Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:13]=2)=[CH:9][CH:8]=1.C(O)(=O)C.O.C(OCC)(=O)C>CC(C)=O>[CH:2]([C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[N:13]=2)=[CH:9][CH:8]=1)=[O:1]
Reactant: c1ccc2c(c1)c(-c1ccc(C3OCCCO3)o1)nn2Cc1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1ccc(-c2nn(Cc3ccncc3)c3ccccc23)o1
Reaction time: 1 h

Procedure:
1 g (2.77 mmol) of 3-(5-(1,3-dioxan-2-yl)furan-2-yl)-1-(4-picolyl)indazole is dissolved in 10 ml of acetone, and 20 ml of 50 per cent strength acetic acid are added. The mixture is boiled for 1 hour, introduced into water and extracted with ethyl acetate and the organic phase is dried with sodium sulphate and evaporated in vacuo to give 0.8 g (95.3% of theory) of an oil. Rf (SiO2, ethyl acetate): 0.25
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[NH:38][CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4.C(N(CC)CC)C>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[N:38]([C:16]([C:12]4[CH:11]=[C:10]5[C:15](=[CH:14][CH:13]=4)[NH:7][CH:8]=[CH:9]5)=[O:18])[CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)c1ccc2[nH]ccc2c1)CC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 27 %

Procedure:
Oxalyl chloride (15 ul, 0.14 mmol) at RT was added to a solution of indole-5-carboxylic acid (0.02 g, 0.12 mmol) in THF (1 ml). After stirring at RT for 10 h, the mixture was added THF (1 ml) followed by (+)-3-methoxy-morphinan hydrochloride (0.04 g, 0.12 mmol), then triethylamine (0.1 ml, 0.7 mmol) was added and stirred for 18 h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was washed with saturated Na2CO3 (5 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude pale brown oil. The crude product was purified by column chromatographed eluting with (MeOH:CH2Cl2=1:10) to give a pale yellow oil (0.013 g, 28% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])=[N:9]S(C(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.I[C:26]1[CH:27]=[C:28]([C:34]([F:37])([F:36])[F:35])[C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[C:28]([C:34]([F:37])([F:36])[F:35])[CH:27]=3)[C:16]3[C:17](=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=3)[C:23]([NH2:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(I)cc1C(F)(F)F
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Product: COc1ncc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C(F)(F)F
Yield: 71 %

Procedure:
The title compound was synthesized as described for Example 14i in 71% yield, starting from N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (815 mg, 2 mmol) and 5-iodo-2-methoxy-3-(trifluoromethyl)pyridine (606 mg, 2 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([O:7][CH3:8])=[O:6].C(O)[CH2:30][CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([O:7][CH2:8][CH2:30][CH2:31][OH:32])=[O:6]
Reactant: OCCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1F

Procedure:
A mixture of 2.25 g of methyl 3-fluoro-4-(hexadecylamino)benzoate, 280 mg of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 3-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: C[N:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2)[C:3](=O)C.[N+:16]([O-])([O-:18])=[O:17].[K+].O.[OH-].[Na+]>C(Cl)Cl.S(=O)(=O)(O)O>[CH3:3][NH:2][C:6]1[C:7]([N+:16]([O-:18])=[O:17])=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[N:9]2
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N(C)c1ccc2nccnc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNc1ccc2nccnc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 34.3 %

