Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O.O1CCOCC1.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([N:23]=[N+:24]=[N-:25])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 98 %

Procedure:
At from 23° to 30° C add a warm solution of 7.5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 200 ml of acetone and 250 ml of dioxane dropwise to a solution of 1.84 g of sodium azide in 24 ml of water. Stir the resulting reaction mixture for a further 15 minutes and then dilute it with 600 ml of water cooling with ice to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid azide [m.p. 134° C (with decomposition)].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(S)-tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67 mmol) was dissolved in 14 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled to 0° C. Triethylamine (1.30 mL, 945 mg, 9.34 mmol) was added followed by the dropwise addition of benzyl chloroformate (0.99 mL, 1.20 g, 7.00 mmol). After 16 h, the reaction mixture was partitioned between H2O and CH2Cl2, and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to a light yellow oil. Purification via silica gel chromatography using 97% CH2Cl2/3% MeOH gave benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate as a clear, colorless oil (895 mg, 55%). LC/MS: m/z 349.5 (M+H)+ at 3.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1C=O
Yield: 67.2 %

Procedure:
35.5 g (0.125 mol) of methyl alpha-(2-bromomethylphenyl)-β-methoxyacrylate are dissolved in 500 ml of CCl4. 43.4 g (0.321 mol) of methylmorpholine N-oxide monohydrate are added, and the mixture is refluxed for 20 hours. The solid is filtered of f and the CCl4 phase is washed with water, with 2 N hydrochloric acid and again with water, dried and concentrated. 18.5 g (67%) of product are obtained as a reddish brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:21][CH:20]([OH:22])[CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.CSC1SC2C(=NC=CC=2OC2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2F)C=1.[CH3:58][O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][C:67]([N:69]=[C:70]=[S:71])=[O:68]>>[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:70]([NH:69][C:67](=[O:68])[CH2:66][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[O:59][CH3:58])=[S:71])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH:20]([OH:22])[CH2:21]3)=[O:17])[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: CSc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Yield: 39 %

Procedure:
Starting from the amine 299, following the procedure described above for the synthesis of compound 232a (scheme 50, example 203) but replacing 2-phenylacetyl isothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate and title compound 300 was obtained in 39% yield as a creamy solid. 1HNMR: (CD3OD) δ (ppm): 12.58 (s, 1H), 11.77 (s, 1H), 8.62 (m, 1H), 8.09 (d, J=12.3 Hz, 1H), 7.95 (s, 1H), 7.56 (m, 2H), 7.26 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 6.50 (d, J=5.9 Hz, 1H), 4.81 (m, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.87-3.78 (m, 6H). MS (m/z): 567.0 (M+1).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[ClH:36].[NH2:16][C@H:15]([C:24](=[O:26])[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:14][CH2:13][CH2:12][NH:11][S:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: Cl
Product: N[C@@H](CCCNS(=O)(=O)C1CCCCC1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclohexanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2Cl.[N:13]1(C(OC(C)(C)C)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>COCCCOCCCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc2c(Cl)ccnc12
Agent: COCCCOCCCO
Product: Cc1cccc2c(N3CCNCC3)ccnc12
Temperature: 140 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
8-Methyl-4-chloroquinoline (355 mg, 2 mmol) was suspended in dipropyleneglycolmonomethylether (4 ml), a solution of tert-butyl piperazine-1-carboxylate (440 mg, 2.4 mmol) in dipropyleneglycolmonomethylether (4 ml) was added and the mixture was stirred at 140° C. overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and trifluoroacetic acid (1:1, 4 ml) and stirred at room temperature for 90 minutes. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia) to yield 364 mg of a solid (1.6 mmol, 80%). MS (APCI): m/z=227.9 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1>N1C=CC=CC=1>[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3C)-c3cnccc3C(=O)c24)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2cnccc2C(=O)c13
