Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20](=[N:31][OH:32])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NO
Reactant: O=C1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A mixture of 0.20 g of 1-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-piperidinone, 0.04 g of hydroxylamine hydrochloride, 0.09 g of sodium acetate and 4 ml of methanol was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was added with aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, and dried, and the solvent was evaporated to give 0.25 g of a colorless solid. Recrystallization from ethyl acetate gave colorless crystals having the melting point of from 201 to 207° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]1([N:20]2[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]2)[C:12]2[N:13]([CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:11]3[C:12]4[N:13]([CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:15][N:16]=3)[CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: Cc1cnc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cnc(C(=O)N[C@H]2CCN(c3nccn4cccc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of 5-methylpyrimidine-2-carboxylic acid (0.03 g, 0.22 mmol, 1 eq) and (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine (0.060 g, 0.22 mmol, 1 eq) in 1 mL of DMSO was added triethylamine (0.12 mL, 0.86 mmol, 4 eq) and HATU (0.09 g, 0.24 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by HPLC to afford (S)-5-methyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.029 g, 0.09 mmol, 41%). 1H NMR (400 MHz, CD3OD) δ 8.75 (s, 2 H), 7.76 (s, 1 H), 7.71 (d, J=5.5 Hz, 1 H), 7.54 (s, 1 H), 6.91 (s, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H), 2.40 (s, 3 H); MS: (ES) m/z calculated for C17H18N6O [M+H]+ 323.2, found 323.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cncnc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cncnc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyrimidin-5-yl)propan-2-ol (1 g, 2.80 mmol, 1 eq.) was refluxed with 25% sulfuric acid (7 ml) for 2 h. The reaction mixture was cooled to 5 deg C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture till pH of 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 ml) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) followed by preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 9.20 (s, 1H), 9.10 (s, 2H), 7.58 (s, 1H), 7.30-7.20 (m, 3H), 4.78 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C([O-])([O-])=[O:31].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
A mixture of compound 5 (100 mg, 0.3 mmol), compound 5A (89 mg, 0.6 mmol), Cs2CO3 (2 M, 0.45 mL) and Pd(PPh3)2Cl2 (10 mg) in 1,4-dioxane (5 mL) under a nitrogen atmosphere was stirred in microwave at 120° C. for 15 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified pre-TLC to give compound 6 (40 mg, yield 30%) as a white solid. 1H NMR (CDCl3 400 MHz): δ 8.05 (m, 1H), 7.87 (m, 3H), 7.72 (m, 3H), 7.60 (m, 1H), 3.69-3.75 (m, 2H), 3.17 (m, 2H), 3.01 (m, 2H), 2.30 (m, 4H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=O)[CH2:3]1.[CH3:7][C:8](O)([CH:10]=C)[CH3:9].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>>[CH3:9][C:8](=[CH:7][CH2:4][CH2:3][C:2](=[O:6])[CH3:1])[CH3:10]
Reactant: C=CC(C)(C)O
Reactant: C=C1CC(=O)O1
Agent: CC(C)[O-]
Agent: [Al+3]
Product: CC(=O)CCC=C(C)C
Yield: 83 %

Procedure:
Apart from the improvements according to the present invention, this process has been disclosed by Teisseire et al. "Recherches," June 1956, page 31. The yield is only about 56%, which is entirely inadequate for industrial syntheses. If, instead of an alkyl acetoacetate, diketene is reacted with 2-methyl-3-buten-2-ol in the presence of aluminum triisopropylate, 2-methyl-2-hepten-6-one is obtained in a yield of 83% (cf. "Advances in Organic Chemistry," Volume II, 1960, page 246). It is to be deduced from the last-mentioned publication that for the manufacture of 2-methyl-2-hepten-6-one, diketene is to be preferred over an alkyl acetoacetate as the starting material. This is undoubtedly true on a laboratory scale, but unacceptable for the industrial manufacture of methylheptenone. For safety reasons alone, the instability of diketene demands the use of expensive apparatus. In addition, in order to achieve high yields and smooth operation of the plant, measures are required which substantially cancel out the advantage of the good yield. Further, German Pat. No. 1,068,696 discloses the preparation of 2-methyl-2-hepten-6-one by passing 2-methyl-3-buten-2-ol into a reaction mixture which has been preheated to 160°-250° C. and comprises an alkyl acetoacetate, a mixture of an alkyl acetoacetate and an inert solvent, or a mixture of 2-methyl-3-buten-2-ol, an alkyl acetoacetate and a solvent. However, this process also gives yields of only from 63 to 66% of theory, based on alkyl acetoacetate converted.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccccc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.85 min; Mass spectrum (ESI+): m/z=456 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:5][N:6]=1)([O-:4])=[O:2]
Reactant: c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Nitric acid (2 mL) was added to a stirred solution of indazole (5.0 g, 42 mmol) in acetic acid (40 mL) at 0° C. The resulting mixture was stirred at RT for 30 min. Acetic anhydride (6 mL) was added in one portion and the mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 3-nitro-1 H-indazole (3.4 g, 49% yield). 1H NMR (400 MHz, DMSO-d4): δ 14.46 (s, 1 H), 8.12 (m, 1 H), 7.76 (m, 1 H), 7.57 (m, 1 H), 7.48 (m, 1 H).