Procedure:
To a solution of N-methyl-N-(quinoxalin-6-yl)acetamide (4.02 g, 0.02 mol) in DCM (60 mL) was added a solution of potassium nitrate (4.02 g, 0.04 mol) in sulfuric acid (10 mL) cooled to 0° C. The mixture was then warmed and stirred at room temperature for 4 h. Water (20 mL) was added. The mixture was adjusted to pH ˜9 with saturated NaOH aqueous solution. Then the mixture was extracted with EtOAc (5×150 mL). The extracts were dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give N-methyl-5-nitroquinoxaline-6-amine as a yellow solid (1.4 g, yield 35%). ESI MS: m/z 205.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=1.6 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.67 (brs, 1H), 7.41 (d, J=9.2 Hz, 1H), 3.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv), and piperidine (78 mg). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane and the resulting mixture was washed with saturated aqueous ammonium chloride, water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (20/1) gave 28.5 mg (17%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+, 1H-NMR (300 MHz, CDCl3, ppm): δ 8.54 (s, 1H); δ7.68 (d, 2H); δ7.20 (d, 2H); δ7.16 (d, 2H); δ6.95 (m, 1H); δ6.55 (d, 1H); δ5.52 (s, 2H); δ6.98 (m, 1H); δ4.76 (m, 1H); δ4.34 (m, 1H); δ3.82 (m, 1H); δ3.23 (m, 1H); δ2.01˜δ2.42 (m, 4H); δ1.88 (m, 1H); δ0.85˜δ1.21 (m, 4H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.[CH3:21][C:22](=NO)[C:23](=O)C.C1C2C(=CC=CC=2)C=CC=1C=O>>[CH3:8][C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[CH:21][CH:22]=[CH:23][CH:20]=3)[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1]
Reactant: CC(=O)C(C)=NO
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: O=Cc1ccc2ccccc2c1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, butane-2,3-dione-2-oxime and naphthalene-2-carbaldehyde gave 5-methyl-4-iodomethyl-2-naphthalen-2-yloxazole.
Reaction SMILES: [C-:1]#[N:2].[Na+].BrBr.[CH:6]([N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][S:10]1(=[O:21])=[O:20])([CH3:8])[CH3:7].[OH-].[Na+]>O>[C:1]([N:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([CH:6]([CH3:8])[CH3:7])[S:10]1(=[O:20])=[O:21])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)N1C(=O)c2ccccc2N(C#N)S1(=O)=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
5.4 parts of sodium cyanide in 40 parts of water are added dropwise to 17.6 parts of bromine in 150 parts of water at from 5° to 10° C. A solution of 24 parts of 3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide and 4 parts of sodium hydroxide in 100 parts of water is then added and the mixture is stirred for 2 hours at 50° C. When it has cooled, the precipitate is filtered off and dried. 25 parts of 1-cyano-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide of melting point 99°-101° C. are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][CH:14]([CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:15]>>[CH3:13][CH:14]([CH2:16][CH:17]([NH:21][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:11])[CH2:18][CH2:19][CH3:20])[CH3:15]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCCC(N)CC(C)C
Product: CCCC(CC(C)C)NC(=O)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and 2-methylheptan-4-amine (example 2a). 1H NMR (500 MHz, CDCl3): δ 0.93 (m, 9H); 1.38 (m, 5H); 1.53 (m, 1H); 1.66 (m, 1H); 4.21 (m, 1H); 5.61 (d, 1H); 6.01 (s, 2H); 6.82 (d, 1H); 7.26 (m, 2H). MS (278, M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4]1.Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:3]2[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]2)[CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2cccnc2)n1
Temperature: 50 °C
Yield: 62 %

