 g, 47%; MS (ESI) m/z 495.24 [M−1]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:28]=[C:22]2[C:21]3[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)[NH:24][C:23]2=[O:27])=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1
Yield: 61.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (5 g, 1.3 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (3.12 g, 17.4 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (4.1 g, 61%).
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])[P:4]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[O:5][CH:6]([CH3:8])[CH3:7].C([O:26][C:27](=[O:30])[CH2:28]Br)C.O>C1(C)C=CC=CC=1>[CH:16]([O:15][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([CH:3]([P:4]([O:10][CH:11]([CH3:12])[CH3:13])([O:5][CH:6]([CH3:8])[CH3:7])=[O:9])[CH2:28][C:27]([OH:30])=[O:26])=[O:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OP(=O)(OC(C)C)C(CC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.25 h
Yield: 13.7 %

Procedure:
Sodium hydride (700 mg, 0.29 mmol) was added in small portions under a stream of dry nitrogen to a vigorously stirred solution of tetraisopropyl methane-1,1-bisphosphonate (1) (5.0 gm, 14.5 mmol) in dry toluene (25 ml). After the effervescence had stopped, stirring was continued for 15 minutes. Ethylbromoacetate (3.2 gm, 19.2 mmol) was then added dropwise over a period (2 min) whereupon the flask became warm and a white precipitate began to form. Stirring was continued for a further 2 hours at room temperature. Water (20 ml) was added then carefully and the mixture vigorously stirred. The toluene layer was separated and extracted with water (20 ml). The aqueous extracts were combined, washed with ether (50 ml), acidified to pH 1 and re-extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and solvent evaporated under reduced pressure to leave the acid (3) as a pale yellow liquid (800 mg). The toluene layer was also dried (MgSO4), filtered, and solvent evaporated to leave an oil which was found to be the ethyl ester (2) and unreacted starting material. This oil was dissolved in a methanol:water mixture (20 ml, 3:1) containing lithium hydroxide (1 g, 24 mmol) and the solution stirred at room temperature for 16 h. The methanol was removed by evaporation and water (20 ml) was then added. This aqueous solution was washed with ether (2×20 ml), acidified to pH 1 with dilute HCl and then extracted with dichloromethane (2×25 ml). The dichloromethane extracts were combined, dried (MgSO4), filtered and volatile components removed under reduced pressure to leave the acid (3) (2.77 g) as a pale yellow liquid. The combined product (3) (3.57 g, 61%) was sufficiently pure to be used in subsequent reactions without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:24][C:25]1[CH:26]=[C:27]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31][OH:32])(=[O:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67]>O1CCCC1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([O:24][C:25]1[CH:26]=[C:27]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31][O:32][N:57]1[C:58](=[O:67])[C:59]2=[CH:66][CH:65]=[CH:64][CH:63]=[C:60]2[C:61]1=[O:62])(=[O:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCON2C(=O)c3ccccc3C2=O)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
Diethyl azodicarboxylate (67 (L, 0.40 mmol) was added dropwise over 5.5 min to 3-[3-(2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (118 mg, 0.33 mmol, prepared in the preceding step), triphenylphosphine (106 mg, 0.40 mmol), and N-hydroxyphthalimide (55 mg, 0.33 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred at 0° C. for an additional 20 min then at ambient temperature overnight. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (dichloromethane) to give the title compound (116 mg, 69%) as a colorless resin. 1H-NMR (300 MHz, CDCl3) (7.88-7.73 (m, 5H), 7.61 (ddd, 1H, J=8.4, 7.4, 1.7 Hz), 7.10 (d, 1H, J=8.4 Hz), 7.01 (dt, 1H, J=7.7, 0.9 Hz), 6.60 (br s, 1H), 6.56, (br s, 1H), 6.42 (t, 1H, J=2.2 Hz), 4.36 (t, 2H, J=6.2 Hz), 4.09 (t, 2H, J=6.2 Hz), 4.04 (s, 3H), 2.25 (s, 3H), 2.18 (pentet, 2H, J=6.2 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H23NO8S: 520.1 (M+Na). Found: 520.2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH2:26][CH3:27])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(=S)=S>[CH2:10]([C:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:25][C:20]=2[O:19][C:18]=1[CH2:26][CH3:27])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)Cl
