Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[CH3:7][O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:3]=[CH:4][S:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: Brc1cscn1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cscn2)cc1
Yield: 45 %

Procedure:
A suspension of 4-bromothiazole (1.13 g, 6.89 mmol), 4-methoxycarbonylphenylboronic acid (1.85 g, 10.3 mmol) and Tetrakis (triphenylphosphine) palladium (0) (0.35 g, 0.30 mmol) in dioxane (45 mL) and 2M Na2CO3 (17.2 mL) is heated to reflux for 18 h. The reaction is allowed to cool and filtered. The filtrate is evaporated in vacuo, and the residue is dissolved in ethyl acetate and washed with water (2×) and brine (2×). The combined organic layers are dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography (100% hexanes-40% ethyl acetate/hexanes) to give 4-thiazol-4-yl-benzoic acid methyl ester as a white solid (0.68 g, 45%) MS (ES+) 220.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.[H-].[Na+].I[CH3:19]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:9]([CH3:19])[C:6]2=[CH:7][N:8]=1
Reactant: COC(=O)c1cc2cc(OC)ncc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OC)ncc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a stirred solution of methyl 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (910 mg, 4.41 mmol) in N,N-dimethylformamide (35 ml) at room temperature under a nitrogen atmosphere was added slowly sodium hydride (60 w/w % in mineral oil, 177 mg, 4.41 mmol). After 30 minutes iodomethane (0.302 ml, 4.85 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. Then the reaction was quenched in water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (gradient of heptane to heptane/ethyl acetate 1/1) to give methyl 5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (878 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[S:9][CH2:10][CH2:11][CH2:12][S:13]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Clc1cccc(C2SCCCS2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C1(c2cccc(Cl)c2)SCCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The crude 2-(3-chlorophenyl)-1,3-dithiane is dissolved in anhydrous THF (400 mL). After chilling to −78° C., a solution of n-butyl lithium (2.5 Molar, 42 mL) is added slowly by syringe. The solution is stirred for 30 min at −78° C., followed by the addition of acetyl chloride. The mixture is warmed to room temperature, quenched by the addition of a saturated aqueous solution of NH4Cl, washed with water, brine, and dried (Na2SO4). After removing the dessicant, the filtrate was concentrated in vacuo to provide the desired product.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[CH2:7]([SH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1CCN2C(=NCCC2)CC1>[CH2:7]([S:13][CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CC(=O)OC
Reactant: CCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCSC=CC(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (5°) solution of methyl propiolate (1.96 g, 23.0 mmol) is added 2 drops of DBU. 1-Hexanethiol (2.5 g, 21.0 mmol) is then added over a period of 3 minutes. The ice bath is removed, and the reaction mixture is stirred at RT for 1.5 hours. It is then purified by prep. TLC (preparative thin layer chromatography) to give methyl 3-hexylthio-2-propenoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:19][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[Cl:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=Cc1ccncc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc(NCc2ccncc2Cl)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To 6-amino-nicotinic acid methyl ester (553, 2.15 g, 0.014 mol) in acetonitrile (60.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), triethylsilane (11.00 mL, 0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80° C. overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (555, 1.5 g, 38.2%). MS (ESI) [M+H+]+=278.9.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:3]2([O:2][CH3:1])[CH2:4][CH2:5]2)=[CH:7][CH:8]=1)#[CH:13]
Reactant: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-methoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate 60, 285.0 mg, 1.18 mmols) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].[OH-].[Na+]>Cl.O.C(Cl)Cl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1)=[N+:31]=[N-:32]
