Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1.C(OCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu-]=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][CH:10]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=[Cu-]
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Cl)cn1
Temperature: 130 °C
Reaction time: 24 h
Yield: 54.9 %

Procedure:
Cesium carbonate (71 g, 218 mmol) was added to 2-bromo-5-chloropyridine (14 g, 73 mmol) and diethyl malonate (22 mL, 145 mmol) in dry 1,4-dioxane (280 mL) and the solution was degassed with argon for 30 minutes. Then copper (I) oxide (2.8 g, 14.55 mmol) and picolinic acid (3.6 g, 29 mmol) were added and the mixture was stirred in a sealed vessel at 130° C. for 24 hours. The mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc: Hexane 92: 8 to afford the title compound as a yellow oil (54%, 8.0 g).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N.[C:17]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:22]=[CH:21][C:20]([NH:23][C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1.[Br:45][C:46]1[CH:51]=[CH:50][C:49](I)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.[Cu]Cl.O>[C:17]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:22]=[CH:21][C:20]([N:23]([C:49]2[CH:50]=[CH:51][C:46]([Br:45])=[CH:47][CH:48]=2)[C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21
Reactant: Brc1ccc(I)cc1
Agent: Cl[Cu]
Agent: N#N
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 130 °C

Procedure:
A degassed solution of 490 mg (0.16 mmol) of copper(I) chloride and 906 mg (5 mmol) of 1,10-phenanthroline in 100 ml of toluene is saturated with N2 for 1 h and heated to 130° C. 18 g (50 mmol) of N-[1,1-biphenyl]-4-yl-9,9-dimethyl-9H-fluoren-2-amine and 14 g (50 mmol) of 1-bromo-4-iodobenzene are subsequently added to the solution, which is then heated at 180° C. for 2 h. After cooling, 180 ml of water are added to the mixture, the organic phase is separated off, and the solvent is removed in vacuo. The product is recrystallised from n-hexane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[C:7]1([N:6]2[C:2]3[N:1]=[N:16][NH:15][C:13](=[O:14])[C:3]=3[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1cnn(-c2ccccc2)c1N
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nnc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
1 g of 5-amino-1-phenyl-4-pyrazolecarboxamide in 18 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid was stirred at 0° C. during the addition of a solution of 0.4 g of sodium nitrite in 6 ml of water. The mixture was held at 0° C. for 20 minutes, then allowed to warm to room temperature and stirred for a further 2 hours. The precipitated product was filtered off and recrystallized from ethanol to yield 580 mg of 7-phenyl-7H-pyrazolo[3,4-d]-1,2,3-triazin-4(3H)-one of melting point 150°-151° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]#[N:13])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClC1[N:27]=[C:26]([NH:28][C@H:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:30])[N:25]=[C:24]([NH:38][C:39]2[CH:44]=[N:43][CH:42]=[CH:41][N:40]=2)[CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(Cl)Cl.O1CCOCC1.C(OCC)(=O)C.C(N(CC)CC)C>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:29]([NH:28][C:26]2[N:27]=[C:6]([N:8]3[CH2:9][CH:10]([C:12]#[N:13])[CH2:11]3)[CH:23]=[C:24]([NH:38][C:39]3[CH:44]=[N:43][CH:42]=[CH:41][N:40]=3)[N:25]=2)[CH3:30])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(C#N)C2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
216 mg of 1-(t-butoxycarbonyl)-3-cyanoazetidine was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure to obtain brown oil. The obtained oil was dissolved in 4 ml of degassed 1,4-dioxane, and 302 mg of triethylamine, 205 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 57 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 229 mg of sodium t-butoxide and 62 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 90° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 58 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[N:11]/N(C)C)=[C:4]([O:15][CH2:16][C:17]#[CH:18])[CH:3]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:17](=[CH:18][N:11]=[CH:10][CH:9]=3)[CH2:16][O:15][C:4]=2[CH:3]=1
Reactant: C#CCOc1cc(Br)ccc1/C=C/C=N/N(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1cc(C)cc(C)c1
Product: Brc1ccc2c(c1)OCc1cnccc1-2
Temperature: 140 °C
Reaction time: 138 h
Yield: 0 %

