Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl.O1CCOCC1>O1CCOCC1>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
The compound Boc-L-Ile-D-Pro-OBzl (967 mg, 2.31 mmol) obtained in step 12-3 was dissolved in dioxane (12 ml) and 4N HCl/dioxane (12 ml) was added and the mixture was allowed to stand at room temperature for 1.5 hours. The reaction mixture was concentrated and diethyl ether/petroleum ether (1/3) was added to the residue followed by decantation to yield H-L-Ile-D-Pro-OBzl (745 mg, 91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCOCC1.ClCCl>[CH2:14]([O:21][C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Aminomethyl)benzoic acid 15.1 g (100 mmol) was dissolved in 200 mL dioxane and 100 mL 1.000 N NaOH and cooled in a 0° C. ice bath. The mixture was treated dropwise with benzylchloroformate 14.3 mL (100 mmol) followed by the dropwise addition of 100 mL of 1.000 N NaOH. The mixture was stirred at room temperature for 18 hours. The mixture was neutralized by adding 100 mL of 1.000 N HCl followed by dilution with dichloromethane. A white solid precipitated out which was filtered. The solid was dried in vacuo to afford 10.8 g (38.9%). 1H NMR (300 MHz, DMSO-d6): δ 4.24 (d, 2H, J=6.2 Hz); 5.01 (s, 2H); 7.31-7.34 (m, 7H); 7.84-7.88 (m, 3H); 12.85 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1.[C:35](Cl)([CH3:37])=[O:36]>C(Cl)Cl>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([N:7]3[CH2:6][CH:5]([CH2:4][CH2:3][CH:2]([NH:1][C:35](=[O:36])[CH3:37])[CH2:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[N:26]=[CH:25][CH:24]=4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(=O)Cl
Reactant: COc1ccc2nccc(CCC(N)CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Solvent: ClCCl
Product: COc1ccc2nccc(CCC(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)NC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of the compound of Example 116 (0.05 g, 0.1 mmol) in DCM (1 mL) at rt was treated sequentially with TEA (0.03 mL, 2 eq.) and AcCl (1.5 eq.). The mixture was stirred at rt for 1 h, washed with water (2 mL) and purified by FC (EA, EA/MeOH 9:1) to give the title compound as a colourless foam (0.048 g, 88% yield).
Reaction SMILES: C1(C)C=CC(S(N2C3=NC=CC=C3C(C3C=C(N)SC=3)=C2)(=O)=O)=CC=1.COC1C=C(CC(O)=O)C=CC=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([NH:49][C:50]2[S:51][CH:52]=[C:53]([C:55]3[C:63]4[C:58](=[N:59][CH:60]=[CH:61][CH:62]=4)[N:57](S(C4C=CC(C)=CC=4)(=O)=O)[CH:56]=3)[CH:54]=2)=[O:48])[CH:43]=[CH:44][CH:45]=1.O[Li].O>C1COCC1.O.CCOC(C)=O>[NH:57]1[C:58]2=[N:59][CH:60]=[CH:61][CH:62]=[C:63]2[C:55]([C:53]2[CH:54]=[C:50]([NH:49][C:47](=[O:48])[CH2:46][C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[CH:41]=3)[S:51][CH:52]=2)=[CH:56]1
Reactant: COc1cccc(CC(=O)Nc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncccc34)cs2)c1
Agent: COc1cccc(CC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3csc(N)c3)c3cccnc32)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CC(=O)Nc2cc(-c3c[nH]c4ncccc34)cs2)c1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
4-[1-(Toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-thiophen-2-ylamine was coupled to 3-methoxyphenylacetic acid according to General Method B and the product 2-(3-methoxyphenyl)-N-(4-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl)acetamide (70 mg, 0.14 mmol) was dissolved in 6 mL THF and LiOH hydrate (63 mg, 1.5 mmol) was added in 1 mL of water. The reaction mixture was heated to 150° C. by microwave irradiation for 15 minutes and then diluted with EtOAc and water and the organic layer dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (40 to 100% EtOAc/hexanes to give 20 mg of a light brown solid, 0.055 mmol, 39%. 1H NMR 500 MHz (DMSO-d6) 11.80 (1H, s), 11.37 (1H, s) 8.28 (2H, m), 7.78 (1H, s), 7.25 (1H, t), 7.16 (2H, m), 7.07 (1H, s) 6.88 (2H, m), 6.82 (1H, m), 3.78 (3H, s), 3.69 (2H, s). MH+ 364.20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[O:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2[C:15]1=[O:24])=[O:5])[CH3:2].[OH2:46].NN>C(O)C>[C:38]([O:46][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[O:28][CH2:27]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:24])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 183.4 %

