Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]S(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:22]([O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of (2S,4R)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (32.3 g) and sodium benzoate (28.8 g) in dimethyl sulfoxide (320 ml) was stirred at 90° C. overnight and cooled to room temperature. The mixture was diluted with ethyl acetate (600 ml) and washed successively with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was crystallized from n-hexane to give (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (31.0 g) as a colorless crystal.
Reaction SMILES: O=[Zn:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Zn:2].[C:3]([O-:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=[Zn]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Zn]

Procedure:
Zinc white is reacted with stearic acid to give zinc, stearate functioning as a vulcanization auxiliary.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:54][S:55]([O:43][CH2:42][C@H:14]1[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]1[CH2:12][C:11]1[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(C)(=O)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethysilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methanol (50 g, 0.075 mol) in dry CH2Cl2 (500 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (31.3 ml, 0.225 mol), then with methanesulfonyl chloride (11.6 ml, 0.15 mol). The mixture was poured to saturated sodium bicarbonate aqueous and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 81%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:31]1([CH2:39]I)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:39][CH:31]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: ICC1CCCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CC1CCCCCCC1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a stirred solution of (Benzhydrylidene-amino)-acetic acid tert-butyl ester (3.00 g; 10.1 mmol) in 60 mL of tetrahydrofuran under argon at −78° C. was added lithium diisopropylamide solution (11.5 mL; 1.5 M solution in cyclohexane) dropwise. After 30 minutes, a solution of cycloheptylmethyl iodide (Prepared in Step A; 3.83 g; 15.2 mmol) was added dropwise via syringe and the mixture allowed to warm to room temperature and stirred for 18 h. The mixture was quenched with saturated sodium bicarbonate solution and most of the tetrahydrofuran was removed in vacuo. The mixture was diluted with water and extracted with methylene chloride. The combined extracts were dried (sodium sulfate) filtered and concentrated in vacuo. The crude product was chromatographed (eluent:4% ethyl acetate/hexanes) to give 3.34 g (79%) of 2-(Benzhydrylidene-amino)-3-cyclooctyl-propionic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[CH:4][C:3]=1[O:19][CH3:20].[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2.[Cl-].[Na+].[CH3:36]C1C=CC=CC=1C>[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:36])[CH2:9][C:10](/[CH:11]=[N:21]/[C:22]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: Cc1ccccc1C
Reactant: COc1cc(C(C)CC(O)(C=O)C(F)(F)F)ccc1Cl
Agent: [Ti+4]
Agent: [Cl-]
Agent: [Na+]
Product: COc1cc(C(C)(C)CC(O)(/C=N/c2ccc(F)c3nc(C)ncc23)C(F)(F)F)ccc1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 62.8 %

Procedure:
350 mg (1.08 mmol) of (rac.)-4-(4-chloro-3-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanal is mixed in 5.8 ml of o-xylene with 190.9 mg (1.08 mmol) of 5-amino-8-fluoro-2-methylquinazoline. After 0.64 ml (2.16) of titanium(IV) isopropylate is added, it is refluxed for three hours (bath temperature 120° C.). After cooling, the batch is added to saturated sodium chloride solution and stirred vigorously for 20 minutes. After being extracted twice with ethyl acetate, the combined organic extracts are washed with brine. After drying on sodium sulfate, suctioning off the dessicant and spinning off the solvent, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 327.5 mg (62.8%) of the desired imine is isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])([O-:3])=[O:2].Cl>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:18][C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 95 %

