Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:24][CH2:23][C:22]5[C:18](=[CH:19][N:20]([CH2:25][CH2:26][OH:27])[N:21]=5)[C:17]=4[S:28][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:15]=2[C:16]2[CH:24]=[CH:23][C:22]4[C:18](=[CH:19][N:20]([CH2:25][CH2:26][OH:27])[N:21]=4)[C:17]=2[S:28]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: OCCn1cc2c(ccc3c2sc2ncnc(Nc4ccc(F)c(Cl)c4)c23)n1
Temperature: 90 °C
Yield: 116 %

Procedure:
To a stirring solution of 2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl}ethanol (2.6 g, 6.25 mmol) in dioxane (25 mL) was added 2,3-dichloro-5,6-dicyanobenzoquinone (2.1 g, 9.38 mmol). The reaction mixture was heated to 90° C. for 2.5 h. The solid was filtered and separated by column chromatograph (90% methylene chloride/10% methanol) to give 2-[6-(3-chloro-4-fluoro-phenylamino)-10-thia-2,3,7,9-tetraazacyclopenta[a]fluoren-2-yl]-ethanol as a brown solid (3.0 g, yield 116% containing some carried over silica gel). 1H-NMR (DMSO-d6) δ 9.25 (bs, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 8.40 (t, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 4.50 (t, 2H), 3.90 (t, 2H); LCMS RT=2.95 min; [M+H]+=414.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=C(Cl)[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[N:3]=1.COCCOC.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1.C(N(C(C)C)CC)(C)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:28]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=2)[N:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Yield: 81.1 %

Procedure:
To a suspension of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)acetate (4 g; 17.02 mmol) in a mixture of degassed DME (75 mL) and water (25 mL) was added p-tolylboronic acid (4.63 g; 34 mmol), Tetrakis(triphenylphosphine) palladium(0) (2 g; 1.731 mmol) and diisopropyl ethylamine (11.73 mL; 68.1 mmol). The reaction was stirred under reflux for 3.5 h. The reaction mixture was then partitioned between brine and ethyl acetate. The phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 3.82 g (61%) of the title compound as a white solid (purity: 80%). ESI/APCI(+): 291 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:26]([CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:27])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CCC2)nn1
Yield: 64 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using cyclobutanecarbonyl chloride instead of methoxyacetyl chloride, to the title compound (165 mg, 64%) which was obtained as a white solid. MS: m/e=365.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[C:11]([NH2:16])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH2:1]([O:7][C:8](=[O:17])[C:9]1[CH:10]=[C:11]([NH:16][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[CH:12]=[C:13]([NH:15][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)c1cc(N)cc(N)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CCCCCCOC(=O)c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 82 %

Procedure:
Using n-hexyl-3,5-diaminobenzoate (24.0 g, 101.7 mmol) and 4-nitrobenzoyl chloride (39.7 g, 214.4 mmol), n-hexyl[3,5-bis(4-nitrobenzoylamino)]benzoate was obtained (44.5 g, yield: 82%) in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 32 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), methanesulfonyl chloride (1 mL) and NEt3 (2 mL) in CH2Cl2 (30 mL) was stirred at room temperature overnight and then the mixture was washed with saturated NaHCO3 (20 mL) and saturated NaCl (2×15 mL) and dried (Na2SO4). The solvent was removed under reduced pressure. The resulting crude solid was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 0.02 g (32%) of a white solid, mp 147-150° C.; 1H NMR (CDCl3): δ 1.14 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.70 (3H, m, H-7α,β and H-11β); 1.81 (1H, m, H-6α); 2.11 (1H, dd, J=2.9, 11.3 Hz, H-8); 2.16 (1H, s, H-10); 2.19 (1H, m, H-6β); 2.42 (1H, dd, J=13.2, 13.2 Hz, H-3α); 2.50 (1H, m, H-3β); 2.52 (1H, dd, J=4.8, 13.2 Hz, H-11α); 2.75 (1H, dd, J=3.6, 13.2 Hz, H-4); 3.25 (3H, s, CH3SO2); 3.74 (3H, s, CO2CH3); 5.07 (1H, dd, J=8.0, 12.2 Hz, H-2); 5.55 (1H, dd, J=5.1, 11.7 Hz, H-12); 6.41 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.42 (1H, dd, J=1.8, 1.8 Hz, H-15); 7.45 (1H, br d).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[C:9]2[S:14][CH:15]=[CH:16][C:8]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Product: Clc1nnc(-c2ccccc2)c2ccsc12