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of N,N-dimethylethylenediamine in pyridine (0.10 mL) is added to a stirred suspension of 2-methyl-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (0.02 g) in dry pyridine (2 mL). After stirring at room temperature for one hour the reaction mixture is heated at 70° C. for 13 hours while additional amounts of N,N-dimethylethylenediamine solution (0.1; 0.05; 0.05 mL) are added after 2, 4 and 11 hours respectively. Pyridine and excess N,N-dimethylethylenediamine are removed by distillation at reduced pressure and the obtained residue is partitioned between CH2Cl2 (50 mL) and brine (10 mL) to which NaHCO3 saturated solution is added (1 mL). The organic solution is dried over anhydrous Na2SO4 and the solvent removed by distillation. The orange residue obtained is purified by silica-gel column chromatography (eluant: CHCl3 /MeOH 95/5 (30 mL) followed by CHCl3 /MeOH/NH4OH 90/15/0.5 (50 mL) to give 2-methyl-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.011 g) as a reddish orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:15][C:14]2[C:9]3[N:8]([CH2:17][CH3:18])[C:7]([C:3]4[C:2]([NH2:1])=[N:6][O:5][N:4]=4)=[N:16][C:10]=3[CH:11]=[N:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.074 g, 0.369 mmol) and tributylphosphine (0.074 g, 0.369 mmol) in tetrahydrofuran (5 ml) was treated with 1,1′-(Azodicarbonyl)-dipiperidine (0.093 g, 0.369 mmol) and heated at reflux for 18 hours. The reaction was then cooled to RT and then applied to a SCX ion exchange column and eluted with methanol and then a mixture of methanol/0.880 ammonia (9:1). The basic fractions were then reduced and the solid residue chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.03 g, 17%); MS (ES+) m/e 430 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:17])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid (2.1 mmol) in CH2Cl2 (20 mL) are added oxalyl chloride (4.2 mmol) and one drop of DMF at 0° C. After stirred at room temperature for 3 h under N2 atmosphere, the reaction mixture is concentrated and dried in vacuo, to give 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride as a yellow crystal.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]([CH3:22])[C:12]2[NH:17][C:16]([Cl:18])=[N:15][C:14](=[N:19][NH2:20])[C:13]=2[F:21])[N:9]=1.[CH:23]1([CH2:28][C@H:29]([CH2:33][N:34]([CH:42]=[O:43])[O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:11]([CH3:22])[C:12]2[N:17]=[C:16]([Cl:18])[N:15]=[C:14]([NH:19][NH:20][C:30](=[O:31])[C@H:29]([CH2:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:33][N:34]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:42]=[O:43])[C:13]=2[F:21])[N:9]=1
Reactant: CN(Cc1csc(N)n1)c1[nH]c(Cl)nc(=NN)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CN(Cc1csc(N)n1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-[[(2-Amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4(1H)-pyrimidinone hydrazone trihydrochloride (150 mg, 0.29 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (120 mg, 0.4 mmol), and HOAt (59 mg, 0.43 mmol) were dissolved in 10 mL of DMF. NMM (0.2 mL, 1.8 mmol) was added, followed by EDC (85 mg, 0.43 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC [(2R)-3-(2-{6-[[(2-amino-1,3-thiazol-4-yl)methyl](methyl)amino]-2-chloro-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (110 mg, 52%). LCMS: (M+H)+: 585.2.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1[C:26](OC)=[O:27].COC1C=CC(OC)=CC=1B(O)O>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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([O:27][CH3:26])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(B(O)O)c1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2,5-dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g (69%) of methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.70 (d, J=2.4, 1H), 8.37 (dd, J=8.4, 2.5, 1H), 7.52 (d, J=8.5, 1H), 6.92 (dd, J=8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[O:18]=[C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][N:20]1[CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([F:17])[C:2]([C:23]3[CH:22]=[CH:21][N:20]([CH:34]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:35]4)[C:19](=[O:18])[CH:24]=3)=[CH:16][C:6]=2[N:7]=1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(B3OC(C)(C)C(C)(C)O3)cc2=O)C1
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3ccn(C4CCN(C(=O)OC(C)(C)C)C4)c(=O)c3)c(F)cc2s1
Temperature: 80 °C
