Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[OH2:15].Cl.[NH2:17]O>CCO>[OH:15][NH:8][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[NH:17]
Reactant: N#Cc1ccccn1
Reactant: NO
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ccccn1
Yield: 57 %

Procedure:
To a mixture of 2-pyridinecarbonitrile (3 g, 29 mmol) and potassium carbonate (4.1 g, 30 mmol) in EtOH (30 ml) was added water (15 ml) and, cautiously, hydroxylamine hydrochloride (2.9 g, 42 mmol) and then heated at reflux for 6 h, cooled and evaporated to dryness. The residue was treated with water (100 ml) and the suspended solid product filtered off, washed with water and dried to yield the title compound as a white solid (2.28 g, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].[CH:10](OCC)(OCC)OCC.[N+:20]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])([O-:22])=[O:21]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[CH:10][N:26]([C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(N)C#N
Reactant: CCOC(OCC)OCC
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2cccc([N+](=O)[O-])c2)c1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of amino-cyano-acetic acid ethyl ester (17.06 g, 133.3 mmol) and triethyl orthoformate (19.7 g, 133.3 mmol) in acetonitrile (175 mL) is heated at reflux for 45 min. The reaction mixture is allowed to reach rt and 3-nitro aniline (18.4 g, 133.3 mmol) is added and stirred at rt for 12 h. The crude product obtained is purified by column chromatography to afford the product as pale yellow solid (1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1I>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: Clc1ccc(Cl)c(I)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)ccc3Cl)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 1,4-dichloro-2-iodobenzene according to the coupling procedure described in example 2. 1H NMR (DMSO-d6): δ 7.85 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.7, 2.4 Hz, 1H), 7.09 (m, 2H), 6.89 (d, J=2.4 Hz, 1H), 6.83 (dd, J=8.5, 2.4 Hz, 1H), 3.29 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.3 Hz, 6H); MS (ESI) m/z [M+H]+ (379/381/383); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.11; H, 5.36; N, 6.84.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=4)(C)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1C2C(=CC(C3OCCNC3)=CC=2)[CH:44]=[N:43]1>>[C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH:19]([C:24]4[CH:25]=[C:26]5[C:27](=[CH:28][CH:29]=4)[N:43]([CH3:44])[N:42]=[CH:41]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2cc(C3CNCCO3)ccc21
Reactant: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(N3CCOC(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-5-yl)morpholino)benzo[d]thiazol-6-yl)acetic acid was prepared using the similar procedure as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid except 2-(1-methyl-1H-indazol-5-yl)morpholine was used instead of 2-(4-chlorophenyl)-2-methylmorpholine. LCMS-ESI+: calc'd for C32H33ClN4O4S: 605.2, 607.2 (M+H+); found: 605.3, 607.3 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.99 (s, 1H), 7.82 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.49-7.56 (m, 5H), 7.32 (s, 1H), 5.13 (s, 1H), 4.72 (d, J=7.2 Hz, 1H), 4.11 (m, 2H), 4.05 (s, 3H), 3.85 (m, 2H), 3.35 (m, 1H), 3.30 (t, J=12 Hz, 1H), 2.50 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.NN.CCCCCC>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: CCCCCC
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cccnc1-2

Procedure:
Following the procedure described in Example 608, Part C, 3.45 g (19 mmole), of 4-azafluoren-9-one, 6.8 g (0.213 mole) of hydrazine in 50 ml of diethyleneglycol were combined and heated to 205° over a 30 -minute period. TLC showed no remaining starting material. Identical workup yielded 2.33 g of pure 4-azafluorene, Rf-0.46 (hexane ethylacetatetriethylamine, 29.75:69.46:0.79).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C1COCC1.CO>[NH2:16][C:12]1[CH:11]=[C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A round-bottom flask containing tert-butyl methyl(3-nitrophenyl)carbamate (19) (8.8 g, 34.9 mmol), 10% palladium on charcoal (880 mg), and THF-MeOH (80 mL/80 mL) was evacuated and flushed with hydrogen three times. The mixture was stirred vigorously overnight under an atmosphere of hydrogen. The catalyst was removed by filtration through a pad of Celite, and the filtrate evaporated to afford tert-butyl 3-aminophenyl(methyl)carbamate (20) 7 g as yellow solid (yield 91%). LC-MS (ESI): m/z (M+1) 223.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]([N:24]=[C:25]=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:26]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: NC1CCN2CCc3ccccc3C2C1
Solvent: c1ccccc1
Product: O=C(NC(=O)c1ccccc1)NC1CCN2CCc3ccccc3C2C1
Yield: 72.4 %