Procedure:
To 4-phenylthieno[2,3-d]pyridazin-7(6H)-one (0.714 g, 3.13 mmol) was added POCl3 (2.92 ml, 31.3 mmol). A water condenser was attached to the reaction flask and the mixture was heated to reflux for 15.5 hours. The reaction was concentrated and diluted with CH2Cl2 and ice water. The mixture was basified with solid sodium bicarbonate. The organic layers were separated and dried over sodium sulfate. To the residual crude after concentration, 50% EtOAc was added and the solution was filtered through a pad of silica gel. The product fraction were concentrated to yield 7-chloro-4-phenylthieno[3,2-d]pyridazine as a light yellow solid. MS m/z=247 [M+1]+. Calc'd for C12H7N2S: 246.71.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[C@@H:12]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:11]([CH3:34])[O:10][C:9]1=[O:35])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Na+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][OH:19])[C@@H:12]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:11]([CH3:34])[O:10][C:9]1=[O:35])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO[Si](C)(C)C(C)(C)C)[C@H]1Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-((tert-butyldimethylsilyl)-oxy)ethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (3.01 g, 5.77 mmol) in anhydrous THF (58 mL) was added a 1M solution of TBAF in THF (8.65 ml, 8.65 mmol). The resulting yellow solution was stirred at room temperature for 4 h, poured into 100 mL ½ saturated NaCl solution, and extracted with EtOAc (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated to provide a light yellow oil, which was purified by column chromatography on SiO2 (5→25% acetone/hexanes) to provide the title compound as a hard white foam (1.95 g, 83%): 1H NMR (400 MHz, CDCl3) δ 7.44-7.17 (m, 2H), 6.95 (t, J=8.2 Hz, 3H), 5.17-4.98 (m, 2H), 4.29-4.11 (m, 2H), 3.75-3.53 (m, 2H), 2.28 (dt, J=13.4, 6.7 Hz, 1H), 2.03-1.88 (m, 1H), 1.88-1.74 (m, 2H), 1.74-1.62 (m, 1H), 1.62-1.48 (m, 2H), 1.44 (s, 10H), 1.28 (d, J=6.5 Hz, 3H), 1.26-1.19 (m, 1H), 1.14 (ddd, J=15.1, 7.5, 3.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 173.30, 159.23, 154.90, 129.69, 121.20, 115.33, 80.99, 79.92, 74.68, 60.96, 52.99, 39.55, 34.07, 28.56, 28.33, 19.13, 18.36; ESIMS m/z 408.3 ([M+H]+), 430.3 ([M+Na]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH2:20][CH3:21])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: CCc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC(=O)[N:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH:27]=[O:28])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13][C:12]1=[O:18])C1C=CC=CC=1.Br>C(O)(=O)C>[O:18]=[C:12]1[CH:11]([NH:10][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][CH:27]=[O:28])[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1
Reactant: O=CNc1ccccc1CN(C(=O)OCc1ccccc1)C1CCC(=O)NC1=O
Agent: Br
Solvent: CC(=O)O
Product: O=CNc1ccccc1CNC1CCC(=O)NC1=O

Procedure:
1.00 g of the product from stage 1 was reacted as described in Example 1, stage 5, with 3 ml of hydrobromic acid in acetic acid (33% HBr). After similar working-up, 0.79 g (91% of theory) of the title compound was obtained in the form of a yellowish solid, which was reacted further without purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]1(O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(P(CCCC)CCCC)CCC.N1CCCCC1.N1CCCCC1.N(C(O)=O)=NC(O)=O>CCOC(C)=O.O.C1COCC1>[CH:10]1([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(O)cc1
Reactant: OC1CCCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(O)N=NC(=O)O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(OC2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
Under a nitrogen atmosphere, add 4-hydroxybenzonitrile (4 g, 33.5 mmol), cycloheptanol (2.55 g, 22.3 mmol), tri-n-butylphosphine (8.25 mL, 33.5 mmol), and azodicarboxylate dipiperidine (8.45 g, 33.5 mmol) to anhydrous THF (60 mL) at 0° C. Stir the mixture at 0° C. for 1 h and then at room temperature for 12 h. Dilute with EtOAc (50 mL) and water (50 mL). Separate the layers and extract the aqueous phase with EtOAc (4×30 mL). Wash the combined organic extracts with water (30 mL) and brine (20 mL). Dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g RediSep column) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 1.25 h; 80 mL/min) to provide the desired intermediate as a colorless oil (2.77 g, 58%). MS (APCI) m/z: 216 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[CH2:15](Br)[CH:16]=[CH2:17]>>[CH2:17]([C:10]1([OH:13])[CH2:11][CH2:12][C:5]2([O:4][CH2:3][C:2]([CH3:14])([CH3:1])[CH2:7][O:6]2)[CH2:8][CH2:9]1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Product: C=CCC1(O)CCC2(CC1)OCC(C)(C)CO2