Reaction SMILES: [CH:1]1([N:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1.O>C(Cl)Cl>[Cl:29][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:15][CH:14]=1
Reactant: O=C(Nc1nccs1)N(C1CCCCC1)N1CCCCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ncc(Cl)s1)N(C1CCCCC1)N1CCCCC1

Procedure:
1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea (50 mg, 0.16 mmol), prepared in an identical manner to Example 94 was dissolved in DCM (1 mL) and NCS (26 mg, 0.19 mmol)) was added. The reaction mixture was stirred for 3 days before DCM (20 mL) and water (20 mL) was added. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. MeCN (1 mL) was added whereupon the product precipitated. The product was filtered off and dried. Yield: 20 mg.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(F)c2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (35%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:30][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:31])=[O:32])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.31 mmol) of pivaloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.06 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 260 mg (2.12 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 360 mg (yield: 73.0%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:5])[CH3:2].O.O[N:35]1C2C=CC=CC=2N=[N:36]1.ClCCCl.C(Cl)Cl>C(OCC)(=O)C>[CH2:31]([O:30][C:28]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:35][NH2:36])=[O:27])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(C(=O)O)cc2)nc1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(C(=O)NN)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
A mixture of affording 1-[6-(4-Carboxy-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.4 g, 0.97 mmol), 1-hydroxybenzotriazole hydrate (0.176 g, 1.3 mmol), 1,2-dichloroethane (0.25 g, 1.3 mmol) and 6 mL of methylene chloride was stirred at room temperature for 20 minutes. The mixture was treated with boc-hydrazide (0.17 g, 1.3 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, sodium bicarbonate solution, brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue was dissolved in 5 mL of 1:1 V/V methylene chloride-trifluoroacetic acid, stirred for 1 hours at ambient temperature and was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M sodium hydroxide, brine, dried over sodium sulphate, filtered and concentrated, affording 1-[6-(4-Hydrazinocarbonyl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.20 g) as a colorless syrup. HPLC: 2.770 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75.8 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-L-valine (2.50 g, 11.5 mmol) in methylene chloride (125 ml) were added p-nitrobenzyl alcohol (3.52 g, 23.0 mmol), WSC (4.41 g, 23.0 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen for 4.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford N-(t-butoxycarbonyl)-L-valine p-nitrobenzyl ester (3.07 g, yield 76%) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:29][C:30]1[CH:66]=[CH:65][CH:64]=[CH:63][C:31]=1[CH2:32][NH:33][C:34]([C@@H:36]1[C:40]([CH3:42])([CH3:41])[S:39][CH2:38][N:37]1[C:43](=[O:62])[C@@H:44]([OH:61])[C@@H:45]([NH:53][C:54](=[O:60])[C@H:55]([CH:57]([CH3:59])[CH3:58])[NH2:56])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:35]>CN(C=O)C.C(OCC)(=O)C>[CH3:29][C:30]1[CH:66]=[CH:65][CH:64]=[CH:63][C:31]=1[CH2:32][NH:33][C:34]([C@@H:36]1[C:40]([CH3:42])([CH3:41])[S:39][CH2:38][N:37]1[C:43](=[O:62])[C@@H:44]([OH:61])[C@@H:45]([NH:53][C:54](=[O:60])[C@@H:55]([NH:56][C:4](=[O:6])[CH2:3][O:2][CH3:1])[CH:57]([CH3:59])[CH3:58])[CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:35]
Reactant: COCC(=O)O
