Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br.Br[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl.O>[N:15]1([CH2:14][CH2:13][NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCCN1CCCCC1
Reactant: Nc1n[nH]c2ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc2c(NCCN3CCCCC3)n[nH]c2c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
4.0 g of 3-aminoindazole prepared by the method described in C. E. KWARTLER et. al., J. Am. Chem. Soc., 65, 1804 (1943), 8.18 g of 1-(2-bromoethyl)piperidine hydrobromide obtained from Referential Example 1, 8.28 g of anhydrous potassium carbonate and 80 ml of dried N,N-dimethylformamide were mixed and stirred for 24 hours at 80° C. After the reaction mixture was condensed under reduced pressure, 100 ml of chloroform and 50 ml of water were added to the condensed residue. Then the chloroform layer was separated, dried with anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to alumina-column chromatography (alumina: 200 g) using chloroform as the solvent to give 4.09 g of 3-(2-piperidinoethylamino)indazole in a yield of 56%.
Reaction SMILES: [OH:1][C@@:2]1([C:22]#[C:23][CH3:24])[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH2:4][CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][C@@:2]1([C:22]#[C:23][CH3:24])[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH2:4][CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:27])[CH3:26]
Reactant: CC#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Under nitrogen, 250 mg. of 17β-hydroxy-18-methyl-17α-propinyl-4,15-estradien-3-one in 2.5 ml. of pyridine is agitated at room temperature for 2 hours with 1 ml. of acetic anhydride and 10 mg. of 4-(dimethylamino)-pyridine. After the reaction mixture has been worked up as described in Example 36, and after the crude product has been chromatographed on silica gel with acetone-hexane, 110 mg. of 17β-acetoxy-18-methyl-17α-propin-1-yl-4,15-estradien-3-one is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(Cc4ccccc4)c(F)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20FN5O3, 433.2
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([O:27][CH2:28][CH3:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:26].[Li+].[OH-]>>[CH2:28]([O:27][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:26])[C:3]([OH:30])=[O:2])[CH3:29]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless solid, which was crystalized from hexane/dichloromethane to afford colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-OJ), the enantiomeric excess amounts to 99.0%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:11][C@H:12]([OH:26])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([OH:5])=[O:4].C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](O)CCNC(OCC1C=CC=CC=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:11][C@@H:12]([OH:26])[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CCCCN(C[C@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Yield: 62 %

Procedure:
According to the method described for the preparation of 17a, 16b (78 mg, 0.12 mmol) was reacted with trifluoroacetic acid (704 mg, 6.20 mmol) and triethylsilane (140 mg, 11.92 mmol) in CH2Cl2 (0.98 mL) to give 17b (37 mg, 62%) as a colorless oil: 1H NMR δ 1.20-2.10 (m, 8H), 3.05-3.70 (m, 7H), 3.82 (m, 1H), 5.05 (s, 2H), 5.10 (s, 2H), 7.20-7.60 (m, 10H); HRMS m/z calcd for C26H36N3O7 502.2553, found 502.2546. [α]23D+3.6° (c 1.00, CH3OH).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:23][CH2:24][C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:11][C:12]1[C:21]2[N:22]=[C:1]([CH2:2][CH2:3][CH3:4])[N:23]([CH2:24][C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH:26]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 20.2 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol), trimethyl orthobutyrate (2.1 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and heated at 110° C. for 18 hours. The volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel (250 g, eluting with 20% to 40% ethyl acetate in hexane) to provide 0.806 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:29])[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: Cc1cccc(C(N)c2ccccc2)c1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: Cc1cccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-m-tolyl-methylamine (CA [55095-20-0]).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][N:6]([C:14]1[C:19]2[N:20]=[CH:21][N:22]([CH3:23])[C:18]=2[CH:17]=[C:16]([N:24]=C(C2C=CC=CC=2)C2C=CC=CC=2)[N:15]=1)[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl>C1COCC1>[NH2:24][C:16]1[N:15]=[C:14]([N:6]([CH2:5][C:4]2[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=2[O:2][CH3:1])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C:19]2[N:20]=[CH:21][N:22]([CH3:23])[C:18]=2[CH:17]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N=C(c3ccccc3)c3ccccc3)cc3c2ncn3C)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc(N)cc3c2ncn3C)c(OC)c1
Reaction time: 0.03 h
Yield: 100 %