Procedure:
The title compound is prepared from 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: quantitative; Mass spectrum (ESI+): m/z=223 [M+H—H2O]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][C@H:15]([CH2:17][O:18][CH3:19])[CH2:14][N:13]3[C:20](=[O:30])[C@@H:21]([NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:22]([CH3:24])[CH3:23])=[N:11][C:7]=1[CH:6]=[CH:5]2.[CH3:34][CH:35]([CH3:71])[C@H:36]([NH:66][C:67](=[O:70])[O:68][CH3:69])[C:37](=[O:65])[N:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]1[NH:47][C:46]2[C:48]3[C:53]([CH:54]=[CH:55][C:45]=2[N:44]=1)=[CH:52][C:51](B1OC(C)(C)C(C)(C)O1)=[CH:50][CH:49]=3.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:69][O:68][C:67]([NH:66][C@@H:36]([CH:35]([CH3:71])[CH3:34])[C:37]([N:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]1[NH:47][C:46]2[C:48]3[C:53]([CH:54]=[CH:55][C:45]=2[N:44]=1)=[CH:52][C:51]([C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[C:8]1[NH:9][C:10]([C@@H:12]4[CH2:16][C@H:15]([CH2:17][O:18][CH3:19])[CH2:14][N:13]4[C:20](=[O:30])[C@@H:21]([NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:22]([CH3:24])[CH3:23])=[N:11][C:7]=1[CH:6]=[CH:5]2)=[CH:50][CH:49]=3)=[O:65])=[O:70]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
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: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8CCCN8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Yield: 41.5 %

Procedure:
Methyl (S)-1-((2S,4S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (210 mg, 0.406 mmol), methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (253 mg, 0.487 mmol), Pd(PPh3)4 (47 mg, 0.0406 mmol) and K2CO3 (2M in H2O, 0.50 mL, 1.0 mmoL) were combined in DME (4 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85° C. for 15 h. After cooling, the reaction mixture was diluted with 5 mL MeOH, filtered and concentrated. The crude residue was purified by reverse phase HPLC to afford methyl {(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (140 mg, 42%). MS (ESI) m/z 831 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:20][CH:19]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(Nc2ccc3c(c2)C(C)(C)OC(=O)N3C)cc1

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-dimethylaminophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(326).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19](O)=[O:20])=[CH:4][CH:3]=1.[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[NH:22][C:19]([C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: Nc1nc2ccccc2s1
Reactant: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)O)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccccc3)nc2C(=O)Nc2nc3ccccc3s2)cc1
Yield: 6.8 %

Procedure:
5-(4-Methylphenyl)-2-phenylimidazole-4-carboxylic acid (0.5 g) and 2-aminobenzothiazole (0.35 g) were reacted and treated in the same manner as in Example 1 to give N-(benzothiazol-2-yl)-5-(4-methylphenyl)-2-phenylimidazole-4-carboxamide (0.05 g), melting point 269-270° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH:22]([C:24]([O:26]C)=[O:25])[CH3:23])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[C:24]([CH:22]([N:17]([C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[NH:5][C:6](=[O:15])[C:7](=[O:13])[NH:8]2)[S:18]([CH3:21])(=[O:19])=[O:20])[CH3:23])([OH:26])=[O:25]
Reactant: COC(=O)C(C)N(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)N(c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12)S(C)(=O)=O
Temperature: 150 °C
Yield: 8.9 %

Procedure:
A 1:1 mixture of the two isomers of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(1 -methoxycarbonyl- 1-ethyl)-methanesulphonamide (Preparation 23, 1.40 g, 32 mmol), 2M hydrochloric acid (40 ml) and dioxane (40 ml) was heated in an autoclave at 130° C. for 48 h and 150° C. for 24 h. The mixture was cooled, concentrated to low volume under reduced pressure and the solid filtered off and washed with ether. The product was dissolved in 1M aqueous sodium hydroxide (40 ml) and precipitated by the addition of 2M hydrochloric acid (to pH3). The white solid was filtered off and dried in vacuo, to give the title compound (1.13 g, 89%), as a mixture of diastereomers, m.p. 282° C. (dec).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)[CH3:2].[C:18](O)(=O)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5]2[NH:4][C:1]([CH3:2])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:8])[CH3:18]
Reactant: CC(=O)O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(C)[nH]c12

