Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCO)O2
Yield: 74.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 507 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.03 mmol), 356 mg CDI (2.20 mmol) and 196 mg 4-aminobutanol (2.20 mmol) produced 488 mg of 6-hydroxy-N-(4-hydroxybutyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:15]1)(=[O:3])[NH2:2].[ClH:32].O1CCOCC1>O1CCOCC1>[ClH:32].[NH2:24][CH2:23][CH2:22][O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=3)[CH:10]=[N:9][CH:8]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCOCC1CCCN(c2cncc3ccc(C(N)=O)cc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCCOCC1CCCN(c2cncc3ccc(C(N)=O)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Tert-butyl (2-{[1-(6-carbamoylisoquinolin-4-yl)piperidin-3-yl]methoxy}ethyl)carbamate (158 mg, 0.368 mmol) produced in Example 21 was dissolved in dioxane (5 mL), to which a 4M hydrochloric acid/dioxane solution (2 mL) was added, followed by stirring overnight at room temperature. Upon completion of the reaction, the solvent was distilled off under reduced pressure to give the desired title compound (148 mg, yield 100%).
Reaction SMILES: OC1C(O)CCN(C(C)[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[C:26]([O:29][CH2:30][C:31]3[C:35]5[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=5[O:33][CH:32]=3)[CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:13][CH2:12]2)C1.[CH2:42]1[CH:47]2C(CO)[CH2:49][CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1>>[CH2:42]1[C@@H:47]2[C@H:49]([CH2:10][N:11]3[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]4[NH:21][C:22]5[C:27]([CH:28]=4)=[C:26]([O:29][CH2:30][C:31]4[C:35]6[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=6[O:33][CH:32]=4)[CH:25]=[CH:24][CH:23]=5)=[O:19])[CH2:15][CH2:16]3)[CH2:50][CH2:51][N:46]2[CH2:45][CH2:44][O:43]1
Reactant: CC(CN1CCC(NC(=O)c2cc3c(OCc4coc5ccc(Cl)cc45)cccc3[nH]2)CC1)N1CCC(O)C(O)C1
Reactant: OCC1CCCN2CCOCC12
Product: O=C(NC1CCN(C[C@@H]2CCN3CCOC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from the compound 176 (see example 138) and (9RS,9aSR)-1-(octahydro-pyrido[2,1-c][1,4]oxazin-9-yl)-methanol (67) analogously to the method described in example 127.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O.Cl>[C:5]1([NH:15][NH2:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium nitrite (4.8 g) in water (20 ml) was added over 15 minutes to a stirred ice-cold suspension of 1-naphthylamine (9.58 g) in 6M hydrochloric acid (80 ml). After an additional 30 minutes in the ice bath, stannous chloride (44.5 g) in 6M hydrochloric acid (80 ml) was added slowly and the resulting suspension was stirred at 0° for 3 hr. The resulting solid was filtered off and dissolved in a mixture of 40% potassium hydroxide solution (100 ml) and ethyl acetate (150 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried and concentrated under reduced pressure to afford the title compound as a purple solid (10.58 g Rf =0.1 in EA/CH (1/4)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([S-])(=[S:17])OCC.[K+]>N1C=CC=CC=1>[S:17]=[C:13]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C

Procedure:
Methyl 3-amino-4-hydroxybenzoate (5.09 g, 30.4 mmol) and potassium O-ethyl carbonodithioate (6.35 g, 39.6 mmol) were combined in pyridine (50 mL) and heated to reflux for two hours. The reaction mixture was cooled to ambient temperature. The mixture was filtered, washed with a 1 N aqueous hydrochloric acid solution, and dried on a vacuum filter overnight to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.63 (d, J=8.48 Hz, 1 H) 7.69 (d, J=1.70 Hz, 1 H) 7.89 (dd, J=8.82, 1.70 Hz, 1 H); MS (ESI−) m/z 207.87 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].[OH2:29].N.[OH2:31]>C(O)(=O)C>[Cl:11][C:7]1[CH:8]=[CH:9][C:10]([N:2]([CH3:1])[C:3](=[O:29])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[C:5]([C:4](=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: O
Reactant: Cn1c(NC(=O)OCc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc21
Agent: N
Solvent: CC(=O)O
Product: CN(C(=O)NC(=O)OCc1ccccc1)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a suspension of 1.0 g of benzyl 1-methyl-3-phenyl-5-chloroindole-2-carbamate in 10 ml of acetic acid, a solution of 1.0 g of chromic anhydride in 1 ml of water was added dropwise with stirring below 25° C. The resulting mixture was stirred at room temperature for 6 hours, and then 25 ml of water was added to the reaction mixture. The resulting reaction mixture was neutralized with concentrated ammonia water and extracted with ether. The extracted ether layer was washed with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure to give 0.94 g of oily benzyl 4-(4-chloro-2-benzoylphenyl)-4-methylallophanate. After dissolving the oily material in 9 ml of ethanol and adding 3 ml of concentrated hydrochloric acid thereto, the resulting mixture was refluxed for 1 hour. After removing the solvent by distillation under reduced pressure, the obtained residue was neutralized with concentrated ammonia water. The obtained crystals were collected by filtration, washed with water and recrystallized from ethanol to give 1-methyl-4-phenyl-6-chloro-2(1H)-quinazolinone having a melting point of 220° - 221° C.
Reaction SMILES: O.[NH2:2][NH2:3].[SH:4][C:5]1[N:10]=[C:9](S)[CH:8]=[C:7]([CH3:12])[N:6]=1>C(O)C>[NH:2]([C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([SH:4])[N:10]=1)[NH2:3]
Reactant: Cc1cc(S)nc(S)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(NN)nc(S)n1

