Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2cc3c(cc12)OCO3
Reactant: NCCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: OCCCCCNc1nccc2cc3c(cc12)OCO3

Procedure:
A mixture of 1.8 g. of 1-chloro-6,7-methylenedioxyisoquinoline and 5 g. of 5-hydroxypentylamine is heated at 140°C. for 5.5 hours. The resulting material is dissolved in methanol, sodium carbonate added and the resulting mixture refluxed for 15 minutes. The resulting mixture is filtered and evaporated in vacuo to an oil which is dissolved in chloroform. The resulting solution is evaporated in vacuo and the residue purified by chromatography over silica gel. The resulting oily product is then crystallized from ethanol/ethyl acetate and recrystallized from ethyl acetate/methanol to obtain 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline, m.p. 132.5°-134°C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Cn1ccnc1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 1-methylimidazole
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18](O)=[O:19])[O:14][C:13]=2[CH:21]=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:19])[O:14][C:13]=2[CH:21]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Product: O=C(Nc1ccccc1)C1=COc2ccc(O)cc2O1
Yield: 63 %

Procedure:
That compound is obtained in a yield of 63% starting from aniline and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[C@H:8]([CH2:10][OH:11])[NH2:9].ClC1C([O:29][C:30](=O)[C@H:31]([CH2:43][C:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=C(Cl)C(Cl)=C(Cl)C=1Cl.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[C@H:8]([CH2:10][OH:11])[NH:9][C:30](=[O:29])[C@H:31]([CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)[NH:32][C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
L-Seryl-L-tyrosine methyl ester hydrochloride (taken directly from part a) and 11.7 g. of Nα -benzyloxycarbonyl-L-tryptophan pentachlorophenyl ester [cf. Kovacs et al. J. Org. Chem. 32, 3696 (1967)] are dissolved in 60 ml. of dimethylformamide, cooled to -10° C. with stirring and treated with 28 ml. of triethylamine. The reaction is stirred 11/2 hours at -10° C. and allowed to warm to room temperature with stirring overnight. The mixture is filtered and the filtrate evaporated at 50° C. and reduced pressure. The residue is twice dissolved in methanol and the solvent removed under reduced pressure. The residue is then again taken into 30 ml. of methanol and precipitated by addition of 300 ml. of ether and 100 ml. of petroleum ether. The precipitated oil is obtained by decantation and stirred with 30 ml. of hot ethyl acetate. The product is obtained by cooling and precipitating by addition of ether and petroleum ether. It is further purified by repeating the precipitation from methanol with petroleum ether. The supernatant is decanted and the oil dried at 50° C. and under reduced pressure. The product thus obtained is a tan foam which can be crystallized from methanol, ether and petroleum ether by seeding; m.p. 149°-152° C.; [α]D23 -1.8° (c 1.00, methanol); ultraviolet in methanol, λmax 289.5 E11 92, λmax 280 E11 122.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:17][C:18]3[CH:32]=[CH:31][C:21]([CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C>CO>[NH2:23][CH2:22][C:21]1[CH:31]=[CH:32][C:18]([NH:17][C:15]([C:12]2[N:10]3[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]3=[N:14][CH:13]=2)=[O:16])=[CH:19][CH:20]=1
Reactant: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Solvent: CC(=O)Cl
Solvent: CO
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CN)cc3)n2n1
Reaction time: 8 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (230 mg, 0.53 mmol) in methanol (15 mL) was added acetyl chloride (0.37 mL, 5.25 mmol) dropwise. The reaction mixture was stirred for overnight, concentrated and purified by Prep HPLC (neutral) to give N-(4-(aminomethyl)phenyl)-6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 20% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.54 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=8.38 Hz, 2H), 7.77 (d, J=9.92 Hz, 1H), 7.50 (d, J=8.38 Hz, 2H), 6.92 (d, J=9.70 Hz, 1H), 4.12 (s, 2H), 3.48 (t, J=7.17 Hz, 2H), 1.79 (quin, J=7.33 Hz, 2H), 1.55 (dq, J=15.02, 7.41 Hz, 2H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 339.2 [(M+H)+, calcd for C18H23N6O 339.4].
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6].CC(C)=O.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>O.[OH-].[Na+]>[C:24]([NH:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:6])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A suspension of 16 g (0.058 mols) of γ-glutamylglutamic acid in 55 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 27 ml of acetone were added thereto. To the solution were added dropwise 12.6 g (0.058 mole) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the completion of the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 23.6 g of N-(N'-lauroyl-γ-glutamyl)glutamic acid in a yield of 89%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively. FAB mass spectrum: 459 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH3:34])[CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:22][CH:21]=3)=[O:18])=[CH:7][C:6]=2[CH:35]=1.B([O-])([O-])O[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.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>[CH2:48]([O:47][CH2:46][CH2:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH2:10][CH2:9][C:8]([C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:34])[CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:24][CH:25]=4)=[O:18])=[CH:7][C:6]=3[CH:35]=2)=[CH:43][CH:42]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CCOCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCOCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
In toluene/ethanol/water (=20/1/1, 14.3 ml) was dissolved 7-bromo-1-(2-ethoxyethyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g). To the solution were added 4-(2-butoxyethoxy)phenyl borate (0.17 g) and potassium carbonate (0.18 g), and the mixture was stirred for 30 minutes under argon atmosphere. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was heated to reflux for 14 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1). The purified residue was dissolved in ethyl acetate, which was filtered to give a solution. The solvent was removed under reduced pressure, which was recrystallized from isopropyl ether/ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethoxyethyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 90) (15 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][N:6]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH3:22])C2)C1)[CH2:2][CH3:3].[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[ClH:23].[CH2:20]([NH:16][CH2:17][CH2:18][CH2:19][NH:14][CH2:13]/[CH:12]=[CH:11]/[CH2:10][NH:6][CH2:7][CH2:8][CH2:9][NH:4][CH2:1][CH2:2][CH3:3])[CH2:21][CH3:22]
Reactant: CCCN1CCCN(C/C=C/CN2CCCN(CCC)C2)C1
Agent: Cl
Solvent: CO
Product: CCCNCCCNC/C=C/CNCCCNCCC