Procedure:
A mixture of 14 g. (36.3 mmoles) of diethyl 2-nitro-4-benzoylphenylmalonate, 300 ml. of 4N hydrochloric acid and 300 ml. of dioxane was heated to reflux for 10 hours. The reaction mixture was concentrated in vacuo and the crude product was triturated with hot methylene chloride, 9.88 g. (95% yield), m.p. 168°-170° C.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1.COC1C=CC(CN2C[C@H](C)NC2=O)=CC=1.[CH3:40][C:41]1[C:42]([N:48]2[CH2:53][CH2:52][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[C@@H:66]([CH3:67])[CH2:65][N:64](CC5C=CC(OC)=CC=5)[C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:50][CH2:49]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1>>[CH3:40][C:41]1[C:42]([N:48]2[CH2:49][CH2:50][N:51]([C:54]([C:56]3[CH:57]=[CH:58][C:59]([N:62]4[C@@H:66]([CH3:67])[CH2:65][NH:64][C:63]4=[O:77])=[N:60][CH:61]=3)=[O:55])[CH2:52][CH2:53]2)=[N:43][CH:44]=[C:45]([CH3:47])[CH:46]=1
Reactant: COc1ccc(CN2C[C@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C[C@H](C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC[C@@H]4C)nc3)CC2)c(C)c1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and (S)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 204 and by the reaction and treatment in the same manner as in Example 426, the title compound (96 mg) was obtained via (S)-3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) and commercially available cyclopentanecarboxylic acid (66 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (110 mg) was added, and the admixture was stirred at room temperature for 17 hours. The reaction mixture was purified in the same manner as described in Example 51 to obtain 35 mg of the title compound (yield: 50%).
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([CH:14]3[C:16]([CH3:18])([CH3:17])[C:15]3([CH3:20])[CH3:19])=[O:13])[CH2:7][C:6]=2[NH:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27]C)=O)[C:3]1=2.O.[NH2:30][NH2:31]>>[CH3:18][C:16]1([CH3:17])[C:15]([CH3:20])([CH3:19])[CH:14]1[C:12]([N:8]1[CH2:7][C:6]2[NH:5][C:4]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:25](=[O:27])[NH:30][N:31]=[C:2]([C:3]=34)[C:11]=2[CH2:10][CH2:9]1)=[O:13]
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1C(C)(C)C1(C)C)C3
Solvent: O
Product: CC1(C)C(C(=O)N2CCC3=C(C2)Nc2cccc4c(=O)[nH]nc3c24)C1(C)C

Procedure:
The target product was prepared from methyl 5-oxo-2-(2,2,3,3-tetramethylcyclopropanecarbonyl)-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and hydrazine hydrate according to the same procedure described as in Example 16 (Step 4). 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.6-10.65 (m, 1H), 7.62-7.67 (m, 1H), 7.47-7.48 (m, 1H), 7.24-7.31 (m, 1H), 4.36-4.41 (m, 2H), 3.70-3.76 (m, 2H), 2.29-2.33 (m, 2H), 1.03-1.23 (m, 12H). MS (ESI) m/e [M+1]+ 369.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].CO>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:23][N:20]1[CH2:19][CH2:18][N:17]([C:14]2[N:15]=[CH:16][C:11]([C:9]3[S:10][C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:31]=[CH:30][C:7]=4[N:8]=3)=[CH:12][CH:13]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc([N+](=O)[O-])cc4s3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CCN(c2ccc(-c3nc4ccc([N+](=O)[O-])cc4s3)cn2)CC1
Temperature: 70 °C