Procedure:
Hydrazine monohydrate (6.4 ml) was added dropwise to a suspension of 2,4-dimercapto-6-methylpyrimidine (7.0 g) in 100 ml of ethanol at room temperature, the mixture was refluxed for two hours, and the crystals formed upon cooling were collected by filtration and washed with 100 ml of ethanol, giving 6.4 g of the objective compound as yellow crystals.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])[CH:5]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2ncoc2C)c1
Agent: [Li]
Product: Cc1ocnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(5-methyl-oxazol-4-yl)-benzoic acid methyl ester (0.87 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(5-methyl-oxazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.46 g) as a pale-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1=[N:33]NC1C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:33][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]1=[O:32]
Reactant: CC(C)N(C(=O)Cn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
Zinc powder (9.1 g) was added in portions to a slurry of 2-[2,4-dioxo-5-phenyl-3-(phenylhydrazono)-2,3,4,5-tetrahydro benzo[b][1,4]-diazepin-1-yl]-N-isopropyl-N-phenylacetamide (7.5 g), in glacial acetic acid, cooled to 0° C. The reaction was allowed to warm to R.T. and stirred an additional hour. The zinc was filtered through a celite pad and the glacial acetic acid was evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 10% aqueous sodium carbonate (2×100 ml) and water (2×100 ml), dried (Na2SO4) and evaporated to a tan oil. Trituration with hexane and ethyl acetate provided the title compound as a light tan powder (6.3 g). 1H-NMR (300 MHz, CDCl3): d 7.6-6.8 (m, 14H), 5.05 (m, 1H), 4.3-4.0 (m, 3H) 1.05 (d, 6H); MS (FAB)=448 (MH+); TLC, Rf =0.25 (chloroform:methanol, 9:1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:15]=1)=[O:4]
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (350 mg, 0.91 mmol) was dissolved in pyridine (10 ml), and methanesulfonyl chloride (576 mg, 5.04 mmol) was added thereto. The reaction mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (228 mg, 68%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:7][CH2:8][N:9]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CCCOC)CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
4-(3-Methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (3.36 g) was dissolved under an argon atmosphere in pyridine (80 ml), benzensulfonyl chloride (2.59 g) was added and the mixture was stirred overnight at RT. The pyridine was evaporated off, the residue dissolved in ethyl acetate and washed with 0,05M HCl and brine. The layers were separated, the organic layer was dried over sodium sulphate, the solvent was then removed in vacuo and the crude oil was purified by flash chromatography over silica gel (AcOEt/heptane gradient from 0 to 25%) to give 1-benzenesulfonyl-4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.15 g) as a yellow semi-solid. MS (ESI): 370.16 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([O:22][C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:36])[CH3:35])([C:31](O)=[O:32])[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:26]1[CH2:30][CH2:29][C@:28]([CH:34]([CH3:35])[CH3:36])([C:31]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)=[O:32])[CH2:27]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: Cc1cc(C(F)(F)F)cc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazine (280 mg, 1.1 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (460 mg, 1.7 mmol) in methylene chloride (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.60 g, 1.4 mmol), and triethylamine (0.20 g, 2.0 mmol). After being stirred overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to provide the desired product (200 mg, 35.1%). LCMS calculated for C25H37F3N4O3: (M+H) 499.3; found 499.2.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>CO.[N+](C1C=CC=CC=1)([O-])=O>[N:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:9]=1[C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=1
Reactant: Nc1ccccc1N
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene is heated to boiling under reflux. After 15 minutes crystals begin to separate from the red solution. After 18 hours the reaction mixture is cooled to room temperature and diluted with 60 ml of methanol. The crystals are filtered under suction and washed with methanol. There is obtained 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol of m.p. 198°-200° (from N,N-dimethylformamide/methanol).
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18](O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].C1C=CC2N(O)N=NC=2C=1.[NH2:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
13.8 g of Z-Val-Tyr-OH [R. Schwyzer et al., Helv. Chim. acta. 41, 1273 (1958)] and 5.1 g of HOBt×H2O are dissolved in 100 ml of DMF and there is added thereto the above solution of H-Lys(Boc)-OMe in a small amount of DMF. The whole is cooled to 0°, 7.6 g of DCCI are added and the whole is stirred for 6 hours at 0° and for 10 hours at room temperature. The DCH which has separated out is filtered off and the filtrate is concentrated to dryness. Purification is carried out by triturating with diisopropyl ether and by dissolving and reprecipitating from trifluoroethanol/ethyl acetate/petroleum ether, yielding Z-Val-Tyr-Lys(Boc)-OMe; Rf (F)=0.39.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1COCC1>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13])=[O:20]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: O=C(Cl)CCCCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CCCCCl)c(OC)c1