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.260 g) and benzoyl isocyanate (0.213 g, 5% excess) were condensed together in benzene (50 ml) in a manner analogous to that of Example 1 to give the title compound (0.325 g). Crystallization from EtOH/HCl afforded the hydrochloride (0.343 g). m.p. 171.0° C. C21H23N3O2.HCl.2H2O requires C, 59.78; H, 6.69; N, 9.96%, Found: C, 60.06; H, 6.50; N 9.89%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:29][C:30](=[O:35])[C:31](Br)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26].CN(C)C=O>O>[C:25]([O:29][C:30](=[O:35])[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1)([CH3:33])[CH3:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCCCCCC(=O)NCCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)NCCc1ccc(NC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
1H NMR (400 MHz, CDCl3) δ6.94 (d, 2H), 6.61 (d, 2H), 5.35 (s, 1H), 3.57 (s, 2H), 3.43 (m, 2H), 2.66 (t, 3H), 2.07 (t, 2H), 1.55 (m, 3H), 1.24 (m, 5H), 0.84 (t, 3H). A mixture of heptanoic acid [2-(4-amino-phenyl)-ethyl]-amide (1.50 g, 6.04 mmol), cesium carbonate (7.87 g, 24.2 mmol), tert butyl-2-bromoisobutyrate (10.78 g, 48.3 mmol) and dimethylformamide (14.6 mL) was heated at 80° C. for 4 days. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ether (2×). The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column chromatography (2:3 ethyl acetate/hexanes) to provide 1.37 g (58%) of 2-[4-(2-heptanoylamino-ethyl)-phenylamino]-2-methyl-propionic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:31]1([CH:34]=O)[CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO.FC(F)(F)C(O)=O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH2:34][CH:31]2[CH2:33][CH2:32]2)[CH2:11][CH2:10]1
Reactant: O=CC1CC1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCN(CC3CC3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
Mixture of isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg) and cyclopropanecarbaldehyde (1.4 mg) in methanol (0.15 mL) was stirred at room temperature for 0.5 hr, then sodium cyanoborohydride (1.0 M solution in THF, 0.02 mL) was added followed by 1 drop of trifluoroacetic acid. The mixture was stirred at room temperature for overnight and concentrated under vacuum. Then saturated sodium bicarbonate and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear sticky oil (1.4 mg, 41% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33])#[N:21].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[C:23]([C:32]([F:33])([F:34])[F:35])[CH:24]=2)(=[O:30])=[O:29])[C:3]([C:9]([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1C(F)(F)F

Procedure:
Prepared from 40 mg (0.15 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 137 mg (0.51 mmol) of 4-cyano-3-trifluoromethyl-benzenesulfonyl chloride in 0.3 mL pyridine using procedure x. After the sulfonylation was complete, 3 mL methanol, 0.5 mL water and 71 mg sodium hydroxide were used. Yield: 10 mg of a yellow solid. LC-MSD, m/z for C21H12ClF3N5O3S [M+H]+=505.9, 507.9
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1cc(F)c(Br)cc1F
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,4,5-trifluorobenzene (2.2 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (35%).
Reaction SMILES: [NH:1]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:43]([N:45]1[CH2:73][CH2:72][CH2:71][C@H:46]1[C:47]([NH:49][C@H:50]([C:61]([O:63]CC1C=CC=CC=1)=[O:62])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:60])[NH:56][N+]([O-])=O)=[O:48])=[O:44])[CH2:32][C:33](=[O:42])[O:34]CC1C=CC=CC=1)=[O:29])[C@@H:18]([CH3:27])[O:19]CC1C=CC=CC=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[H][H]>C(O)(=O)C.O.CO.[Pd]>[NH:1]([C:74]([O:76][C:77]([CH3:78])([CH3:80])[CH3:79])=[O:75])[C@H:2]([C:14]([NH:16][C@H:17]([C:28]([NH:30][C@H:31]([C:43]([N:45]1[CH2:73][CH2:72][CH2:71][C@H:46]1[C:47]([NH:49][C@H:50]([C:61]([OH:63])=[O:62])[CH2:51][CH2:52][CH2:53][NH:54][C:55](=[NH:56])[NH2:60])=[O:48])=[O:44])[CH2:32][C:33](=[O:34])[OH:42])=[O:29])[C@@H:18]([CH3:27])[OH:19])=[O:15])[CH2:3][C:4](=[O:5])[OH:13]
Reactant: [H][H]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 30 h
Yield: 40 %

