Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C@@H:2]2[C:7]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=3[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]2[OH:16])=[O:30])=[CH:27][CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)c2ccc(Cl)cc2)[C@@H]1O
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-amino-6cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (1.0 g), triethylamine (0.64 mL) and dichloromethane was added 4-chlorobenzoyl chloride (0.55 mL). The solution was stirred for a further 1.5 hours. The solution was washed with water and brine and dried over anhydrous magnesium sulphate. The solution was filtered and evaporated and recrystallised from ethyl acetate--60-80° petroleum ether as a white solid of mp 226-229° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([OH:24])[CH2:22][OH:23].CC(C)([O-])C.[K+]>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[O:23][CH2:22][CH2:21][OH:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCO)cc1CS(=O)(=O)c1ccccc1
Yield: 99.9 %

Procedure:
A mixture of 2-benzenesulfonylmethyl-4-fluoro-1-nitrobenzene (10.2 g, 34.7 mmol), ethylene glycol (80 mL, 1.4 mol), and 1 M potassium tert-butoxide in THF (78 mL, 78 mmol) in THF (50 mL) was refluxed under nitrogen for 30 minutes. After cooling to about ambient temperature, the reaction mixture was solvent evaporated. Water was added to the residue, and it was poured into 2.0 N hydrochloric acid and ice. The mixture was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated and dried in vacuo at 74° C. for 20 minutes. 2-(3-Benzenesulfonylmethyl-4-nitro-phenoxy)-ethanol as a dark brown gum (11.7 g, 100% yield) was obtained; Mass spectrum (−EI, [M−H]−) m/z 336. 1HNMR (500 MHz, DMSO-d6): δ8.01 (d, 1H, J=9.15 Hz), 7.67-7.73 (m, 1H), 7.54-7.63 (m, 4H), 7.10 (dd, 1H, J=9.51 Hz and 2.93 Hz), 6.85 (d, 1H, J=2.81 Hz), 5.12 (s, 2H), 4.88-4.90 (m, 1H), 3.93-3.96 (m, 2H), 3.65 ppm (d, 2H, J=4.51 Hz). Elemental Analysis for C15H15NO6S: Calcd: C, 53.41; H, 4.48; N, 4.15; Found: C, 53.47; H, 4.69; N, 4.04;
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2sccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3sccc23)cc1
Temperature: 130 °C
Reaction time: 30 h
Yield: 51.7 %

Procedure:
After adding 600 mg of 4-nitrophenol, 1.2 g of potassium carbonate and 2 ml of dimethylformamide to 302 mg of the 4-chlorothieno[2,3-d]pyrimidine described in Seans Acad. Sci., Ser, C (1967) 264(2)207, and stirring the mixture for 30 hours at 130° C., the mixture was returned to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 250 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([C:18]([NH:49][CH2:48][CH2:47][CH2:46][CH2:45][C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)=[O:20])=[CH:15][CH:16]=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3]
Reactant: NCCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3c(C(=O)O)cccn3c(=O)c2c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2nc3c(C(=O)NCCCCc4cccnc4)cccn3c(=O)c2c1
Temperature: 25 °C
Yield: 6 %

Procedure:
A solution of 2.82 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxylic acid, 2.75 g of diphenylphosphoryl azide, and 1.50 g of 3-pyridinebutanamine in 30 ml of dry dimethylformamide was cooled in an ice bath as 1.0 g of triethylamine was added to the mixture. The reaction mixture was allowed to warm to room temperature over 18 hours, was diluted with water and was extracted with dichloromethane. The combined organic layer was washed with dilute sodium carbonate solution, dried over potassium carbonate and evaporated to dryness. The residue was crystallized repeatedly from ethyl acetate to give 0.25 g (6%) of 2-(1-methylethyl)-N-[4-(3-pyridinyl)butyl]-11-oxo-11H-pyrido[2,1-b]quinazoline-6-carboxamide, mp 129°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([NH2:15])[S:11][N:10]=2)=[CH:5][CH:4]=1.N1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH2:22]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([NH:15][C:17]([C@@H:18]3[CH2:19][C@H:20]3[CH3:21])=[O:22])[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: c1ccncc1
Reactant: O
Reactant: COc1ccc(-c2nsc(N)c2C)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nsc(NC(=O)[C@@H]3C[C@H]3C)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (280 g, 1.00 equivalent) and pyridine (catalytic, 0.03 equivalent) in anhydrous THF (350 mL) is added the above acid chloride solution dropwise over 30 min at 6 to 13° C.; and the reaction mixture is stirred at room temperature 1 h. (The progress of the reaction may be followed by HPLC, and acid chloride addition terminated if monitoring indicates complete reaction of the amine.) Water (2.5 L) is added, the phases are separated and aqueous phase is re-extracted with dichloromethane. The combined organic phase is washed (aqueous NaOH (1 L), then water (1 L)). partially evaporated to about 1 kg, and then diluted with THF (2 L) to give an homogeneous solution, from which some water separates. The mixture is allowed to stand overnight at room temperature during which the two phases separate, with the aqueous phase above the organic phase. The phases are separated, THF is added to each phase, water is added to the upper (organic) phase, and each layer is reequilibrated, with very slow phase separation and the organic phase as the top layer. The combined organic phase is charged to a rotary evaporator (10-L flask) through a clarifying membrane (5 μm), toluene (4 L) is added, resulting in opacification of the mixture, and THF/water are evaporated (160 mbar, bath temp 45° C.). As the THF/water are evaporated, crystals begin to form. When 2 L has been distilled, toluene (2 L) is added and distillation continued (85 mbar, bath temp 45° C.). After distillation of a further 2 L of solvent, the system is set to atmospheric pressure, cooled to ambient temperature, and, after 1 h, the resulting suspension is filtered. The filter cake is resuspended in toluene (1 L), refiltered, and washed with toluene (1 L) before it is dried overnight to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 357 g, 92%.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(SCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 57 %