Procedure:
A solution of (E)-2-((E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)allylidene)-1,1-dimethylhydrazine (116 mg, 374 mmol) and 2,6-di-tert-butyl-4-methylphenol (82 mg, 374 mmol) in mesitylene (4.5 mL) was degassed at 50° C. by bubbling argon for ˜15 min while sonicating in a thick glass vial. The vial was capped under argon and heated to 140° C. in an oil bath with stirring for 138 h (5.75 days). The reaction mixture was cooled to ambient temperature and the solvent was concentrated under reduced pressure. The dark residue was purified by silica gel chromatography with EtOAc:dichloromethane (1:19) as the eluant. Fractions containing the required product were combined and concentrated under reduced pressure to give 8-bromo-5H-chromeno[3,4-c]pyridine (27 mg, 0.088 mmol, 25% yield based on 89% purity) as a pale yellow powder. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=5.2 Hz, 1H), 8.45 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.52 (d, J=5.2 Hz, 1H), 7.27-7.22 (m, 2H), 5.20 (s, 2H); LCMS (Method A) (ESI) m/e 262.0, 264.0 Br pattern [(M+H)+, calcd for C14H15BrN2O 262.0].
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC=CCCCCCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCCCCCC=CCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pentadeca-12-ene-1-ol (22.6 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled pentadeca-12-ene-1-ol with vigorous stirring in about 2 hours. Triethylarnine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCl) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield pentadeca-12-ene-1-yl methacrylate in good yields. Pentadeca-12-ene-1-yl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [NH2:1]CCC1N=CN(CCCNC(C)(C)COC2C=CC=CC=2)C=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([NH2:1])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: NS(=O)(=O)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.05 g) was reacted with benzenesulphonyl chloride (1.15 g) in a similar manner to Example 55 to give N-(2-{1-3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl]benzenesulphonamide, as an oil. The compound contained 7% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl]benzenesulphonamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:14])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(Cc3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-benzylpiperidin-4-ol (9.5 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H24N2O3: 376.1787, found 376.1790.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:8][C:7]1[C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cccc(Cl)c2n1-c1ccccc1
Yield: 66.7 %

Procedure:
Method A applied to 2,3-dichloronitrobenzene (96 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a brown solid (81 mg, 67%). mp 103-105° C. 1H NMR (DMSO) δ 2.38 (s, 3H), 7.30-7-33 (m, 2H), 7.56-7.62 (m, 5H), 7.70 (dd, J=5.4, 3.7Hz, 1H); 13C NMR δ 13.2, 115.9, 116.0, 124.5, 125.0, 128.7, 129.3, 130.2, 134.6, 138.9, 153.7, 158.5. HRMS (FAB): cal. for C14H12N2Cl [M+H+]: 243.0689; found: 243.0683.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[CH2:20]([O:19][C:5]1[CH:6]=[CH:7][C:8]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH3:18])[CH2:11]2)=[CH:9][C:4]=1[C:3]([OH:27])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)OC)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(C(=O)O)c2)C1
Yield: 100 %

Procedure:
To the methyl ester from example 32 (105 mg, 0.28 mmol) in methanol (5 ml) was added 10% sodium hydroxide (aq) (15 ml) and the milky white suspension was refluxed for 2 hours. The now colourless reaction mixture was cooled then neutralised by addition of 2M HCl (aq) (few drops). The reaction mixture was then concentrated in vacuo to give the title compound as an off-white solid (99 mg, 0.28 mmol, 100%). LRMS: m/z 355 (M-H+). This material was taken on crude to example 34.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1>CO.[Ni]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2N)cc1

Procedure:
2 g of a suspension of [4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester and 0.600 g of Raney Ni in 40 ml of MeOH (40 mL) is stirred for 4 hours at rt under a hydrogen atmosphere. The mixture obtained is filtered through a pad of Celite and concentrated. [4-(3-Amino-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester is obtained in the form of a solid: ES-MS: 258.0 [M+H]+; tR=2.30 min (System 1); Rf=0.15 (Hexane/EtOAc, 1:1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClC(Cl)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O
Product: COc1ccc(CNC(=O)c2ccc(C#N)cc2)cc1
Reaction time: 2.5 h

Procedure:
825 mg of 4-cyanobenzoyl chloride was dissolved in 9 ml of dichloroethane, and mixed with 0.69 ml of 4-methoxybenzylamine and 1.57 ml of triethylamine, followed by stirring for 2.5 hours. Thereafter, the reaction was stopped by the addition of 1 ml of distilled water. After the product was extracted with chloroform, the extract was successively washed with 2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 20:1 mixture of chloroform and acetone as the eluent) to obtain 1.29 g of 4-cyano-N-(4-methoxy-benzyl)benzamide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.[CH3:11][N:12]=[C:13]=[O:14]>>[CH3:11][NH:12][C:13]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:14]
Reactant: NCCNCc1cc[nH]n1
Reactant: CN=C=O
Product: CNC(=O)NCCNCc1cc[nH]n1

