Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][C:37](C)=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1)([CH3:31])([CH3:30])[CH3:29].[C:51]([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([C:34]1[C:35]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])=[NH:9])[S:11][C:12]=3[S:25][CH3:26])(=[O:17])=[O:16])[CH:19]=2)=[C:36]([CH3:51])[CH:37]=[CH:38][CH:39]=1)=[O:50])([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C([O-])[O-]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2C(=O)OC(C)(C)C)c1
Yield: 58.1 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 4-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester ((Example 4: step b) 127 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (35 mg, 58%) as a light-yellow glass. 1H-NMR (CDCl3): δ 8.01 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.92 (s, 1H), 7.83 (t, 1H, J=1.7 Hz), 7.65 (m, 1H), 7.56 (t, 1H, J=7.8 Hz), 7.43 (dt, 1H, J=1.4, 7.7 Hz), 7.36 (m, 2H), 2.58 (s, 3H), 2.00 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C29H34N2O6S3: 602.8; found: 602.9.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:4]([CH2:3][NH:2][C:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:24])#[N:5]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: N#CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCNC(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride and 20.2 g (0.2 moles) triethylamine in 200 ml chloroform which had been stirred for about 15 minutes to give a clear solution, the naphthoyl chloride from step (a) in 25 ml methylene chloride was dropped in over about 30 minutes in a slightly exothermic addition. The reaction mixture was stirred 20 minutes, and then was mixed with 200 ml ice water. A precipitate formed immediately; however, the mixture was cooled in an ice bath for about 15 minutes before being filtered. The precipitate was filtered, washed with 100 ml water and vacuum dried at about 55° C. to a constant weight, to give 18.7 g of the above-identified product as a beige solid, melting point 160° C. to 163° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28].C(Cl)Cl.[CH:33]([NH2:35])=O>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[N:35]=[CH:33][N:1]=[C:2]2[N:6]([C:7]3[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=3[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=12
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1ccccc1Cl
Reactant: NC=O
Solvent: ClCCl
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ncnc(-c3ccccc3Cl)c12
Temperature: 150 °C

Procedure:
A suspension of 669 mg (1.39 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-chlorobenzoyl)-3-methylthiopyrazole in 5 mL of formamide was heated at 150° C. overnight. A pale yellow solid precipitated upon cooling of the reaction mixture. A total of 50 mL of water was added to the stirred suspension to complete the precipitation of the product which was filtered off and washed with water. An inseparable trace of starting material was observed in the product by thin layer chromatography (TLC) and so the above procedure was repeated on the mixture giving a brown solid containing no trace of starting material. Trituration of this solid with methylene chloride gave a pale yellow solution which was concentrated to give the desired product as a white crystalline solid, m.p. 156°-158° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19]>>[NH2:19][C:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9](=[O:14])[CH:10]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: CC(=O)[O-]
Product: NC1=CC(=O)CC(c2ccccc2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-phenylcyclohexan-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:11]([O-])=O>C(O)C.Cl.[Pd]>[NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: Nc1c([N+](=O)[O-])ccc2[nH]nnc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2[nH]nnc2c1N
Yield: 117.3 %

Procedure:
A suspension of 4-amino-5-nitrobenzotriazole (0.72 g, 4 mmol) in 100 ml of ethanol and 1 ml of conc. hydrochloric acid was hydrogenated at atmospheric pressure and room temperature for 6 h in the presence of 100 mg of 5% palladium-on-charcoal. The mixture was filtered and the catalyst was washed with about 50 ml of water. The combined filtrate was evaporated to dryness giving 0.70 g of the 4,5-diamino-benzotriazole as an hydrochloride. A solution of the crude diamino compound in 40 ml of 4M hydrochloric acid was refluxed with oxalic acid dihydrate (0.50 g, 4 mmol) for 3 h. The mixture was cooled on ice, and pH was adjusted to 5-6 with 2N sodium hydroxide. The precipitate was filtered off and washed with water and ethanol. It was then dissolved in 10 ml of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. After adjustment to pH 6-7 with 4M hydrochloric acid the reprecipitated product was isolated, washed with water and ethanol, and dried at 100 ° C. affording 0.12 g (15%) of pure title compound; m.p.>300° C.; IR (KBr): 3200-2000, 1670 cm-1 ; 1H-NMR (DMSO-d6): 6.9 (broad s, 3H, NH+2OH); 7.03 (d,J=8 Hz, 1H, ArH); 7.43 (d,J=8 Hz,1H, ArH).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1)[CH2:12][CH2:13][CH2:14][C:15]1[N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[CH:18][N:19]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][CH2:13][CH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)[CH:39]1[C:48]2[N:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][CH2:41][CH2:40]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2CCCN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(CCCc1ncc[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.5 %