Procedure:
BOC-Asp(OBzl)-Thr(Bzl)-Asp(OBzl)-Pro-Arg(NO2)-OBzl, was dissolved in a mixture of acetic acid (500 ml), water (500 ml), and methanol (3-5 liters). Palladium 10% on activated carbon (100-200 g) was added to the solution and hydrogen gas passed through the mixture for 20-40 hours. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was triturated with ether (3-4 liters), and the resulting solid filtered to produce BOC-Asp-Thr-Asp-Pro-Arg. The yield was about 40-60%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=O)=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@@H:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[OH:61])=[CH:56][CH:55]=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([C@H:60]([OH:61])[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=5)=[CH:56][CH:55]=4)=[O:29])=[CH:20][C:19]=3[CH:30]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc([C@H](O)c2ccccn2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg) and 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, a solution of (S)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.28 ml) in DMF (10 ml) were added dropwise. The mixture was stirred for 4 days at room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 75) (247 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][C:12]([CH3:18])([CH:15]([CH3:17])[OH:16])[CH2:11][O:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].O>C1C=CC=CC=1>[C:26]([O:16][CH:15]([CH3:17])[C:12]1([CH3:18])[CH2:11][O:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=2)[O:14][CH2:13]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(O)C1(C)COC(c2ccc(N(C)C)cc2)OC1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)OC(C)C1(C)COC(c2ccc(N(C)C)cc2)OC1

Procedure:
2-[4-(Dimethylamino)phenyl]-α,5-dimethyl-1,3-dioxan-5-methanol (195 mg), dry pyridine (2.0 ml), and acetyl chloride (1.0 ml), in benzene (10 ml) were refluxed for 3 hrs. The cooled mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), and evaporated. The residue was purified by preparative layer chromatography on silica gel (eluting with benzeneethyl acetate 5:1) and distilled to give an oil, b.p. 155°-160°/0.05 torr.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.C[O-].[Na+]>CO.O1CCOCC1>[NH:31]1[CH2:32][CH2:33][CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:41])([F:1])[F:42])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.965 g, 1.65 mmol) was dissolved in methanol (1.0 mL). To the solution was added 4 N HCl in dioxane (1.5 mL). The mixture was stirred at r.t. for 2 h. The mixture was cooled with ice-water, and was carefully neutralized with sodium methoxide in methanol solution (25% w/w, about 4.375 M, 1.38 mL) to pH about 8. The volatiles were removed under reduced pressure. The residue was dried in vacuo to afford the desired product which contained residual NaCl, and was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=485.2.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].[OH-:18].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:6]=1[C:7]([NH2:8])=[O:18]
Reactant: [OH-]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Temperature: 80 °C

Procedure:
A suspension of 0.26 g (1.139 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carbonitrile in 5 cm3 of concentrated sulphuric acid is heated at a temperature in the region of 80° C. for 1 hour. After having cooled the reaction mixture to a temperature in the region of 20° C., it is poured over crushed ice and then a 5N aqueous sodium hydroxide solution is slowly added to a basic pH in the region of 10. The reaction mixture is extracted with 7 times 10 cm3 of a dichloromethane/MeOH mixture (98/2 by volume). All the organic phases are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.19 g of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide, in the form of a red-brown solid; EI: m/z=246 (M+) base peak, m/z=229 (M−NH3+).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]=[CH:9][CH:8](O[Si](C(C)(C)C)(C)C)[O:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)=O.CC(C)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([O:4][CH:5]1[CH:10]=[CH:9][CH2:8][O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)OC1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OC1C=CCOC1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
6-(tert-Butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-yl acetate (13.6 g, 49.9 mmol) was dissolved in DCM (250 mL), placed under a nitrogen atmosphere, and cooled to −30° C. (dry ice/acetone, until temperature was reached). Triethylsilane (15.95 mL, 100 mmol) was then added slowly via syringe, followed by drop wise addition of boron trifluoride etherate (7.59 mL, 59.9 mmol). The reaction was kept under nitrogen and slowly allowed to warm. After 1 h, the reaction mixture was quenched by additions of saturated sodium bicarbonate. After transferring to a separatory funnel, the organic layer was washed with water and brine, dried over sodium sulfate, filtered and condensed. The crude material was purified on a 340G SNAP Biotage column (0-80% ethyl acetate in hexane). Evaporation of clean fractions gave 3,6-dihydro-2H-pyran-3-yl acetate (5.5 g, 38.7 mmol, 77% yield) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ ppm 5.09 (dtt, J=5.73, 2.21, 2.21, 1.17, 1.17 Hz, 1H), 4.19-4.28 (m, 1H), 4.04-4.15 (m, 1H), 3.89-3.98 (m, 1H), 3.76-3.84 (m, 1H), 2.10 (s, 3H).