Procedure:
In a 1000 mL round bottom flask, tert-butyl 2,4-dimethoxybenzyl(6-(diphenylmethyleneamino)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate (example 1C, 9.2 g, 15.93 mmol) was stirred in THF (50 mL). 1 N HCl (33 mL) was added. After 2 min, the reaction was quenched with 1 N NaOH (65 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dried under vacuum for 1 h and triturated with ether (4×). Isolated tert-butyl 6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (6.587 g, 15.93 mmol, 100% yield) as a cream solid. Material carried forward with no further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[O:17])[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([N:14]([CH2:15][CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CSc1nnc(N=C=O)s1
Reactant: CCCNCC=O
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(SC)s1

Procedure:
A mixture of 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)-ureido]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]=[C:33]=[O:34]>N1C=CC=CC=1>[NH2:18][C:16]1[C:17]2[C:9]([S:8][C:4]3[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:26]4[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:34])[CH:7]=[CH:6][CH:5]=3)=[CH:10][N:11]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=C=Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: Nc1ncnc2c1c(Sc1cccc(NC(=O)Nc3c(F)cccc3F)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a round-bottom flask with pyridine (3 mL) was added 5-(3-Amino-phenylsulfanyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (16.3 mg, 0.05 mmole) and 1,3-Difluoro-2-isocyanato-benzene (15.5 mg, 0.1 mmole). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (40 mL) and water (40 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification through flash column (methylene chloride/methanol: 96/4) gave the title compound as a light yellow solid (9.8 mg, 41%). MS: 481.1 (MH+); HPLC Rf: 7.559 min.; HPLC purity: 96%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:28]([CH:35]([CH3:39])[C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36](=[O:37])[CH:35]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH3:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(Oc1ccccc1)C(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)C(C)Oc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenoxypropionyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8]2)=[N:3]1.[Li+].[OH-].Cl>CO>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1ccc2nn(C)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc2cc(C(=O)O)ccc2n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of methyl 2-methyl-2H-indazole-5-carboxylate (210 mg, 1.10 mmol) in methanol (5 mL) was added 1.0 M LiOH (1.2 mL, 1.2 mmol). The mixture was agitated at 40° C. overnight. After cooling to room temperature, 1 N HCl (1.17 mL, 1.1 eq) was added. The solution was cooled and the solid was isolated by filtration. The solid was dried in a vacuum oven at 50° C. to provide the title compound (147 mg, 76%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][S:63]([NH2:66])(=[O:65])=[O:64]>CN1C(=O)CCC1.O>[Cl:73][C:70]1[CH:69]=[CH:68][C:67]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:62][S:63](=[O:64])(=[O:65])[NH2:66])=[CH:72][CH:71]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CS(N)(=O)=O)c1ccc(Cl)cc1
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: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (115 mg, 0.32 mmol) and N-ethyldiisopropylamine (0.066 mL, 0.38 mmol) in NMP (2.5 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanesulfonamide (Intermediate 80) (75 mg, 0.32 mmol). The solution was stirred for 1 hour at room temperature. The mixture was treated with water (5 mL) and the resulting colourless precipitate was isolated by filtration, washed with water and then acetonitrile to give tert-butyl 4-(1-(4-chlorophenyl)-2-sulfamoylethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (157 mg, 85%) as colourless solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:67])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:24]([O:61][CH3:62])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:59][CH3:60])[C@@H:34]([CH3:58])[C:35](=[O:57])[NH:36][C@H:37](/[CH:45]=[CH:46]/[C:47]1[CH:52]=[CH:51][C:50]([S:53]([OH:56])(=[O:55])=[O:54])=[CH:49][CH:48]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=[O:2].O[N:69]1[C:73](=[O:74])[CH2:72][CH2:71][C:70]1=[O:75].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:75]=[C:70]1[CH2:71][CH2:72][C:73](=[O:74])[N:69]1[O:2][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:67])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:24]([O:61][CH3:62])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:59][CH3:60])[C@@H:34]([CH3:58])[C:35](=[O:57])[NH:36][C@H:37](/[CH:45]=[CH:46]/[C:47]1[CH:48]=[CH:49][C:50]([S:53]([OH:56])(=[O:55])=[O:54])=[CH:51][CH:52]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 8 mg (7.5 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(2S,3E)-1-phenyl-4-(4-sulphophenyl)but-3-en-2-yl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 2 ml of DMF were added 8.6 mg (74.8 μmol) of N-hydroxysuccinimide, 8.5 mg (22.4 μmol) of EDCI and 0.1 mg (0.75 μmol) of DMAP. The reaction mixture was stirred at RT for 20 h. Subsequently, 1.3 μl (7.5 μmol) of Hünig's base were added and the mixture was stirred for 1 h. The reaction mixture was then purified by prep. HPLC. 2.6 mg (72% purity, 21% of theory) of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([S:7]([CH2:10][CH3:11])(=[O:9])=[O:8])[S:4][C:3]=1[O:12][CH2:13][CH3:14].[CH3:15][N:16]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:35].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]([O:12][C:3]1[S:4][C:5]([S:7]([CH2:10][CH3:11])(=[O:9])=[O:8])=[CH:6][C:2]=1[C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:35])[N:16]([CH3:15])[CH:25]=1)[CH3:14]
Reactant: CCOc1sc(S(=O)(=O)CC)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1sc(S(=O)(=O)CC)cc1-c1cn(C)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 46.4 %