Procedure:
NaH (0.9 g., 60% suspension in liquid paraffin) is dissolved in DMF (10 ml) and 2-(1H-pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added at 0° C. To this solution is added 3-chloromethyl-pyridine (10.1 mmol) and the mixture is heated to 50° C. for 16 hours. The solvent is removed in vacuo. The residue is dissolved in ethanol (100 ml) and hydrazinium-hydroxide (30 ml) is added and the reaction is heated to 120° C. for 9 days. The solvent is removed in vacuo. 1-Pyridine-3-ylmethyl-1H-pyrazole-3-ylamine is obtained after column chromatography as colorless oil in a yield of 62%; LC-MS (method B): 0.39 min, 175.15 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccnn1Cc1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nccc2CO)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To ethyl 1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate (1.81 g, 6.95 mmol) in THF (20 mL) at 0° C. was added lithium aluminum hydride (0.317 g, 8.34 mmol). The cold bath was removed. The reaction mixture was stirred for 5 hours, diluted with Et2O (50 mL) and Celite (5 g) was added to the reaction mixture. The mixture was cooled to 0° C. and sodium sulfate decahydrate was cautiously added to quench the reaction. The mixture was filtered and washed with EtOAc (100 mL). The solution was concentrated under reduced pressure to give the product (1.36 g).
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:17][CH:18]3[CH:25]4[CH2:26][C:21]5([OH:28])[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[N:4]=1.[CH2:31]([NH2:33])[CH3:32].CO.C(OCC)(=O)C.O1CCCC1>CN1CCCC1=O.O>[CH2:31]([NH:33][C:3]1[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:17][CH:18]3[CH:19]4[CH2:20][C:21]5([OH:28])[CH2:22][CH:23]([CH2:24][CH:25]3[CH2:26]5)[CH2:27]4)=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[N:4]=1)[CH3:32]
Reactant: CCN
Reactant: OC12CC3CC(C1)C(Nc1c(-c4noc(C(Cl)(Cl)Cl)n4)cnc4[nH]ccc14)C(C3)C2
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1nc(-c2cnc3[nH]ccc3c2NC2C3CC4CC2CC(O)(C4)C3)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-({5-[5-(trichloromethyl)-1,2,4-oxadiazole-3-yl]-1H-pyrrolo[2,3-b]pyridine-4-yl}amino) adamantan-1-ol (80 mg) in 1-methyl-2-pyrrolidinone (1.6 ml) was added ethylamine/methanol solution (2.0M) (1.7 ml) under ice cooling. The reaction solution was stirred for 5 hours under ambient temperature. To the reaction solution were added ethyl acetate, tetrahydrofuran, and water. The mixture was extracted with a mixture solvent of tetrahydrofuran and ethyl acetate, and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel (NH silica gel) column chromatography (chloroform:methanol=100:0 to 91:9) to obtain 4-({5-[5-(ethylamino)-1,2,4-oxadiazole-3-yl]-1H -pyrrolo[2,3-b]pyridine-4-yl}amino)adamantan-1-ol (50 mg) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[CH3:13][NH2:14]>CO.C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:14][CH3:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0° C. was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5° C. The resulting mixture was stored at 3° C. for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:28](=O)[CH2:27][CH2:26][C@H:25]1[C:30]([OH:32])=O>CN(C)C=O>[NH:24]1[C:28]2[C:27](=[CH:3][CH:2]=[CH:8][CH:7]=2)[CH:26]=[C:25]1[C:30]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:32]
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Cc2ccccc21
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Cc2ccccc21

Procedure:
In 20 ml of dimethylformamide are dissolved 1.00 g of trans-3-amino-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide as obtained in (ii) of Example 30 and 0.42 g of L-pyroglutamic acid, and the same reaction and treatment as in Example 3 is carried out to give A isomer (0.41 g) and B isomer (0.42 g) of trans-2-oxo-3-[5-oxo-2(S)-pyrrolidinecarboxamido]-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C([O-])(=O)C.[K+]>O.C(O)C.COCCOC>[CH2:16]([O:15][C:13]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCN
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
A solution of 46 g of methane sulfonic acid in 50 ml of water was added without exceeding 30° C. to a mixture of 23 g of 1,4-diamino butane and 50 ml of water and the reaction medium was diluted with 140 ml of ethanol. A solution of 39 g of benzyl chloroformate in 50 ml of 1,2-dimethoxy ethane and 100 ml of a 50% aqueous solution of potassium acetate were added alternately at pH 3.5 to 5.0. The additions were made alternately to maintain the pH value between 3.5 and 5.0. The mixture was stirred for 90 minutes at 20° to 25° C. and evaporated under reduced pressure. The residue was poured over 500 ml of water and the insoluble part was filtered off. The filtrate was washed 3 times with 150 ml of benzene, and then 100 ml of 30% sodium hydroxide saturated with sodium chloride were added. After extraction with benzene, the extracts were evaporated to dryness under reduced pressure to obtain 19.10 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccc(O)cc1