Procedure:
Prepared analogously to Example 10 from 1-methyl-2-[(4-amidinophenyl)methylthio]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 57% of theory, C26H25N5O3S (487.58); Rf value: 0.23 (Reversed Phase silica gel RP-8; Methanol/5% saline solution=6:4); EKA mass spectrum: (M+H)+=488; (M+Na)+=510; (M+Na+H)++=255.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8].C([Li])CCC.[Li+].[C:22]([O-:30])(=[O:29])C1C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>O.C(O)(=O)C.C1COCC1>[C:7]([C:6]1[CH:9]=[C:2]([CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])[C:22]([OH:30])=[O:29])#[N:8]
Reactant: O=C([O-])c1ccccc1
Reactant: CC[C@H](C)COc1ccc(Br)cc1C#N
Agent: O=C(O)c1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@H](C)COc1ccc(C(=O)O)cc1C#N

Procedure:
Quantities: compound 41 (5.00 g, 0.016 mol), n-butyllithium (2.5 M, 7.2 ml, 0.018 mol), THF (100 ml). The experimental procedure was as described for compound 36 except that the n-butyllithium was added between −90° C. and −100° C. Acidification of the resultant benzoic acid lithium salt was achieved by boiling with glacial acetic acid. The benzoic acid was crashed out of solution by diluting with a large volume of water, the resultant product was washed with water (until acid-free) and then purified as described for compound 36 to leave an off-white semi-solid.
Reaction SMILES: CO.[CH2:3]([N:6]([CH2:34][CH2:35][CH3:36])[CH2:7][CH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:33]=[CH:32][C:19]([CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5].O.NN>C(Cl)(Cl)Cl>[NH2:21][CH2:20][C:19]1[CH:32]=[CH:33][C:16]([C:14]2[N:15]=[C:10]([CH2:9][CH2:8][CH2:7][N:6]([CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][CH3:5])[CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CCCN(CCC)CCCc1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CN)cc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 105.3 %

Procedure:
A methanol solution (2.0 ml) containing the compound (40.0 mg) obtained in Example 36-4 was added with hydrazine monohydrate (44 mg) and the whole was stirred at 60° C. for 1.5 hours, followed by distillating off the solvent. The residue was dissolved in chloroform and filtrated through Celite, the solvent was distilled off, thereby obtaining the subject compound (30.1 mg) as an amber liquid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[CH2:19]([NH:23][CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]>O>[CH2:19]([N:23]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCCCNCCO
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(CCO)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.62 ml (0.02 mol) of 2-butylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.9 g of yellow powder are obtained, ie a yield of 70%.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[N:16][C:17]([Cl:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[Cl:19][C:17]1[N:16]=[N:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc2c(nn1)CCNCC2

Procedure:
0.15 g (0.53 mmol) 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester (CAS: 1251001-53-2), 0.4 mL trifluoroacetic acid and 2 mL DCM were stirred at RT for 4 hours. The reaction was concentrated to dryness. Yield: 0.16 g (quantitativ). ESI-MS: m/z=184/186 (M+H)+; Rt(HPLC): 0.41 min (Method K).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[N:23]2)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C(OCC)(=O)C>O1CCCC1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:24]=[N:23]2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.9 %