Procedure:
A mixture of 0.265 g (0.859 mmol) of (E)-1,4-bis(3-propylhexahydro-pyrimidin-1-yl)but-2-ene, 3 ml of methanol and 3.4 ml (6.8 mmol) of 2N hydrochloric acid is heated for 19 h under reflux and is then concentrated by evaporation in vacuo. Recrystallisation of the residue from methanol/water yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ0.96(t,6H); 1.62-1.76(m,4H); 2.05-2.16(m,4H); 3.02(t,4H); 3.11-3.18(m,8H); 3.77(d,4H); 6.03-6.06(m,2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[NH:20][C:21](=[O:34])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([F:32])=[CH:27][C:26]=3[Cl:33])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[C:28]([F:32])[CH:27]=[C:26]([Cl:33])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[CH:8][CH:7]=3)=[N:15][CH:16]=2)[NH:20][C:21]1=[O:34]
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cc(F)cc1Cl
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2ccc(Nc3ncc4c(=N)n(-c5c(Cl)cc(F)cc5Cl)c(=O)[nH]c4n3)cc2C1

Procedure:
15 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichloro-4-fluorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 4 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N+:23]([O-])=O)[C:20]=1[NH:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15].[CH:26]1([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[CH:39]=O)[CH2:28][CH2:27]1>O.C(O)C.C(Cl)Cl>[CH:26]1([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[C:39]2[N:21]([CH3:22])[C:20]3[C:11]([O:10][CH3:9])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][C:19]=3[N:23]=2)[CH2:27][CH2:28]1
Reactant: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: O=Cc1cc2cccnc2n1CC1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(OC)c2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C
Temperature: 100 °C
Yield: 80 %

Procedure:
A solution of sodium hydrosulfite (512 mg, 2.498 mmol) in water (3.25 mL) was added to a solution of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (200 mg, 0.833 mmol) and 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (167 mg, 0.833 mmol) in ethanol (6.5 mL) in a microwave vial. The reaction mixture was heated in the microwave for 5 h at 100° C. The reaction mixture was diluted with DCM (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product as a colourless oil. The crude product was purified by column chromatography on a silica cartridge (25 g) using a gradient of 60% EtOAc/cyclohexane→100% EtOAc/cyclohexane. (The product eluted near the solvent front). The appropriate fractions were combined and evaporated under vacuum to give the product as a yellow oil—methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate (260 mg, 0.666 mmol, 80% yield)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:25])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][N:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:25][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[CH:3][C:2]=3[CH3:1])[C:9]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:16]1
Reactant: Cc1cc(O)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reactant: OCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2cccnc2)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a degassed solution of 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenol (0.071 g, 0.2 mmol, Ex. #D.42) in anhydrous THF (10 mL) was added 3-pyridinemethanol (0.033 g, 0.3 mmol) and triphenylphosphine (0.131 g, 0.5 mmol), at rt. After 30 min the mixture was cooled to about 0° C. and diisopropyl azodicarboxylate (0.1 mL, 0.5 mmol) was added dropwise. The resulting mixture was stirred for about 16 h at rt, and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 95:5) followed by trituration with diethyl ether to give 1-methyl-4-[2-methyl-4-(3-pyridylmethoxy)phenyl]-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.012 g, 0.03 mmol, 14%) as a pale yellow solid: LC-MS (Table 1, Method e) Rt=5.09 min; m/z 444 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.59 (3 H, s) 2.70 (1 H, ddd, J=14.9, 6.1, 2.3 Hz) 2.88 (1 H, ddd, J=14.9, 8.8, 2.5 Hz) 3.19-3.29 (1 H, m) 3.53-3.62 (1 H, m) 3.78 (1 H, br s) 3.84 (3 H, s) 5.01 (2 H, s) 6.62 (1 H, s) 6.63 (1 H, dd, J=8.4, 2.6 Hz) 6.82 (1 H, d, J=2.6 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 1.2 Hz) 7.16 (1 H, d, J=8.4 Hz) 7.30 (1 H, dd, J=7.8, 4.9 Hz) 7.58 (1 H, td, J=7.8, 1.9 Hz) 7.71-7.79 (2 H, m) 8.48 (1 H, d, J=4.9 Hz) 8.56 (1 H, dd, J=4.8, 1.5 Hz) 8.65 (1 H, d, J=1.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][NH2:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:13](OC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C1(C)C=CC=CC=1>[CH3:17][C:15]1[NH:12][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)[C:13](=[O:18])[CH:14]=1
Reactant: Cc1cc(NN)ccc1[N+](=O)[O-]
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc([N+](=O)[O-])c(C)c2)[nH]1
Temperature: 100 °C