Procedure:
N-(3-Pyrazolylmethyl)ethylenediamine is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [Na+:1].[Na+].[CH3:3][C:4]1([CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:40])=[O:39])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[N+:6]([CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21])=[C:5]1/[CH:24]=[CH:25]/[CH:26]=[CH:27]/NC1C=CC=CC=1.[Na].[C:43]([CH2:46][CH2:47][CH2:48][C:49]1([CH3:70])[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([S:58]([O-:61])(=[O:60])=[O:59])[CH:56]=2)[N+:51]([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:67])=[O:66])=[C:50]1[CH3:69])([OH:45])=[O:44].N1C=CC=CC=1.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[C:43]([CH2:46][CH2:47][CH2:48][C:49]1([CH3:70])[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([S:58]([OH:61])(=[O:60])=[O:59])[CH:56]=2)[N:51]([CH2:62][CH2:63][CH2:64][S:65]([OH:68])(=[O:66])=[O:67])/[C:50]/1=[CH:69]/[CH:27]=[CH:26]/[CH:25]=[CH:24]/[C:5]1[C:4]([CH3:3])([CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:39])=[O:40])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13]([OH:16])(=[O:15])=[O:14])[CH:11]=2)[N+:6]=1[CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:21])=[O:22])([OH:45])=[O:44]
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc21
Reactant: CC1=[N+](CCCS(=O)(=O)O)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCC(=O)O
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC1(CCCS(=O)(=O)O)C(/C=C/C=C/C=C2/N(CCCS(=O)(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCC(=O)O)=[N+](CCCS(=O)(=O)O)c2ccc(S(=O)(=O)O)cc21
Temperature: 25 °C

Procedure:
642 mg (1 mmol) 3-methyl-2-((1E,3E)-4-phenylamino-buta-1,3-dienyl)-5-sulfo-1,3-bis-(3-sulfo-propyl)-3H-indolium disodium salt and 483 mg (1 mmol) 3-(3-Carboxypropyl)-2,3-dimethyl-5-sulfonato-1-(3-sulfopropyl)-3H-indolium sodium salt were dissolved in a mixture of 10 ml acetic acid and 10 ml acetic anhydride. Five ml pyridine was added. The solution was stirred under reflux for 15 min. Twenty ml ether was added after cooling to room temperature. The obtained precipitate (mixture of the diastereomers OB-5.5a and OB-5.5b) was extracted by suction, washed with ether, and dried.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:22]([C:24]1[C:29](Br)=[N:28][CH:27]=[CH:26][N:25]=1)=O.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[CH3:22][C:24]1[C:29]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: COC(=O)c1nccnc1Br
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nccnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 97 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 3-bromo-pyrazine-2-carboxylic acid methyl ester followed by reduction with lithium tri-sec-butylborohydride at 0° C. in THF: MS (m+1)=375.5.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:50][OH:51].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:48])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:45][CH:46]=1)([CH3:22])[CH2:14][C:13]2=[N:50][OH:51])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 120 h

Procedure:
A mixture of 0.5 g of t-butyl α-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example 51), 0.2 g of hydroxylamine hydrochloride, 0.2 g of pyridine and 5 ml of methanol was allowed to stand at 25°-30° C. for 5 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 20:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[C:5]([C:8]([CH3:14])([CH3:13])[C:9](OC)=[O:10])=[N:6][CH:7]=1.C(O)(=O)C>[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[NH:15][C:9](=[O:10])[C:8]([CH3:14])([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc(Br)cnc21
Temperature: 100 °C

Procedure:
Prepared according to procedure J using methyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate (0.780 g, 2.57 mmol), acetic acid (14.73 mL, 257 mmol) and iron powder (0.719 g, 12.87 mmol) and heating at 100° C. for 2 h. After purification 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one was obtained as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (65 mg, 85%), MS (ISP) m/z=306.4 [(M+H)+], mp 297.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:24]([NH2:25])=[N:23][NH:22][C:19]2=[N:20][CH:21]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O>[Cl:8][C:6]1[N:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:25][C:24]2[C:18]3[C:19](=[N:20][CH:21]=[C:16]([F:15])[CH:17]=3)[NH:22][N:23]=2)[CH:7]=1
Reactant: Nc1n[nH]c2ncc(F)cc12
Reactant: Clc1cc(Cl)nc(C2CCCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cnc2[nH]nc(Nc3cc(Cl)nc(C4CCCCC4)n3)c2c1
Temperature: -60 °C
Yield: 50 %

Procedure:
A mixture cooled to −60° C. containing 4,6-dichloro-2-cyclohexylpyrimidine (505 mg, 2.19 mmol), 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (400 mg, 2.63 mmol) and THF (20 mL) was treated drop wise with a 1M solution of lithium bis(trimethylsilyl)amide in THF (5.46 mL, 5.46 mmol). The reaction mixture was then allowed to warm to 0° C. over 1 h before water was added. The reaction mixture partitioned between water and EtOAc, washed with sat. NaCl solution and dried (Na2SO4) and concentrated in-vacuo. The resulting residue was purified by column chromatography (eluting with MeOH/DCM, 5/95) to give the title compound as a solid (380 mg, 50%). MS (ES+) m/e=347. 1H NMR: (DMSO) 1.10-1.96 (10H, m), 2.56-2.69 (1H, m), 7.65 (1H, brs), 8.27-8.39 (1H, m), 8.58 (1H, s), 10.72 (1H, s), 13.34 (1H, s).