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
To a solution of 6.5 g (0.019 mole) of 5-amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole (Example 64) in 5ml of conc. hydrochloric acid and 120 ml of water, cooled to 0°, was added an ice cold solution of 1.5 g (.022 mole) of sodium nitrite in 5 ml of water over a 5 minute period. After stirring 10 minutes at 0°, an ice cold solution of 1.4 g (.022 mole) of sodium azide in 5 ml of water was added portionwise. A cream-colored precipitate formed followed by copious evolution of nitrogen. Stirring was continued for 1 hour at 0°. The reaction mixture was made basic (pH 13) with sodium hydroxide and allowed to stand overnight. It was dissolved in methylene chloride, the organic layer was separated, washed with water and dried over potassium carbonate. Evaporation of the solvent gave 4 g of the crude azide as a deep red oil. It was purified by chromatography on silica gel (5% methanol-chloroform) to give 5-azido-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole; ir spectrum: strong --N=N=N absorption at 2100 cm-1.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[C:18]2[CH:23]=[CH:22][C:21]([O:24][C@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+:37].C(O)C>C(O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[C:18]2[CH:23]=[CH:22][C:21]([O:24][C@H:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([O-:28])=[O:27])=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:37]
Reactant: CCCCCc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 71 %

Procedure:
To a solution of (2R)-2-([4-[1-(4-pentylphenyl)-5-methyl-1H-pyrrol-2-yl]phenyl]oxy)-3-phenylpropanoic acid (621 mg, 1.33 mmol) in ethanol (10 ml) was added 1N sodium hydroxide-ethanol solution (1.3 ml, 1.3 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 460 mg, (yield: 71%)
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=[O:6])=[N+:2]=[N-:3].[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:9]>>[CH2:13]([O:12][C:10]([C:8]1[N:1]([CH2:4][C:5]([OH:7])=[O:6])[N:2]=[N:3][N:9]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=NCC(=O)O
Product: CCOC(=O)c1nnnn1CC(=O)O
Temperature: 110 °C

Procedure:
A mixture of azidoacetic acid (5.0 grams, 50 mmol.) and ethyl cyanoformate (15.0 grams, 150 millimoles,) was heated at 110°C. for 8.5 hours. The reaction mixture was cooled; crystalline product separated which was filtered and washed with toluene. The filtrate was concentrated under vacuum, and the remaining oil was cooled and seeded with a crystal of the product to give a second crop. The yield of the title product was 5.1 grams (51 percent, assuming pure starting materials), m.p. (both crops) 144°-147°C. The analysis was as follows:
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:13]([CH3:16])[C:14]=2[CH3:15])=[O:8])[C:3]=1[CH3:24].[Br-].[CH:26]1([Zn+])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:26]1([C:2]2[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]3[C:11](=[O:23])[N:12]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:13]([CH3:16])[C:14]=3[CH3:15])=[O:8])[C:3]=2[CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: [Zn+]C1CCCCC1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide (75 mg, 0.189 mmol) was added cyclohexylzinc(II) bromide (0.5M in THF) (1133 μL, 0.566 mmol) and bis(tri-t-butylphosphine)palladium(0) (9.65 mg, 0.019 mmol) and the mixture was stirred at 100° C. in the microwave for 30 minutes. The resulting mixture was diluted with EtOAc and filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C=O)C.[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][CH3:29])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-4-(4-hydroxyphenyl)piperazine (XXII, 0.602 g, 2.2 mmol) in dry THF (4 ml) is added to an ice-cooled slurry of sodium hydride (0.1013 g, 2.5 mmol-60% in oil) in THF (1 ml). DMF (15.3 ml) is added to solubilize the solids that had precipitated, after which ethyl iodide (0.34 ml, 4.3 mmol) is added. The ice/water bath is removed and the mixture stirred for five hr. Another portion of ethyl iodide (0.35 ml, 4.4 mmol) is added and the mixture is allowed to stir over the weekend at 20°-250, at which time it is concentrated and the resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99) containing ammonium hydroxide (0.5%), followed by methanol/dichloromethane (2/98) containing ammonium hydroxide (0.5%). The appropriate fractions are pooled and concentrated to give 1-(tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII). 