Procedure:
To a solution of (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[3-(1-trityl-1H-imidazol-2-yl)-propyl]-amine (101 mg, 0.161 mmol) in CH2Cl2 (1.6 mL) was added triethylsilane (0.38 mL, 2.4 mmol) followed by TFA (1.9 mL, 25 mmol), and the solution was stirred at room temperature for 21 h then concentrated in vacuo. The residue was dissolved in CH2Cl2 (15 mL) and washed with 1 N NaOH(aq) (10 mL). The aqueous phase was extracted with CH2Cl2 (2×10 mL), and the combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (150:5:1 CH2Cl2/MeOH/NH4OH) afforded COMPOUND 13 as a colourless foam (47 mg, 69%). 1H NMR (CDCl3) δ 1.62-1.93 (m, 4H), 2.02 (m, 1H), 2.16 (m, 1H), 2.58-2.88 (m, 6H), 3.91 (d, 1H, J=16 Hz), 3.98 (d, 1H, J=16 Hz), 4.02 (m, 1H), 6.86 (s, 2H), 7.18 (m, 3H), 7.43 (d, 1H, J=7.2 Hz), 7.55 (m, 2H), 8.55 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.52, 23.71, 25.96, 26.67, 29.43, 49.21, 51.07, 62.23, 115.28, 120.75, 122.41, 122.81, 135.47, 138.23, 138.86, 146.68, 148.71, 155.28, 157.49. ES-MS m/z 387 (M+H). Anal. Calcd. for C23H26N6.0.21H2O.0.36CH2Cl2: C, 66.67; H, 6.50; N, 19.97. Found: C, 66.77; H, 6.65; N, 19.69.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].[NH4+:21].[OH-]>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:21])=[O:1]
Reactant: [NH4+]
Reactant: O=CCCCCCO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCCCO
Temperature: 90 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
5.26 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 10 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave containing 0.484 grams of Na2S2O8 and 35 milliliters of NH4OH. The reactor was placed under 400 psi air, heated to 80° C. and a 500 psi air purge was established. The reaction was allowed to proceed for 3 hours. At that time, reaction conversion was virtually complete and 6-hydroxycaproamide was formed in 40% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][C:11]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:22]1[C:21]([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:23]=31)=[N:9]2
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Reactant: Nc1ccc(Cl)cc1N
Product: Clc1ccc2nc3c4ccccc4c4ccccc4c3nc2c1
Yield: 83 %

Procedure:
When one tenth mole each of 4-chloro-o-phenylendiamine and phenanthrenequinone were reacted by the method of Example 7(A), 26 g. (83 percent yield) of 11-chlorodibenzo[a,c]phenazine, mp = 241-242° C. were obtained.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][CH:29]([CH2:39]O)[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>ClCCl>[Br:8][CH2:39][CH:29]([F:28])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCC(F)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(F)CBr
Reaction time: 0.17 h