Reactant: CCc1oc2ccccc2c1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Yield: 4.2 %

Procedure:
Propionyl chloride (7.3 mL; 0.784 mol) was added dropwise to the mixture of Aluminum chloride (10.5 g; 0.784 mol), and 3-benzyl-2-ethyl-benzofuran (18.5 g; 0.784 mol) in carbon disulfide (50 mL) while stirring and cooling in an ice bath. The reaction mixture was then stirred at room temperature for 30 minutes then heated at reflux for 2 hours. The solvent was then evaporated and the residue was diluted with ether then poured into water. The organic phase was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was crystallized from ethyl acetate/hexane mixture to give the title compound (9.6 g) as a solid, mp: 86-87° C. Mass spectrum (ESI, [M+] m/z 292. 1HNMR (400 MHz, DMSO-d6): δ 1.08 (t, 3H, J=7.26 Hz), 1.24 (t, 3H, J=7.47 Hz), 2.88 (q, 2H, J=7.47 Hz), 2.04 (q, 2H, J=7.26 Hz), 4.02 (s, 2H), 7.16-7.19 (m,1H), 7.23-7.29 (m, 5H), 7.47 (d, 1H, J=8.09 Hz), 7.78 (dd, 1H, J=8.09, 1.45 Hz), 8.07 (d, 1H, J=1.45 Hz). Elemental Analysis for C20H20O2: Calculated: C, 82.16; H, 6.90 Found: C, 82.22; H, 7.01.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:13]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: O=C(O)c1cccc(I)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-iodobenzoic acid (20.2 g) in DMF (130 mL) were added ethyl acrylate (9.00 g), triethylamine (24 mL) and palladium (II) acetate (92 mg), and the mixture was stirred at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid was added. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.7 g) as an orange amorphous solid.
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=O)[C:3](=[N:15]O)[CH2:2]1.[OH-:17].[Na+]>C(OCC)(=O)C>[NH:15]1[C:3](=[O:17])[CH2:2][CH2:1][C:13]2[N:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: O=C1c2ccccc2CN2C(=NO)CCC12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCc2ncc3ccccc3c2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 300 g of vigorously stirred polyphosphoric acid warmed to 115° C., 10 g of 1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10[2H,5H]-dione oxime was added. The mixture was held at this bath temperature for 10 minutes. The internal temperature rose to 135°-140° C. The mixture was then poured into 1500 ml of ice water, and the mixture was basified with 50% NaOH to about pH=8 and the resultant crystalline precipitate was collected to give 7.14 g of crude product Chromatography on a silica gel column, using ethyl acetate gave 4.8 g of pure product, m.p. 225° C.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][O:14][C:11]2=[CH:12][N:13]=1)[CH2:3]C(OC)=O.O=C(C1C=C2C=COC2=CN=1)CC(OCC)=O.O=C(C1C=C2C=COC2=CN=1)CC(OC(C)(C)C)=O.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:2]([C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][O:14][C:11]2=[CH:12][N:13]=1)(=[O:1])[CH3:3]
Reactant: COC(=O)CC(=O)c1cc2ccoc2cn1
Agent: CC(C)(C)OC(=O)CC(=O)c1cc2ccoc2cn1
Agent: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
The 971 mg of the mixture of methyl β-oxo-5-furo[2,3-c]pyridinepropionate, ethyl β-oxo-5-furo[2,3-c]pyridinepropionate, and tert-butyl β-oxo-5-furo[2,3-c]pyridinepropionate (molar ratio of 55:44:1) obtained in Example 9 was dissolved in 20 mL of toluene, and 1.04 g of 35% hydrochloric acid was added at room temperature with stirring. After addition, the reaction mixture was heated to 60° C., and a reaction was carried out for 3 hours with stirring. The reaction solution was then cooled to room temperature and was neutralized with 8.40 g of 5% sodium hydroxide aqueous solution. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 629 mg of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC (78% yield from 5-ethoxycarbonylfuro [2,3-c]pyridine).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].S([O-])([O-])(=O)=O.[Ca+2].[CH2:19](Br)[CH:20]=[CH2:21]>CCOC(C)=O.[Ag]=O>[CH2:21]([O:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4])[CH:20]=[CH2:19]
Reactant: N#Cc1ccc(C(=O)CO)cc1
Reactant: C=CCBr
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Product: C=CCOCC(=O)c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