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.55 g), hydrazine hydrate (0.22 g) and ethanol (10 ml) is allowed to stand overnight at room temperature. After evaporation of ethanol, the residue is dissolved in water (50 ml) and extracted with ethyl acetate (50 ml×4). Water (50 ml) and sodium bicarbonate (0.6 g) are added to the organic extract, and to the resulting mixture is added dropwise di-tert-butyl dicarbonate (0.29 g) with stirring. After stirring for 30 minutes at room temperature, the ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane:ethyl acetate (2:1-1:1) as an eluent to give tert-butyl 3(S)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.48 g) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO.O.C(O)(=O)C>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:32])=[O:3])[CH:21]=1
Reactant: CCOC(=O)c1cncc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)c1
Yield: 88.6 %

Procedure:
5-{2-[5-Chloro-2-(4-chlorobenzyloxy)-phenyl]-cyclopent-1-enyl}-nicotinic acid ethyl ester (90 mg) was hydrolysed in methanol (3 mL) and 2N sodium hydroxide (2 mL) at 60° C. with stirring for 2 hrs. The reaction mixture was then reduced down to ˜1 mL, diluted with water (10 mL) and treated with a few drops of glacial acetic acid to make the solution ˜pH5. The product was then extracted twice with dichloromethane (10 mL) dried (magnesium sulphate), and evaporated to give the title compound (75 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])[CH2:38][CH3:39]>>[OH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][N:40]([CH2:37][CH2:38][CH3:39])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:35]
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCc1ccccc1O
Agent: Cl
Product: CCCN(Cc1ccccc1O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-((propylamino)methyl)phenol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-5-nitropyrimidine (0.53 g, 2.75 mmol) in THF (2 mL) was added a solution of anthranilic acid (0.37 g, 2.50 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) in THF (2.0 mL). The reaction was stirred for 2.0 hours. The reaction was then poured onto ice and allowed to warm to room temperature then was filtered. The isolated solid was dried under vacuum, then recrystallized from hot ethyl acetate and cold hexane to give 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzoic acid (307 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6/D2O): δ 9.20 (s, 1H), 8.36 (d, 1H), 8.07 (d, 1 H), 7.70 (t, 1 H), 7.37 (t, 1 H). MS m/z 294 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH:17]=[CH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1cccc(C=CCC2SCC(=O)N2CCC2(O)CCCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c1

Procedure:
3-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propenyl}benzoic acid (7.8 g., 0.02 mole) in ethanol (125 ml.) is hydrogenated over 2.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and 27° C. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: N[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].C1CCN2C(=NCCC2)CC1>O>[NH:13]1[C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]([NH2:5])=[N:14][S:10]1(=[O:12])=[O:11]
Reactant: N#Cc1cccnc1N
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=NS(=O)(=O)Nc2ncccc21
Temperature: 160 °C

Procedure:
A stirred mixture of 2-aminonicotinonitrile (238 mg, 2.0 mmol), sulfamide (192 mg, 2.0 mmol), and 1 mL of DBU was heated at 160° C. under nitrogen overnight. After it was cooled down to room temperature, the reaction mixture was diluted with water, and extracted three times with EtOAc. The aqueous layer was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.87 (t, J=5.6 Hz, 1H), 7.95 (brs, 2H), 8.22 (d, J=5.2 Hz, 1H), 8.39-8.37 (m, 1H), 12.58 (brs, 1H). MS 199 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C:12](=O)[CH:11]=[CH:10][N:9]=[C:8]1[CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:14])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCCOC1C(=O)C=CN=C1C
Product: COCCCOc1c(Cl)ccnc1C
Yield: 34 %

Procedure:
A solution of 3-(3-methoxy-1-propoxy)-2-methyl-4-pyridone (0.32 g, 1.6 mmol) in 50 ml POCl3 was refluxed for 14 h. The POCl3 was evaporated off and the residue was partitioned between methylene chloride and water. The aqueous layer was separated, treated with K2CO3 until pH=10 and extracted with methylene chloride. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/methylene chloride (3:97) as eluent. Evaporation off the solvent afforded 0.12 g (34%) product as a red oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.O1CCCC1.[C].[Pd]>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[N:33][CH:34]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a solution of 4-tert-butyl-N-{5-(4-methylphenyl)-6-{2-(5-nitropyridin-2-yloxy)ethoxy}pyrimidin-4-yl}benzenesulfonamide (975 mg) in isopropanol/tetrahydrofuran (1:1) (20 ml) is added 10% palladium-carbon (200 mg), and the mixture is stirred at room temperature for 1.5 hour under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=2:1), and recrystallized from ethyl acetate/n-hexane to give N-{6-{2-(5-aminopyridin-2-yl-oxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (829 mg) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:26][CH3:27])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:26]([N:13]([C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]([CH2:22][CH2:23][O:24][CH3:25])[CH3:21])[CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:27]
Reactant: C#CCN1CCOCC1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 105 °C