Procedure:
To a suspension of NBS (20 g, 110 mmol, 3.0 equiv) in dichloromethane (250 mL) was added dropwise triphenylphosphine (28 g, 110 nmol, 3.0 equiv) in dichloromethane (100 mL). After addition was complete, the reaction mixture was stirred for 10 min and a solution of tert-butyl 2-fluoro-3-hydroxypropylcarbamate (1-8) (7.0 g, 36 mmol, 1 equiv) in dichloromethane (100 mL) followed by pyridine (3.5 g, 44 mmol, 1.2 equiv) were added. The resulting mixture was stirred at 23° C. under nitrogen for 16 h. The reaction solution was concentrated and purified by silica gel chromatography (100% hexanes to 100% ethyl acetate over 1 h, analysis by Ninhydrin stain) to yield tert-butyl 3-bromo-2-fluoropropylcarbamate (1-9) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.89-4.68 (m, 2H), 3.55-3.40 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[CH:10]=[CH:9]2.C(O)(C(F)(F)F)=O.[Cl:40][C:41]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:50])[C:42]=1C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24][C:25](=[O:27])[C:42]1[C:41]([Cl:40])=[CH:49][N:48]=[CH:47][C:46]=1[Cl:50])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[CH:10]=[CH:9]2
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate (compound No 26, international patent application WO 03/093237) (500 mg, 1.05 mmol) was dissolved in DCM (5 ml) and a solution of TFA (0.8 ml, 10.5 mmol) in DCM (2 ml) was added drop wise over 10 minutes. After addition was complete the reaction was stirred at RT over night. The reaction was cooled to 0° C. and TEA (2.1 ml, 15.8 mmol) in DCM (2 ml) was added drop wise over 10 minutes. The reaction was cooled to −10° C. and 3,5 dichloro-isonicotinoylchloride (Bioorg. Med. Chem. Lett. 2002, 12, 1591-1594), (663 mg, 3.0 mmol) was added drop wise over 10 minutes, before allowing the reaction to warm to RT. After 1 hour the reaction was washed with aqueous HCl (1N, 10 ml), followed by washing with aqueous NaHCO3 solution (saturated, 10 ml). The DCM layer was dried over MgSO4, filtered and the solvent removed in vacuo to yield an off white solid. The solid was purified using flash chromatography (eluent EtAc) to yield the title compound as a white powder (432 mg, 75%) LCMS M+1 (552, 550, 548), Retention Time 3.82 min, 1H NMR, 300 Mz, d6-DMSO-9.50 (1H, d), 8.63 (2H, s), 8.42 (1H, d), 7.98 (1H, d), 7.94 (1H, d), 7.78 (1H, dd), 7.65 (2H, d), 7.55 (2H, m), 4.95 (1H, m), 3.74 (3H, s), 3.45 (1H, dd), 3.20 (1H, dd).
Reaction SMILES: O.FC1C(F)=CC=CC=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=[O:20].Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].[CH3:69][O:70][C:71]1[N:76]=[CH:75][C:74](B(O)O)=[CH:73][CH:72]=1>>[OH2:20].[CH3:69][O:70][C:71]1[N:76]=[CH:75][C:74]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[NH:44][N:43]=[C:42]3[C:48]([NH:50][CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=3)[CH2:54][CH2:53]2)=[O:49])=[CH:73][CH:72]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Solvent: O
Product: COc1ccc(-c2ccc3[nH]nc(C(=O)NCC4CCN(Cc5ccc(C(=O)O)o5)CC4)c3c2)cn1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(6-Methoxypyridin-3-yl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid hydrate 17 was prepared, according to the procedure described for compound 12, from compound 15 and (6-methoxypyridin-3-yl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes. Yield: 23 mg, 8%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3O[C:13](=O)[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)(O)O.[NH2:34][NH:35][C:36]([NH2:38])=[NH:37]>N1C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:34]4[N:35]=[C:36]([NH2:38])[N:37]=[C:13]4[C:14]4[C:20]([F:21])=[CH:19][C:18]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)=[CH:17][C:15]=4[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N=C(N)NN
Reactant: CN1CCN(c2cc(F)c3c(=O)oc(Cc4ccc5c(c4)OCO5)nc3c2)CC1
Agent: O=C(O)O
Solvent: O
Solvent: c1ccncc1
Product: CN1CCN(c2cc(F)c3c(c2)nc(Cc2ccc4c(c2)OCO4)n2nc(N)nc32)CC1
Temperature: 180 °C
Yield: 46 %