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII, 0.43 g) is dissolved in methanol and methanol saturated with hydrochloric acid gas is added. After stirring at 20°-25° for 5 hours the slurry is concentrated and ether is added. The solids are collected, washed with ether, and dried to give 1-(4-ethoxyphenyl)piperazine dihydrochloride (XXIV), MS (m/z) 206; IR (mineral oil) 1253, 1511, 2542, 2432, 1475 and 2622 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=1>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2cccc([N+](=O)[O-])c2O)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Yield: 94.1 %

Procedure:
A solution of 2′-hydroxy-3′-nitrobiphenyl-3-carboxylic acid (800 g, 3.2 mol) in methanol (5 L) was hydrogenated over 5% Pd/C (160 g) at room temperature for 8 hours. The reaction mixture was filtered, concentrated and slurried in THF (2.5 L) to give 3′-amino-2′-hydroxybiphenyl-3-carboxylic acid (690 g, 50.5%) as a brown solid. PXRD analysis provided the diffractogram as shown in FIG. 32.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[C:19](=O)[C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[NH:12]3)=[C:9]([F:21])[CH:8]=[C:7]([Cl:22])[C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:19]1[N:11]([C:10]2[C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[C:7]([Cl:22])=[CH:8][C:9]=2[F:21])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1c(F)cc(Cl)c3nc(Cl)sc13)CCCC2
Product: Fc1cc(Cl)c2nc(Cl)sc2c1-n1nc2c(c1Cl)CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.2 g 2-(2,4-Dichloro-6-fluorobenzothiazol-7-yl)1,3,4,5,6,7-hexahydro-2H-indazol-3-one was treated with 2 ml phosphorus oxychloride and the mixture stirred for one hour under reflux. After cooling, it was poured into ice-water, extracted with ethyl acetate and the organic phase washed with sodium hydrogen carbonate and water. It was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography. Yield: 0.07 g=32% of theory m.p.: 161°-163° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:8][C:9]#[N:10]>C1COCC1>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:8][C:9]#[N:10])[CH2:3]1
Reactant: OC1CCNC1
Reactant: N#CCBr
Solvent: C1CCOC1
Product: N#CCN1CCC(O)C1
Yield: 64545.7 %

Procedure:
The method follows that of S3 using 3-hydroxypyrrolidine (15 g, 0.172 mol), BrCH2CN (22.67 g, 0.189 mmol) and dry THF (60 mL). The title-compound was yielded as a straw-coloured oil (15.39 g, 71%) after flash chromatography using CH2Cl2/CH3OH (9:1) as eluent. δH (250 MHz; CDCl3); 1.9-2.25 (m, 2H, 2×ring-H), 2.3 (m, 1H, ring-H), 2.65 (d, OH), 2.85-3.05 (m, 3H, 3×ring-H), 3.95 (d, 2H, NCH2CN) and 4.2 (m, 1H, CH2CHOH); FAB MS, m/z (M+H)+ 127.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC)CC)C>O1CCCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc([N+](=O)[O-])cc1
Yield: 81.3 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (2.8 g, 15 mmol), 4-nitrobenzoyl chloride (3.0 g, 16 mmol), and triethylamine (6.4 mL, 45 mmol) in tetrahydrofuran (60 mL) provided 4-nitro-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (4.1 g). Mp 279-280° C.;Anal. Calcd. for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33; Found: C, 67.69; H, 4.61; N, 8.26.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:22]([O-])=O)[CH:6]=[CH:7][C:8]=2[C:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH:12]=2)[C:3]1=[O:25].CCO>[Pd]>[NH2:22][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)=[C:9]2[C:4]=1[C:3](=[O:25])[N:2]([CH3:1])[CH2:10]2
Reactant: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 4-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohex-3-ene-1-carboxylate (1.03 g, 2.99 mmol) in EtOH (2.6 mL, 45 mmol) was charged with palladium 10% wt on activated carbon(0.1:0.9, Palladium:Carbon, 0.11 g, 0.10 mmol). The reaction mixture was evacuated and purged with hydrogen gas (3×). The reaction mixture was allowed to stir under hydrogen gas at rt for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was collected and then concentrated in vacuo to oil. The two isomers were resolved by SFC purification to afford 544 mg (58% yield) of the cis and 232 mg (25% yield) of the trans title compounds. Cis: 1H NMR (400 