Procedure:
To tert-butyl 4-[5-(6-nitro-1,3-benzothiazol-2-yl)pyridin-2-yl]piperazine-1-carboxylate (0.29 g) in DCM (15 mL) was added TFA (1.5 mL) before stirring o.n. at r.t. The solvent was thereafter removed by blowing with nitrogen and the residue, crude 6-nitro-2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole (MS m/z [M+H] 342), was used directly in the next step. To this residue in methanol (3 mL), was added formaldehyde (37% aq., 0.25 mL) and sodium cyanoborohydride (74 mg), followed by heating at 70° C. for 5 minutes. A thick solid formed and additional methanol (3 mL) was added. The mixture was stirred at r.t. for 1 h, then filtered. The solid was washed with ice-cold methanol and was then dried under vacuum over P2O5, to give intermediate 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-6-nitro-1,3-benzothiazole trifluoroacetate (0.26 g) as a solid. MS m/z (M+H) 356. This intermediate (0.26 g) was dissolved in methanol (8 mL) and ammonia (7M in methanol, 2 mL) was added. The flask was evacuated and flushed with argon. Palladium (10% on carbon, 30 mg) was added and the flask was evacuated and filled with hydrogen gas. The reaction mixture was shaken under an atmosphere of hydrogen o.n. at r.t. The mixture was thereafter filtered through diatomaceous earth and evaporated in vacuo, to give the title compound (0.22 g) as a white solid. 1H NMR (CHLOROFORM-d) δ 8.67 (d, 1 H) 8.05 (dd, 1 H) 7.70 (d, 1 H) 7.04 (d, 1 H) 6.74 (dd, 1 H) 6.63 (d, 1 H) 3.33-4.01 (m, 6 H) 2.42-2.55 (m, 4 H) 2.30 (s, 3 H); MS m/z (M+H) 326.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].C(Cl)[Cl:13]>S(Cl)(Cl)(=O)=O.O.[S]Cl.[Cl-].[Cl-].[Cl-].[Al+3]>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([Cl:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Agent: [S]Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Cl

Procedure:
A mixture of 63 g (0.25 mol) 2,5-dichlorothien-3-yl-sulfonyl chloride, 0.5 g sulfur monochloride and 25 g sulfuryl chloride was heated under reflux. To the refluxing reaction was then added dropwise 0.5 g aluminum trichloride in 25 g sulfuryl chloride. The reaction mixture was then heated under reflux for 3 hours, cooled diluted with 400 ml cold water and cooled, with methylene chloride. The methylene chloride extracts were washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate and stripped to give 62 g of 2,4,5-trichlorothien-3-ylsulfonyl chloride, which crystallized from hexane as a solid, m.p. 55° C.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1>CC(O)=O>[C:5]1([C:12]#[N:13])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: N#Cc1cccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of 4-amino-1-naphthalenecarbonitrile (19.2 g, 114 mmol) and maleic anhydride (14.0 g, 113 mmol) in AcOH (230 mL) was heated at 115° C. for 12 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure then diluted with CH2Cl2 (2.5 L). The organic layer was washed 3× with H2O (3 L), 1× with sat. aq. Na2CO8 (1 L) and 1× with brine (1 L), dried over MgSO4 and concentrated to −200 mL under reduced pressure. Purification by flash chromatography on cation exchange resin (60 g, CUBX13M6 from United Chemical Technologies) eluting with CH2Cl2 gave 25.0 g (88%) of 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)]-naphthalenecarbonitrile as a yellow solid. HPLC: 96% at 2.48 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 249.25 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Br:12])[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Br:12])[C:5]2[S:9][C:8]([NH:10][C:25]([NH:24][CH2:22][CH3:23])=[O:26])=[N:7][C:6]=2[CH:11]=1
Reactant: COc1c(Br)cc2nc(N)sc2c1Br
Reactant: CCN=C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)c(Br)c2s1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
5,7-Dibromo-6-methoxy-1,3-benzothiazol-2-amine (208 mg, 0.62 mmol) was dissolved in anhydrous DMSO (1 mL) and triethylamine (0.189 mL, 1.35 mmol) followed by ethyl isocyanate (0.058 mL, 0.74 mmol). The mixture was stirred at rt. A further aliquot of ethyl isocyanate (0.058 mL, 0.74 mmol) was added after 3 h. After 3.75 h, the mixture was diluted with water and extracted into EtOAc (3×30 mL). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The desired compound was obtained as a pale yellow solid, 234 mg (93%). The material was used without further purification in the next step. m/z: 407.83/409.83/411.81 [M+H]+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>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.[Pd]>[C:7]([O:11][C:12]([NH:14][C@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:1]=[O:4])[CH:22]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)[C@@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 35 %