Yield: 36 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.07 g, 0.31 mmol), tert-butyl 3-(2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)pyrrolidine-1-carboxylate (0.24 g, 0.62 mmol) and K3PO4 (0.13 g, 0.62 mmol) in DMF-H2O (5.0 mL, 3:2) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.022 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 80° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 1.50% MeOH-DCM) to obtain the desired product (0.056 g, 36%). MS: 502.20 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:44]([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])[CH3:45].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:50][CH2:49][CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:51])=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-pentanoic acid (0.50 g, 0.89 mmol) prepared in Example 128 was mixed with β-alanine ethyl ester hydrochloride (0.15 g, 1 mmol), N,N-dimethylformamide (10 ml), 1-hydroxybenzotriazole (0.14 g, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (0.19 g, 1 mmol), followed by stirring overnight at room temperature. After distilling off the solvent, the residue was partitioned between ethyl acetate and saturated brine, washed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/7) to give the titled compound (0.48 g, yield: 81%) as a white powder (cis:trans=3:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:25]([O:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH2:1])=[CH:13][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A slurry containing of the product from Example 63A (0.2 g, 0.763 mmole) and cesium carbonate (0.25 g, 0.763 mmole) in dimethylformamide (5 ml) was treated with benzyl bromide (0.091 ml, 0.763 mmole) and the resulting slurry was stirred 18 hours at room temperature. Afterwards ice water (50 mL) was added to the solution and to the resultant slurry was added ethyl acetate (50 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow solid as the title compound (0.24 g, 89%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(NC(C)C)(C)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Cu](I)I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cnc(C#C[Si](C)(C)C)cn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.0 g, 3.5 mmol), copper iodide (0.17 mmol, 0.033 g), diisopropylamine (4.2 mmol, 0.42 g, 0.59 mL) and palladium(II)bis(triphenylphosphine)dichloride (0.17 mmol, 0.12 g) in tetrahydrofuran (30 mL) was degassed with Ar. Then ethynyl(trimethyl)silane (7.60 mmol, 0.75 g, 1.1 mL) was added slowly and the mixture was stirred overnight. The mixture was filtered through a pad of celite which was washed with ethyl acetate and filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (ethyl acetate/cyclohexane: 1/99→99/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)pyrazin-2-yl]amino]butanoate (E, 0.85 g, 2.8 mmol, 80% Yield). 1H NMR (400 MHz, CDCl3) 9.46 (1H, s), 9.00 (1H, s), 8.33 (1H, s), 3.71 (3H, s), 2.88-2.75 (2H, m), 0.20 (9H, s).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[N:16][CH:17]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([F:33])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)Cc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)C(F)c1ccc(Br)cn1
Reaction time: 0.33 h
Yield: 45.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.45 mL, 1M in tetrahydrofuran, 0.45 mmol) is added to a solution of commercially available 5-bromo-2-(methylsulfonylmethyl)pyridine (102 mg, 0.408 mmol) in tetrahydrofuran (5 mL) at −78° C. After 45 minutes N-Fluorodibenzenesulfonamide (156 mg) in tetrahydrofuran (10 mL) is added to the reaction mixture at −78° C. over 5 minutes. After stirring for 20 minutes the reaction is quenched with water (10 mL) and ethyl acetate(10 mL). The reaction mixture is partitioned between saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL). The combined organic layers are washed with brine and concentrated to give the crude product, which is purified by flash column chromatography eluting from neat hexane to neat ethyl acetate to give the title compound (50 mg): m/z (Cl) 268 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][N:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCc2ccccc2)cnc1Cl
Temperature: 80 °C

Procedure:
0.5 g (3.38 mM) of 6-chloro-5-fluoro-3-pyridinol, 10 ml of dimethyl-formamide and 0.843 g (6.08 mM) of potassium carbonate are mixed. 0.8 ml (6.76 mM) of benzyl bromide is added and the mixture is heated at 80° C. for one hour. After hydrolysis in 100 ml of water, the mixture is extracted with ethyl acetate and the organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: pure toluene) to give the expected product in the form of a white solid with a quantitative yield.