MHz, Methanol-d) δ ppm 7.06 (d, J=8.34 Hz, 1 H), 6.61 (d, J=8.34 Hz, 1 H), 4.37 (s, 2 H), 4.20 (q, J=7.07 Hz, 2 H), 3.11 (s, 3 H), 2.72 (d, J=2.53 Hz, 1 H), 2.46-2.56 (m, 1 H), 2.22-2.29 (m, 2 H), 1.60-1.75 (m, 6 H), 1.29 (t, 3 H). MS (ES+): m/z 317.14/319.18 (100/15) [MH+]. HPLC: tR=1.41 min (Micromass TOF: polar—3 min). Trans: 1H NMR (400 MHz, Methanol-d) δ ppm 7.15 (d, J=8.34 Hz, 1 H), 6.62 (d, J=8.34 Hz, 1 H), 4.38 (s, 2 H), 4.13 (q, J=7.16 Hz, 2 H), 3.11 (s, 3 H), 2.34-2.54 (m, 2 H), 2.04-2.11 (m, 2 H), 1.82-1.92 (m, 2 H), 1.48-1.64 (m, 4 H), 1.26 (t, 3 H). MS (ES+): m/z 317.15/319.16 (100/7) [MH+]. HPLC: tR=1.38 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: COc1ccc2c(c1)Cn1ccnc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)Cn1ccnc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]-benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]-benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred for 3 hours at room temperature and worked up to give the product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]2[C:16]([C:17](=[O:27])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)=[C:15]([OH:28])[CH:14]=[C:13]([OH:29])[CH:12]=2)=[O:5])C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]2[C:16]([C:17](=[O:27])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[C:15]([OH:28])[CH:14]=[C:13]([OH:29])[CH:12]=2)=[O:5]
Reactant: CCOC(=O)CCCc1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCc1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of 2-[3-(ethoxycarbonyl)propyl]-7,5-dihydroxy-4′-methoxyisoflavone (104 mg, 0.26 mmol), prepared according to Pelter et al. (Pelter et al, 1998) in anhydrous DCM (2 ml) at −78° C. under nitrogen, 1.0 M BBr3 in DCM (2.1 ml, 2.1 mmol) was added slowly. The mixture was allowed to warm gradually to room temperature overnight. The mixture was then cooled in an ice bath and anhydrous MeOH (2 ml) was added slowly. The solvents were evaporated under reduced pressure leaving a brown solid that was purified by column chromatography on silica gel (gradient elution: DCM to DCM/acetone 8:2) yielding 2-[3-(methoxycarbonyl)propyl]-5,7,4′-trihydroxyisoflavone as a solid (72 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]#[C:13][Si](C)(C)C)[C:3]=1[NH2:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]#[CH:13])[C:3]=1[NH2:18]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cc(Br)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C(F)(F)F)cc(Br)c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
4.26 g of 2-bromo-4-trifluoromethyl-6-trimethylsilanylethynyl-phenylamine (13 mmol) were dissolved in 40 ml THF and the solution was cooled to 0° C. Then 15.2 ml of a 1 M solution of tetrabutylammonium fluoride in THF (15 mmol) were added and the reaction mixture was stirred for 20 min at 0° C. After addition of water, the mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. 1.82 g (54%) of 2-bromo-6-ethynyl-4-trifluoromethyl-phenylamine were isolated as a brown solid after purification (silica gel; cyclohexane/EtOAc 9:1). 1H NMR (CDCl3, 300 MHz): δ 3.48 (s, 1H), 5.03 (br s, 2H), 7.54 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH3:23])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:10]3[N:9]([CH3:23])[C:8]4[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[S:14][C:15]=2[CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 30.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (250 mg) was prepared by following General Procedure E starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (842 mg) and lithium hydroxide (379 mg). LC/MS: m/z 359.9. 1H NMR (DMSO-d6, 400 MHz): δ 8.12 (s, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.55 (s, 1H), 7.48 (d, 1H), 7.38 (dd, 1H), 3.65 (s, 3H), —COOH and —NH proton signal was not observed.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1OC1C.CS([C:20]1[CH:25]=[CH:24][C:23]([O:26]C2C=CC=CC=2)=[CH:22][CH:21]=1)(=O)=O>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH2:1][CH:22]2[CH2:21][CH2:20][CH2:25][CH2:24][CH:23]2[OH:26])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: CC1CO1
Product: O=S(=O)(CC1CCCCC1O)c1ccc(F)cc1

Procedure:
The desired product was prepared by substituting cyclohexene oxide and 4-fluorophenyl methyl sulfone for propylene oxide and 1-(methylsulfonyl)-4-phenoxybenzene, respectively, in Example 120A.