Procedure:
A mixture of 8.03 g of methyl 2-acetylamino-3-nitrobenzoate, 18.8 g of reduced iron, 20 ml of acetic acid and 40 ml of ethanol was heat-refluxed for 18 hours. After the solvent was concentrated, chloroform and 10% hydrochloric acid were added to the residue for extraction. The aqueous layer was acidified with a saturated aqueous solution of sodium hydrogencarbonate, and was extracted with chloroform. Chloroform was then distilled off under reduced pressure to give 1.61 g of 4-ethoxycarbonyl-2-methylbenzimidazole (296).
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[CH:14]([C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][N:5]1[C:4](=[O:13])[C:3]2[N:2]=[C:14]([C:16]3[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:9][C:8]=2[N:7]([CH3:10])[C:6]1=[O:11]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-1,3-dimethyluracil hydrate (5.11 g, 30.0 mmol) and 4-formylcinnamic acid (5.29 g, 30.0 mmol) were refluxed in nitrobenzene (500 mL). The nitrobenzene was allowed to distill slowly with water formed. Fresh nitrobenzene was added to keep the volume constant. After 5 hours of reflux, the mixture was cooled and the precipitate collected (8.07 g). Recrystallization from N,N-dimethylformamide-water gave the monohydrate of the title compound as a pale yellow powder, identical with that of Example 1 by 1H-NMR and elemental analysis.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([S:11]([Cl:14])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.BrC1C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](C2C=CC(Br)=CC=2C2C=CC=CC=2)(=[O:31])=[O:30])=[C:25](C2C=CC=CC=2)[CH:24]=1.ClS(O)(=O)=O>C(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:7]2[CH:6]=[C:5]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(c1ccc(Br)cc1-c1ccccc1)c1ccc(Br)cc1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=S(=O)(O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Brc1ccccc1
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
From 200 g of anhydrous aluminum chloride, 153 ml of benzenesulfonyl chloride, 138 ml of bromobenzene, and 600 ml of methylene chloride was prepared 220 g of p-bromophenyl-phenyl-sulfone according to the method of Journal of Chem. Soc., p. 2508 (1960). To 100 ml of chlorosulfonic acid was added 100 g of p-bromophenylphenylsulfone, and after stirring the mixture for 4 hours at 130° to 140° C., the mixture was poured into ice water to provide 121 g of 3-(4-bromophenylsulfonyl)benzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].[S:29]1[C:33]([C:34](O)=[O:35])=[CH:32][N:31]=[CH:30]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:14]2[O:13][C:12]([C@@H:2]([NH:1][C:34]([C:33]3[S:29][CH:30]=[N:31][CH:32]=3)=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10])=[N:16][CH:15]=2)[C:18]1=[O:28]
Reactant: CCC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Reactant: O=C(O)c1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-(2-(1-amino-7-oxononyl)oxazol-5-yl)-1-methylquinolin-2(1 H)-one (1 eq), prepared as described in steps 1 to 5 of Example 7, was treated with a solution of thiazole-5-carboxylic acid (1.3 eq), HOBT (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 3 min), followed by DIPEA (1.3 eq). The mixture was stirred at room temperature for 2 h and the desired product was isolated by preparative RP-HPLC, using water (+0.01% TFA) and MeCN (+0.01% TFA) as eluents (column C18). The pooled product fractions were lyophilized and the product was obtained as a white solid. MS (ES) C26H28N4O4S requires: 492.59, found: 493. 1H-NMR (400 MHz, DMSO-d6) δ: 9.28 (1 H, d, J=8 Hz), 9.26 (1 H, s), 8.62 (1 H, s), 8.29 (1 H, s), 7.91 (1 H, d, J=7.6 Hz), 7.84 (1 H, s), 7.68 (1 H, t, J=7.2 Hz), 7.61 (1 H, d, J=8.2 Hz), 7.34 (1 H, t, J=7.6 Hz), 5.27-5.22 (1 H, m), 3.75 (3 H, s), 2.39-2.36 (4 H, m), 2.09-2.06 (1 H, m), 2.00-1.96 (1H, m), 1.50-1.27 (6 H, m), 0.89 (3 H, t, J=7.2 Hz).