Procedure:
The mixture of 500 mg of 3-methyl-4-nitrophenylhydrazine, 0.32 ml of methyl acetoacetate and 20 ml of toluene was heated to 100° C. for 8 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was stirred in t-butyl methyl ether. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: Cl.[NH:2]1[CH2:21][CH2:20][CH2:19][C@H:3]1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:8])=[O:5].[NH:22]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:23]([C:41](O)=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:22]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:23]([C:41]([N:2]1[CH2:21][CH2:20][CH2:19][C@H:3]1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH3:8])=[O:5])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
At 0° C. the solution of 72 mg (0.231 mmol) of HCl.Pro-Ala-OBzl in 15 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 100 mg (0.234 mmol) of Boc-Arg(Tos)-OH, 31 mg (0.230 mmol) of 1-hydroxybenzotriazole and 48 mg (0.233 mmol) of dicyclohexylcarbodiimide in 20 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Pro-Ala-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 120 mg (75.6%) of the title compound as a colorless powder. Mp70–71.5° C., FAB-MS (m/e) 688[M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:14](=[O:16])[CH2:13][CH2:12][C:11]#[C:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 1.00 g (3.87 mmol) of 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) in 50 ml CH2Cl2 was treated with 0.45 g (4.65 mmol) N,O-dimethylhydroxylamine hydrochloride, 0.55 ml (5.03 mmol) N-methylmorpholine and at 0° C. with 0.97 g (5.03 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI). The reaction was naturally warmed to ambient temperature over night and partitioned between aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried (Na2SO4) to give 1.165 g of the title compound as brown oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C.CS(C)=O>O>[Br:8][C:6]1[N:7]=[C:2]([NH:19][CH:16]([CH3:18])[CH3:17])[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CNc1ncc(Br)nc1NC(C)C
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.5 g, 4.43 mmol), isopropylamine (0.17 g, 4.87 mmol), N,N-diisopropylethylamine (1.14 g, 8.84 mmol) and dimethylsulfoxide (10 mL) in a reaction vial was heated in an oil bath at 150° C. for 16 h. After being cooled to room temperature, the resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, evaporated under reduced pressure and purified on silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give the title compound (780 mg, 55.7% yield). MS (ESI) m/z 316.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20.0 (0.105 mole) portion of 2,3-dichlorobenzoic acid in 100 ml of toluene was treated with 254 ml (0.315 mole) of diisobutylaluminum hydride (25% in hexane), under a stream of dry nitrogen, at 15°-20° over 0.5 hours using rapid stirring. The reaction mixture was allowed to warm to room temperature over 0.5 hours, heated to reflux over 0.5 hours, refluxed for 1.5 hours, allowed to cool slowly to room temperature, and stored overnight at room temperature. The reaction mixture was then treated with a solution of 100 ml of methanol in 100 ml of water at 10°-15°, followed by 100 ml of concentrated hydrochloric acid at 20°-25°, and 165 ml of water. The organic layer was separated, washed with 50 ml of 5% sodium bicarbonate, 50 ml of water, dried over magnesium sulfate overnight and filtered. The filtrate was concentrated to dryness to given 17.0 g (91%) of a light tan solid, m.p. 81°-84°.