Procedure:
To a solution of 2-amino-3-bromopyridine (44.1 mg, 0.26 mmol) in anhydrous tetrahydrofuran (7 mL) were added 1-(4-benzyloxy-benzyl)-4-tributylstannanyl-1H-pyrazole (141 mg, 0.26 mmol) described in Manufacturing Example 31-1-2, copper (I) iodide (19.4 mg, 0.10 mmol) and bis(triphenylphosphine)palladium (II) (35.8 mg, 0.05 mmol) under nitrogen atmosphere, which was stirred for 4 hours at 70° C. Water and ethyl acetate were added to the reaction mixture at room temperature, which was then filtered through a Celite pad, and the filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (1.8 mg, 2%).
Reaction SMILES: CCOCCOCCO.[BH4-].[Na+].[CH3:12][N:13]([CH3:22])[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH3:12][N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: Cc1ccccc1C
Product: CN(C)Cc1ccccc1
Product: OCc1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
10.7 g (0.08 mole) of ethyl carbitol was added dropwise to a mixture consisting of 1.5 g (0.04 mole) of sodium borohydride and 15 ml of xylene at 120° C. for 1.5 hours. The mixture was agitated at 120° C. for one hour. A mixture consisting of 3 g (0.02 mole) of N,N-dimethyl benzamide and 10 ml of xylene was added dropwise to the mixture over 0.5 hours. Subsequently, the resulting mixture was agitated at 120° C. for 20 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, N,N-dimethylbenzylamine was obtained in 51% yield and benzyl alcohol in 47% yield, respectively.
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1C[CH2:50][O:49][CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:39][CH2:50][O:49][CH2:48][CH2:47]3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1COCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (249 mg) described in Example 769 and morpholine (42 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (60 mg) was obtained.
Reaction SMILES: CCN(CC)CC.[SH:8][CH2:9][C:10]([OH:12])=[O:11].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O>O1CCOCC1>[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[S:8][CH2:9][C:10]([OH:12])=[O:11])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(O)CS
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
Et3N (1.5 g, 15 mmol) and mercapto-acetic acid (1 g, 11 mmol) were added to a solution of 1-chloro-2,4-dinitrobenzene (2.26 g, 10 mmol) in 1,4-dioxane (50 mL) at room temperature. After stirring at room temperature for 5 h, H2O (100 mL) was added. The resulting suspension was extracted with ethyl acetate (100 mL×3). The ethyl acetate extract was washed with water and brine, dried over Na2SO4 and concentrated to give 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 74%), which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[CH2:15][N:16]([CH2:21][C:22]3[CH:38]=[CH:37][C:25]([O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:24][CH:23]=3)[CH2:17][CH2:18][O:19][CH3:20])=[C:9]([CH3:40])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[Cl:48]CCl>>[ClH:48].[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[CH2:15][N:16]([CH2:21][C:22]3[CH:38]=[CH:37][C:25]([O:26][C:27]([CH3:36])([CH3:35])[C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)[CH2:17][CH2:18][O:19][CH3:20])=[C:9]([CH3:40])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCN(CC(=O)Nc1ccc(C2CCCCC2)cc1C)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CC(=O)Nc1ccc(C2CCCCC2)cc1C)Cc1ccc(OC(C)(C)C(=O)O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.398 g (0.72 mmol) of the compound from Example 3-10 is initially charged in 5 ml of dichloromethane. At room temperature, 5 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 2 hours. The mixture is then concentrated under reduced pressure using a rotary evaporator. The residue is taken up in ethyl acetate and washed with water, 20% strength sodium acetate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The product is purified chromatographically on silica gel (dichloromethane/methanol 30:1). With heating, the residue is dissolved in dichloromethane, 1N hydrochloric acid in diethyl ether is added and n-heptane is added dropwise until the mixture becomes slightly turbid. The product is filtered off with suction, washed with diethyl ether and dried at 40° C. under reduced pressure. This gives 0.187 g (49% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.O>O1CCCC1.CO.[OH-].[Na+]>[Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
tert-Butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL) was added dropwise at not more than 10° C. After stirring at the same temperature for 4 hr, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-yellow oil (yield 410 mg, 61%).
Reaction SMILES: [N+](C1C=CC=CC=1C=O)([O-])=O.C([N:14](CC)[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[N:18][CH:17]=1)C.C(OC(=O)C)(=O)C.C(N(CC)C(=O)C1C=CC(C=CC2C=CC=CC=2[N+]([O-])=O)=NC=1)C>>[C:15]([NH2:14])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: CCN(CC)C(=O)c1ccc(C)nc1
Agent: CCN(CC)C(=O)c1ccc(C=Cc2ccccc2[N+](=O)[O-])nc1
Agent: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: NC(=O)c1cccnc1

Procedure:
Reaction of o-nitrobenzaldehyde (41.7 g., 0.276 mole) with N,N-diethyl-6-methylnicotinamide (53.1 g., 0.276 mole) in the presence of acetic anhydride (56.3 g., 0.552 mole) according to the method of L. Horwitz, J. Org. Chem., 21, 1039 (1956) provides 67.4 g. (75%) of N,N-diethyl-6-(o-nitrostyryl)-nicotinamide. Crystallization from acetonitrile affords the analytically pure nicotinamide having a melting point of 145°-147° C. (corr.).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:8]=[CH:7]2.C([Li])CCC.CN(C)[CH:32]=[O:33].O>O1CCCC1>[CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:8]([CH:32]=[O:33])=[CH:7]2
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)c1ccc2c(c1)cc(C=O)n2S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 5-dimethoxymethyl-1-(4-methylphenyl)sulfonylindole (2.37 g, 6.87 mmol) in tetrahydrofuran (35 mL) was added n-butyllithium (1.6 mol/L in hexanes; 6.2 mL, 9.9 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 2 h. Then dimethylformamide (1.1 mL, 14 mmol) was added, and the mixture was stirred for 20 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (4:1 hexane/ethyl acetate) followed by trituration with hexane to afford 5-dimethoxymethyl-1-(4-methylphenyl)sulfonylindole-2-carboxaldehyde (1.89 g, 74%).