Procedure:
100 ml (201 mmol) of an aqueous 2M potassium carbonate solution and 4.4 g (3.80 mmol) of tetrakis palladium are introduced into a solution containing 33 g (77.3 mmol) of methyl (R)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propionate, and 15 g (100 mmol) of 3-boronic acid-benzaldehyde (Example 28b) in 300 ml of ethylene glycol dimethyl ether. The reaction medium is heated at 85° C. for 20 h and, after a return to ambient temperature, extracted with ethyl acetate. The organic phase is washed with water and then a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 10.2 g of coupled product are obtained with a 35% yield.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=2)[CH2:43][CH2:42]1>>[CH3:40][N:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:53]=[CH:52][C:50]([NH:51][C:32]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:9]4[N:8]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:12]=[C:11]([N:13]5[CH:14]6[CH2:20][CH2:19][CH:18]5[CH2:17][O:16][CH2:15]6)[N:10]=4)=[CH:22][CH:23]=3)=[O:38])=[CH:49][CH:48]=2)[CH2:45][CH2:46]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5C6CCC5COC6)n4)cc3)cc2)CC1
Yield: 9.1 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-(4-methylpiperazin-1-yl)aniline (54 mg, 0.18 mmol) gave the title compound as off-white solid (2TFA salt, 3.2 mg, 7% yield). MS (ESI) m/z 586.6.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[CH:52]=[CH:51][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH:40]=[C:41]3[C:46](=[O:47])OC(C)(C)OC3=O)=[CH:35][CH:34]=2)=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([C:33]2[CH:34]=[C:35]3[C:36](=[CH:37][CH:38]=2)[NH:39][CH:40]=[CH:41][C:46]3=[O:47])=[O:32])=[CH:51][CH:52]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccc(C(=O)c3ccc(Cl)cc3)cc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]ccc(=O)c2c1
Temperature: 25 °C

Procedure:
To a flask with DOWTHERM at 245° C. was added 5-(((4-(4-chlorobenzoyl)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 8.55 mmol) in portions. The resulting solution was heated for 10 min and cooled down to room temperature. Solids were precipitated from the solution. To the reaction mixture was added hexanes and the solids filtered. The solids were washed thoroughly with Et2O and hexanes and dried under vacuum to yield 6-(4-chlorobenzoyl)quinolin-4(1H)-one. (M+H)+: 284, 286.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:4][CH2:3]1.OO.C([O-])(=O)/C=C\C([O-])=[O:33].C(O)(C)C>S(=O)(=O)(O)O>[O:33]=[S:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Yield: 41 %

Procedure:
1-(1-Oxido-thiomorpholino)-3-piperazino-5-nitro-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-nitro-isoquinoline hydrochloride by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. of its maleate: 231°-233°C (from isopropanol). Yield: 41% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][C@H:9]2[N:21]([CH3:32])[C:22](=[O:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([C:61](O)=[O:62])[CH2:60][CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22](=[O:31])[N:21]([C@H:9]2[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:61]([CH:57]4[CH2:60][CH2:59][CH2:58]4)=[O:62])[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:32])=[CH:29][CH:28]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3CCC3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A mixture of 27.6 mg (0.06 mmol) 4-fluorophenyl (3S,4R)-4-(4-chlorophenyl)-1-(piperidine-4-carbonyl)pyrrolidin-3-yl(methyl)carbamate, 0.52 mL (0.072 mmol) HATU (0.136 M in DMF), 12 mg (0.072 mmol) cyclobutanecarboxylic acid and 46.5 mg (0.36 mmol) DIPEA in 1.5 mL DMF was shaken at room temperature over night. The mixture was subjected to preparative HPLC chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 12.5 mg (39%) of the title compounds as off-white solid. MS m/e: 542.3 [M+H]+.