To a solution of 2.7 g of 4-(2-hydroxyacetyl)benzonitrile in allyl bromide (15 mL) is added 10.2 g calcium sulfate and 6.7 g of silver oxide. The mixture is stirred under argon and in the dark for 2 hours. The mixture is diluted with AcOEt, filtered on celite, concentrated and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)/C=C/c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl(E)-3-(1-cyclohexyl-4-oxo-4,5-dihydroimidazo-[1,5-a]quinoxalin-8-yl)acrylate as synthesized in Example 154, 2.0 g was dissolved in 100 mL of acetic acid, and to the solution 10% Pd/C 200 mg was added in nitrogen atmosphere. After substituting the atmosphere with hydrogen, the reaction liquid was stirred at 25° C. for 2 days. The reaction liquid was filtered through Celite and from the filtrate the solvent was distilled off to provide 1.48 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2].Cl.[NH2:22][OH:23].CCN(CC)CC>CCO>[OH:23][NH:22][C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C#N)cccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Temperature: 85 °C

Procedure:
Prepared using General Procedure 1. To a stirring solution of (S)-tert-butyl (5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-8 (3.10 g, 11.38 mmol) in EtOH (25 mL) was added hydroxylamine hydrochloride (2.77 g, 39.84 mmol) and NEt3 (3.17 mL, 22.77 mmol). After heating at 85° C. for 15 h, the mixture was concentrated, redissolved in DCM, and washed with NaHCO3. The combined organic layers were dried, concentrated and chromatographed (MeOH/DCM) to provide 3.56 g crude (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (58% product by UV area), which was used in the next reaction without further purification. LCMS-ESI (m/z) calculated for C16H23N3O3: 305.37; found 306.2 [M+H]+, tR=2.00 min.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1)[NH2:38]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:38][C:37]5[CH:39]=[CH:40][C:41]([N:42]6[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]6)=[C:35]([F:34])[CH:36]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(F)c2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 70 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.73 (m, 6H) 1.86-2.06 (m, 2H) 2.22 (s, 3H) 2.35-2.49 (m, 4H) 2.97 (br. s., 4H) 3.94 (s, 3H) 4.09 (t, J=13.89 Hz, 2H) 4.82 (t, J=7.83 Hz, 1H) 7.01 (t, J=9.35 Hz, 1H) 7.26 (d, J=6.82 Hz, 1H) 7.32-7.45 (m, 1H) 7.63 (dd, J=15.03, 1.89 Hz, 1H) 8.10 (s, 1H) 8.19-8.46 (m, 2H) 10.16 (s, 1H). [M+H] calc'd for C32H36F4N8O3, 657. found 657.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:29]4([CH2:28][CH2:27][O:26][CH3:25])[CH2:31][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCC1(N)CC1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 200 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.65-0.73 (m, 2 H) 0.72-0.80 (m, 2 H) 1.86 (t, J=7.1 Hz, 2 H) 2.43 (s, 3 H) 3.21 (s, 3 H) 3.46 (t, J=6.9 Hz, 2 H) 7.64 (dd, J=8.1, 1.5 Hz, 1 H) 7.71 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.14 (s, 1 H) 8.38 (br. s., 2H) 8.83 (s, 1 H) 8.87 (t, J=1.5 Hz, 1 H) 13.17 (br. s., 1 H). MS m/z 418 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[C:14]4C=CC=C[C:13]=4[S:12][C:11]=13)[N:8]=[CH:7][N:6]=[C:5]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1.C(O)(=O)C=C.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:1][C:2]1[C:11]2[S:12][C:4]3[C:5]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)=[N:6][CH:7]=[N:8][C:9]=3[C:10]=2[CH:14]=[CH:13][CH:3]=1
Reactant: Nc1cc2c(Nc3cccc(Br)c3)ncnc2c2c1sc1ccccc12
Agent: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cccc2c1sc1c(Nc3cccc(Br)c3)ncnc12
Temperature: 25 °C
Yield: 30.8 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]-benzothieno-quinazoline (130 mg, 0.35 mmol), acrylic acid (0.05 mL, 0.73 mmol), and triethylamine (0.1 mL, 0.72 mmol) in DMF (3 mL) stirred under N2 at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol). The reaction gradually warmed up to 25° C. and was quenched with water after 20 hours. The formed yellow solid was collected and purified by sonication with acetone to give the desired product (40 mg, 27%), mp 216.4-217.2° C.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:39])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2H, m), 7.00-7.09 (2H, d), 5.54-5.82 (1H, m), 4.38-4.43 (1H, m), 3.66 (1 h, d), 3.54 (1H, d), 3.10-3.35 (2H, m), 2.89-2.98 (3H, m), 2.64-2.73 (2H, m), 2.58 (1H, d), 2.46 (1H, d), 2.27 (1H, t), 1.96-2.13 (3H, m), 1.78-1.83 (2H, m), 1.14-1.66 (10H, m), 0.77 (3H, t).