Procedure:
Prepared from 2-(2-aminophenyl) indole and 4-hydroxybenzoic acid in 35% overall yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 95.6% Purity by LC/MS (230 DAD) Mass-spec (M+H+)=329.8 1H NMR (MeOH-d4): 6.65 s (1H), 6.83 m (2H), 7.01 t, 7 Hz (1H), 7.12 td, 7.1 Hz (1H), 7.34 td, 7.1 Hz (1H), 7.39–7.43 m (2H), 7.51 d, 7 Hz (1H), 7.66 dd, 8.1 Hz (1H), 7.76 m (2H), 7.91 dd, 8.1 Hz (1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:26]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(NC(=N)c2ccc(C)cc2)c1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of 1.1 g (4.0 mmol) of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 5 to 40% ethyl acetate in hexanes gradient then 40% ethyl acetate in hexanes) gave the title compound as a yellow oil. LC/MS 351.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[OH-].[K+].[I:14]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([I:14])=[N:5][NH:6]2
Reactant: II
Reactant: Fc1cc(F)c2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1cc(F)c2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
To a solution of 4,6-difluoro-1H-indazole (1.16 g, 7.53 mmol) in DMF (60 ml) at room temperature was added potassium hydroxide (1.27 g, 22.6 mmol) and iodine (2.87 g, 11.3 mmol). The maroon reaction mixture was stirred at room temperature for 2 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 2.18 g of 4,6-difluoro-3-iodo-1H-indazole as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.O.[BrH:14]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:14])=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: O
Product: FC(F)(F)c1ccc(CBr)cc1

Procedure:
A mixture of 5.5 g of p-trifluoromethyl-benzyl alcohol in 50 mL of 48% HBr was heated on a steam-bath for 6 h with stirring, and cooled. Water (100 mL) was added to the above mixture, and the aqueous layer was extracted with ether, and the organic layer was concentrated in vacuo to afford 4.8 g of p-trifluoromethyl-benzyl bromide.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34](O)=[O:35])[CH:28]=[CH:27]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+].Cl.S1C(N)=NC=N1>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][C:34]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH2:3][C@@H:2]1[CH3:1])=[O:35])[CH:28]=[CH:27]2
Reactant: O=C(O)Cn1ccc2cc(F)ccc21
Reactant: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CCN1C(=O)Cn1ccc2cc(F)ccc21
Yield: 52.7 %

Procedure:
Synthesized according to general procedure 9, method B. The reaction was set up with (S)-4-(3-methylpiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (250 mg, 0.74 mmol), 2-(5-fluoro-1H-indol-1-yl)acetic acid (143 mg, 0.74 mmol), HATU reagent (281 mg, 0.74 mmol), sodium bicarbonate (93 mg, 1.11 mmol), and DMF/CH2Cl2-1/1 (4.0 mL) to obtain the desired amide as a white solid (200 mg, 0.39 mmol, 53% yield). 1H NMR (400 MHz, DMSO-d6) 6 (mixture of rotamers) 7.63-7.59 (m, 2H), 7.35 (s, 1H), 7.30 (dd, J=2.5, 9.9 Hz, 2H), 7.21 (d, J=4.6 Hz, 1H), 7.00 (s, 1H), 6.95 (td, J=9.2, 3.9 Hz, 2H), 6.76 (d, J=4.5 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 5.41-5.04 (m, 2H), 4.52 (s, 1/2H), 4.38 (s, 1/2H), 4.21-4.05 (m, 1/2H), 3.93-3.82 (m, 1/2H), 3.81-3.48 (m, 3H), 1.33 (s, 1.5H), 1.14 (s, 1.5H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=514.5; tR=3.07 min.
Reaction SMILES: C(O)[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)C(O[CH:36]6[C@H:41](O)[C@@H:40](O)[CH:39]([CH:44]7[C@H:49](O)[C@@H:48](O)[CH:47]([O:52][C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]9[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]9CO)O[C@@H]8CO)[O:46][C@@H]7CO)O[C@@H:37]6[CH2:77]O)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO>C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>[CH3:77][CH2:37]/[CH:36]=[CH:41]\[CH2:40]/[CH:39]=[CH:44]\[CH2:49]/[CH:48]=[CH:47]\[CH2:77]/[CH:37]=[CH:36]\[CH2:41]/[CH:40]=[CH:39]\[CH2:44][CH2:49][CH2:48][C:47]([OH:46])=[O:52]
Reactant: OC[C@H]1OC2C3[C@@H](CO)OC(O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]9[C@H](O)[C@@H](O)C(OC1[C@H](O)[C@H]2O)O[C@@H]9CO)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)[C@H](O)[C@H]3O
Agent: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
Four parts of gamma-cyclodextrin powder was dissolved in 100 parts of an aqueous maltose solution, maltose content of 96.5%, d.s.b., moisture content of 18%, and the solution was mixed with 4 parts of eicosapentaenoic triglyceride and a beta-maltose hydrate seed. The mixture was crystallized, solidified, aged, pulverized and dehydrated by the method in Example 3.