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Methoxyacetic acid (23 μl), HOBt (48 mg), and EDC.HCl (63 mg) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was recrystallized from ethyl acetate/n-hexane to obtain the title compound (149 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:30]2[CH2:31][CH2:32][CH:28]([NH2:27])[CH2:29]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: NC1CCNC1
Solvent: CCOC(C)=O
Product: NC1CCN(c2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)C1
Yield: 61 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (40 mg, 110 μmol) and 3-aminopyrrolidine (0.5 ml) were heated at 195° C. for 15 min and then allowed to cool. The reaction mixture was diluted with EtOAc (5 ml) and extracted with 4M HCl (4 ml). The aqueous phase was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (4 ml). The organic phase was evaporated in vacuo and the residue dissolved in acetonitrile (2 ml) and subjected to semi-preparative HPLC-C18. The appropriate fractions were pooled and evaporated in vacuo. The residue was dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (30 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]([OH:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(N(C(C)C)CC)(C)C>[Cu](I)I.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([S:16][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: OC(=S)c1ccccc1
Agent: I[Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Sc1ccc(Cl)nc1)c1ccccc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 23.9 g of 2-chloro-5-iodopyridine, 14 ml of thiobenzoic acid, 1.90 g of copper iodide, 3.60 g of 1,10-phenanthroline, 35 ml of diisopropylethylamine and 200 ml of toluene was stirred at 110° C. for 4 hours. Water was added to the reaction mixture cooled to room temperature, and the insoluble matter was filtered with celite (registered trademark), then the filtered matter was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 21.2 g of thiobenzoic acid S-(6-chloropyridin-3-yl)ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15].P(Cl)(Cl)(Cl)=[O:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl-].[Na+]>O>[Cl:1][CH2:2][CH2:3][N:4]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:15])[CH3:16].[OH:18][CH2:2][CH2:3][N:4]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH3:14])[CH2:6][C:5]1([CH3:16])[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Agent: CC1CC(C)(C)N(CCCl)C2=CC=CCC21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Solvent: O
Product: CC1CC(C)(C)N(CCO)C2=CC=CCC21
Temperature: 95 °C
Reaction time: 2 h

Procedure:
9.2 parts of 4-bromo-N-ethylnaphtholactam and 8 parts of N-β-chloroethyl-2,2,4-trimethyltetrahydroquinoline are stirred with 20 parts of phosphorus oxychloride and 6 parts of phosphorus pentoxide are then introduced whilst stirring. The mixture is gradually heated to 95° C and is then kept at this temperature for 2 hours. It is then stirred into 400 parts of water, 20 parts of sodium chloride are added and the dyestuff is separated from the solution after stirring for several hours. It is recrystallised from 500 parts of water with addition of 1 part of active charcoal. After precipitation with sodium chloride, it crystallises as the salt of the formula ##STR9## This dyestuff gives clear blue dyeings, distinguished by very good fastness properties, on materials of polyacrylonitrile, acid-modified polyesters and acid-modified polyamides. The same dyestuff is also obtained if instead of N-β-chloroethyl-2,2,4-trimethyltetrahydroquinoline the equivalent amount of N-β-hydroxyethyl-2,2,4-trimethyltetrahydroquinoline is employed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH:13]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8].CC1C=CC=C([N+]([O-])=O)C=1C(OCC=C)=O>>[NH2:14][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: C=CCOC(=O)c1c(C)cccc1[N+](=O)[O-]
Product: C=CCOC(=O)c1cc(Cl)ccc1N

Procedure:
The above nitro compound was reduced by the method described in example 6, for the reduction of allyl 2-methyl-6-nitrobenzoate, to give allyl 2-amino-5-chlorobenzoate.