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:31])[C:18]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)([OH:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:3]=1
Reactant: Cc1ccnc(C=O)c1
Reactant: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1ccnc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)c1

Procedure:
75 Milligrams of 4-methyl-2-pyridinecarbaldehyde, 58.3 mg of N-(piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide and 12 mg of acetic acid were dissolved in 10 ml of dichloroethane. To the solution 68 mg of sodium triacetoxyborohydride was added at room temperature, followed by an hour's stirring at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254Art 5744 (Merck), chloroform/methanol=9/1] to give 49.5 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]([CH2:8][CH2:9]O)#[N:7].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CN(C)C1C=CN=CC=1>[C:1]([O:5][CH2:9][CH2:8][C:6]#[N:7])(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: N#CCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)OCCC#N
Temperature: -20 °C
Reaction time: 8 h

Procedure:
2.71 mg (44 mmol) of propiolic acid and 2.73 ml (40 mmol) of 2-cyanoethanol were dissolved in 20 ml of dry ether. The obtained solution was cooled to −20° C. 100 ml of a solution of 9.27 g (45 mmol) of dicyclohexylcarbodiimide and 0.36 g (30 mmol) of 4-dimethylaminopyridine in dry ether was dropped into the solution. The temperature of the obtained mixture was elevated to room temperature. After stirring overnight, the insoluble matter was filtered out. The filtrate was washed with 2 N hydrochloric acid and saturated aqueous salt solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:20])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(CCCCl)N1CCc2ccccc21
Agent: Cl
Product: O=C(CCCN1CCN(c2ccccc2Cl)CC1)N1CCc2ccccc21

Procedure:
from 1-(2-chlorophenyl)piperazine, hydrochloride and 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one. Mp 119–121° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.35–2.50 (m, 4H); 2.55 (s, 4H); 3.95 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H); 7.15 (t, 1H); 7.20 (d, 1H); 7.25 (t, 1H); 7.40 (d, 1H); 8.10 (d, 1H). MS m/z: 384 (MH+), 265, 188.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35])([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=1[N+:27]([O-:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-])C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 42 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2-nitrocinnamic acid under the conditions described in example 86 to yield 42% of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
Pd(OAc)2 (0.031 g, 0.136 mmol) was added to a solution of 5-methoxy-1H-indole (0.2 g, 1.359 m mol) and phenylboronic acid (0.249 g, 2.038 mmol) in acetic acid (2 mL) followed by copper (II) acetate (0.025 g, 0.138 mmol), and the mixture was stirred at 25° C. for 2 h under oxygen atmosphere. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 10% ethyl acetate in hexane to afford title compound (0.08 g, 24%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.3 (s, 1H), 7.82 (d, J=7.2 Hz, 2H), 7.44 (t, J=7.2 Hz, 2H), 7.32-7.26 (m, 2H), 7.02 (d, J=2.4 Hz 1H), 6.81 (d, J=1.2 Hz, 1H), 6.74 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H) 3.78 (s, 3H).
Reaction SMILES: [I-].[Na+].[CH3:3][C:4](=[CH2:18])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=O)=[N:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([CH3:3])=[CH2:18])[N:7]=1)=[O:17]
Reactant: C=C(C)Cn1nc(C(=O)O)c2ccccc21
Reactant: Nc1nccs1
Agent: [I-]
Agent: [Na+]
Product: C=C(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 23.2 %

Procedure:
1-(2-Methylallyl)-indazole-3-carboxylic acid (440 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-chloro-2-methylpropene (0.28 mL, 2.84 mmol, with a catalytic amount of sodium iodide) following the general procedures G and E. 1-(2-Methylallyl)-indazole-3-carboxylic acid thiazol-2-ylamide (45 mg) was prepared from 1-(2-methylallyl)-indazole-3-carboxylic acid (140 mg, 0.65 mmol) and 2-aminothiazole (65 mg, 0.65 mmol) following the general procedure H.