Procedure:
To a suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester (0.15 g, 0.35 mmol) in a mixture of tetrahydrofuran (10 mL), methanol (1 mL) and water (2 mL), was added lithium hydroxide (0.15 g, 3.49 mmol). The reaction was stirred at room temperature overnight then the solvent was evaporated. The residue was diluted with water and 2 N HCl solution was added until pH 7. The solid precipitated was filtered and washed with water to obtain the 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid crude. 2-(2-Benzo[1,3]dioxol-5-yl-acetylamino)-6-fluoro-4-(4-methyl-piperazin-1-yl)-benzoic acid was suspended in acetic anhydride (3 mL) and the reaction mixture was heated under microwave condition at 130° C. for 10 minutes. The solvent was evaporated to obtain the 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one crude. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-5-fluoro-7-(4-methyl-piperazin-1-yl)-benzo[d][1,3]oxazin-4-one in dry pyridine (3 mL) was added aminoguanidine hydrogencarbonate (0.05 g, 0.39 mmol) and the mixture was heated under microwave condition at 180° C. for 15 minutes. The reaction was cooled at room temperature and diluted with water to induce the precipitation of a brown solid which was washed with a mixture MeOH/H2O 8/2, to afford the title compound (0.07 g, 46% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[C:9]([O:23][C@H:24]2[CH2:70][N:27]3[C:28](=[O:69])[C@@H:29]([NH:48][C:49]([O:51][C@@H:52]4[CH2:54][C@H:53]4[CH2:55][CH2:56][CH2:57]/[CH:58]=[CH:59]/[B:60]4[O:64][C:63]([CH3:66])([CH3:65])[C:62]([CH3:68])([CH3:67])[O:61]4)=[O:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][C@@H:37]4[CH2:42][C@@:38]4([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:39][C:40](=[O:41])[C@@H:26]3[CH2:25]2)=[N:10][C:11]2[C:16]([C:17]=1[O:18][CH2:19][CH2:20][CH2:21]Br)=[CH:15][CH:14]=[CH:13][CH:12]=2>CS(C)=O>[Br:7][C:8]1[C:9]([O:23][C@H:24]2[CH2:70][N:27]3[C:28](=[O:69])[C@@H:29]([NH:48][C:49]([O:51][C@@H:52]4[CH2:54][C@H:53]4[CH2:55][CH2:56][CH2:57]/[CH:58]=[CH:59]/[B:60]4[O:61][C:62]([CH3:68])([CH3:67])[C:63]([CH3:66])([CH3:65])[O:64]4)=[O:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][C@@H:37]4[CH2:42][C@@:38]4([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:39][C:40](=[O:41])[C@@H:26]3[CH2:25]2)=[N:10][C:15]2[C:16]([C:17]=1[O:18][CH2:19][CH2:20][CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: C1CCNCC1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCBr)c3Br)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCBr)c3Br)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCN4CCCCC4)c3Br)C[C@H]1C(=O)N2
Solvent: CS(C)=O
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)O[C@@H]1C[C@H]1CCC/C=C/B1OC(C)(C)C(C)(C)O1)C(=O)N1C[C@H](Oc3nc4ccccc4c(OCCCN4CCCCC4)c3Br)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidine (317 μl) was added to a solution of bromide from Step 1 (326 mg) in DMSO (2 mL) and the resulting mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were washed with water then brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ISCO reverse phase, 0 to 95% acetonitrile in water) to give the title compound (262 mg) as a mixture with the boronic acid.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:18](=O)[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[O:9][C:10](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(Cl)(Cl)[Cl:28]>>[ClH:28].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:10](=[O:11])[C:18]=2[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]1=[O:9]
Reactant: ClC(Cl)Cl
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: NCCCCCN
Product: Cl
Product: NCCCCCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Benz[d]indeno[1,2-b]pyran-5,11-dione (4d) (0.100 g, 0.403 mmol) was treated with 1,5-diaminopentane (0.206 g, 2.014 mmol) in CHCl3 (40 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and washed with water (3×15 mL). The solution was dried over sodium sulfate, filtered, and treated with 2 M HCl in Et2O (5 mL). After 30 min, the reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL) and hexanes (50 mL) to provide an orange solid (0.122 g, 82%): mp 265-268° C. IR (film) 3432, 3077, 2856, 1707, 1635, 1611, 1549, and 1504 cm−1; 1H NMR (CDCl3) δ 8.59 (d, J=8.1 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.85-7.80 (m, 3H), 7.74 (d, J=7.4 Hz, 1H), 7.63-7.51 (m, 4H), 4.52 (t, J=7.3 Hz, 2H), 2.81 (m, 2H), 1.83 (m, 2H) 1.65-1.52 (m, 4H); ESIMS m/z (rel intensity) 333 (MH+, 100). Anal. (C21H21ClN2O2.0.75H2O) C, H, N.
Reaction SMILES: [I:1][CH3:2].[F:3][C:4]1[CH:5]=[C:6]([NH:18][C:19]([NH2:21])=[S:20])[CH:7]=[C:8]([O:16][CH3:17])[C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1>C(O)C>[IH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:18][C:19]([S:20][CH3:2])=[NH:21])[CH:7]=[C:8]([O:16][CH3:17])[C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1
Reactant: COc1cc(NC(N)=S)cc(F)c1-n1cnc(C)n1
Reactant: CI
Solvent: CCO
Product: COc1cc(NC(=N)SC)cc(F)c1-n1cnc(C)n1
Product: I
Temperature: 70 °C
Yield: 99.3 %

Procedure:
Step S (4): Iodomethane (0.179 mL, 2.88 mmol) was added to a solution of 1-(3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (0.772 g, 2.74 mmol) in absolute ethanol (50 mL). The resulting mixture was heated at 70° C. for 3 h. The crude reaction mixture was concentrated in vacuo. The residual solid was dried under high vacuum to afford methyl 3-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (1.15 g, 2.72 mmol, 99% yield) as a yellow solid. LC-MS (M+H)+ 296.1.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:42]=[N:41][C:40]([C:43]([O:45]C)=O)=[CH:39][CH:38]=1.[CH:47]1([NH2:50])[CH2:49][CH2:48]1>>[CH:47]1([NH:50][C:43]([C:40]2[N:41]=[N:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)=[O:45])[CH2:49][CH2:48]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Cl)nn1
Product: C[C@@H](c1ccc(-c2ccc(C(=O)NC3CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and methyl 6-chloropyridazine-3-carboxylate following procedures analogous to those described in Example 8 using cyclopropylamine in Step 2. LC-MS Method 2 tR=1.221 min, m/z=457.1; 1H NMR (CDCl3) 0.67 (m, 2H), 0.88 (m, 2H), 1.20 (s, 3H), 1.23 (s, 3H), 1.54 (d, 3H), 2.20 (m, 4H), 2.3 (s, 1H), 2.9 (m, 1H), 3.0 (m, 2H), 5.7 (m, 1H), 7.0 (m, 2H), 7.28-7.34 (m, 5H), 7.8 (m, 2H), 7.90 (m, 1H), 8.2 (m, 1H), 8.3 (m, 1H)