Procedure:
A mixture of 3-bromo-2-ethoxy-5-ethylsulfonylthiophene (18.0 mg, 0.06 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (24 mg, 0.08 mmol), K3PO4 (42 mg, 0.20 mmol) and Pd(dppf)Cl2 (6 mg, 0.008 mmol) in dioxane (0.5 mL) and H2O (0.05 mL) was stirred at 60° C. for 1.5 h. The reaction mixture was then poured over water (6 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography to give the title compound (10.5 mg, 46%). 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J=7.9 Hz, 1H), 7.71 (dd, J=7.6, 7.6 Hz, 1H), 7.57 (m, 3H), 7.35 (d, J=7.9 Hz, 1H), 4.25 (m, 2H), 3.54 (s, 3H), 3.38 (m, 2H), 1.24 (m, 6H). LCMS: 378.05 (M+1)+
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2
Reactant: BrBr
Reactant: CC(=O)N1CCc2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(Br)ccc21
Temperature: 0 °C

Procedure:
To N-acetylindoline, 116.6 g (0.724 mol) in a 1000 ml 3 neck flash fitted with overhead stirrer, thermometer and gas inlet (to a sodium hydroxide trap) in 150 ml acetic acid was added bromine, 32.25 ml (0.68 mol) over a period of 30 minutes. The mixture was kept at 30° C. with ice bath cooling. When addition was complete, the yellow suspension was slowly poured into one liter of ice water and solid sodium bisulfite was added to destroy any residual bromine. The resulting slightly off white solid was filtered and washed several times with water and allowed to dry overnight. The resulting solid was recrystallized from 800 ml of methanol to give 122.86 g (70.7% by weight yield) of 5-bromo-N-acetylindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][CH:28]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([F:47])([F:46])[F:45])[C:29]([NH:31][C:32]([CH3:37])([C:34]([NH2:36])=[O:35])[CH3:33])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:27][CH:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:45])([F:46])[F:47])[C:29]([NH:31][C:32]([CH3:37])([C:34]([NH2:36])=[O:35])[CH3:33])=[O:30])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)C(N)c1ccccc1C(F)(F)F)C(N)=O
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: Cl
Product: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F)C(N)=O

Procedure:
Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 28 mg (76 mol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 28 mg (63% of theory) of the title compound.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Cl[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:17])[C:10]([CH3:16])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH:1]([NH:5][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])([CH2:3][CH3:4])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Reactant: CCC(C)N
Solvent: CCO
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
(-)-sec-Butylamine [prepared according to L. Verbit and P. J. Heffron, Journal of Organic Chemistry 32, 3199 (1967)] was reacted with 4-chloro-3,5-dinitro-o-xylene as by the general procedure of Example 5 to give a yellow-orange solid with melting point 37° C. to 38.5° C., [α]D25° = -51.38° (c 2.071, ethanol). Concentrations, abbreviated c herein, are measured in grams per 100 ml. of solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Br:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3cccc(Br)c3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 56.9 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.2 g), N,N'-carbonyldiimidazole (1.8 g) and 2-amino-7-(3-bromophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (3.1 g; m.p. approximately 140° C.) is dissolved in boiling propanol (100 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (2×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Bromophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (2.2 g), m.p. 144°-146° C., is obtained.