Procedure:
Prepared analogously to Example 6a from methyl 4-amino-3-methoxy-benzoate and 5-chloro-pentanoic acid chloride in THF with TEA.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3cccc(S(N)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (48 mg, 42%). MS (ISN) 454.9 [(M−H)−]; mp 214–216° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23]>>[OH:23][CH2:22][CH:21]([NH:20][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:24][OH:25]
Reactant: NC(CO)CO
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: O=C(NC(CO)CO)c1nc(Cl)c2ccccc2c1O

Procedure:
Prepared from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propane-1,3-diol analogously to Example C-1: MS-(−)-ion: 295.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:28]=[C:22]2[C:21]3[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)[NH:24][C:23]2=[O:27])=[CH:12][CH:13]=1)[CH3:16]
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(F)ccc32)cc1
Yield: 61.4 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (5 g, 1.3 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (3.12 g, 17.4 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (4.1 g, 61%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:21][NH2:22]>C(O)C>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:9]2[CH:10]([C:12](=[O:13])[NH:21][N:22]=1)[CH2:11]2
Reactant: O=C(c1ccccc1-c1ccccc1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: CCO
Product: O=C1NN=C(c2ccccc2-c2ccccc2)C2CC12
Yield: 95.7 %

Procedure:
7.0 g (26.3 millimoles) of cis-2-(p-biphenylcarbonyl)-cyclopropanecarboxylic acid, 1.45 g (29.0 millimoles) of hydrazine and 100 ml of ethanol are refluxed for 8 hours. After filtering off the product at 0° C. and drying it under reduced pressure at 50° C., 6.6 g (96% of theory) of 2-(p-biphenylyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 220°-221° C. after recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(=O)n(-c3ccsc3)c2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 51.3 %

Procedure:
In a reaction vessel, 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (50 mg, 0.197 mmol), thiophene-3-boronic acid (50 mg, 0.393 mmol), and copper acetate (4 mg, 0.0197 mmol) were suspended in N,N-dimethylformamide (3 ml). Pyridine (31 mg, 0.393 mmol) was added thereto, followed by stirring at room temperature for 14.5 hours in the air. After the reaction was terminated, the mixture was concentrated and suspended in dimethylsulfoxide. Subsequently, the insoluble matters were removed by filtration and the resulting filtrate was purified by HPLC, to give the title compound (34 mg, 51%) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]>ClCCl>[Cl:22][C:23]1[C:28]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 g. (0.2 moles) of cyanoacetic acid are dissolved in 150 ml. of dichloromethane and 40 g. (0.2 moles) of dicyclohexylcarbodiimide and 52 g. (0.2 moles) of pentachlorophenol dissolved in 200 ml. of dichloromethane are added dropwise at room temperature. The mixture is stirred for 4 hours at room temperature. The mixture is cooled to 0° C. and the precipitated dicyclohexylcarbodiimide is filtered and the solvent is distilled off. The residue is taken up in diisopropyl ether, filtered and dried.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH2:2][CH3:3].[CH:10]([NH2:12])=[O:11].C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:10]([NH:12][CH:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3])=[O:11]
Reactant: CCC(=O)c1cccs1
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: CCC(NC=O)c1cccs1
Reaction time: 22 h
Yield: 79.9 %

Procedure:
A mixture of 100 g of 2-propionylthiophene, 161 g of formamide and 98 g of formic acid is stirred at 150°-160 ° C. for 22 hours. After cooling, the mixture is poured into a solution of 30 g of potassium carbonate in 200 ml of water and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove solvent. The residue is distilled under reduced pressure to give 96.5 g of 2-(1-formylaminopropyl) thiophene as a colorless oil. b.p. 154°-156° C./4 mmHg