Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[O:7])=[CH:17][CH:18]=1
Reactant: COC(C)(C)OC
Reactant: O=C(c1ccc(Br)cc1)[C@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of cis-2-(4-bromobenzoyl)-1-cyclohexanecarboxylic acid (4.0 g, 12.85 mmol) in MeOH (50 mL) was added 2,2-dimethoxypropane (2.01 g, 19.28 mmol) and HCl (4.0 M in dioxane, 1.20 mL). The resulting solution was stirred at 40° C. for 3 days, and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 3 to 6% ethyl acetate in hexanes to afford methyl cis-2-(4-bromobenzoyl)cyclohexane-carboxylate (1.76 g, 42%). LC-MS ret. time 3.40; m/z 326 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.35-1.51 (m, 3H), 1.72-1.86 (m, 2H), 1.91-2.05 (m, 2H), 2.11-2.20 (m, 1H), 2.74 (m, 1H), 3.58 (s, 3H), 3.82 (q, 1H), 7.62 (m, 2H), 7.73 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][Zn+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccc(C[Zn+])cc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(F)c(F)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen. (3,4-Difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) was added and the brown solution was stirred at 60° C. overnight. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq). The organic layer was dried over MgSO4, filtered and evaporated to yield a yellow oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(3,4-difluorobenzyl)isonicotinate (7.7 g, 90%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.16 (s, 2H), 6.94-7.01 (m, 1H), 7.02-7.12 (m, 2H), 7.66-7.71 (m, 2H), 8.70 (dd, 1H). MS m/z 264 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=1)[CH:6]=[N:5]2
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1cnc2cc(Br)ccc2n1
Solvent: CS(C)=O
Solvent: O
Product: Clc1cccc(CNc2cnc3cc(Br)ccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-Bromo-2-chloro-quinoxaline (0.3 g, 1 eq., 1.23 mmol) in DMSO (9 mL), was added 3-chloro benzyl amine (0.87 g, 5 eq., 6.2 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, water (60 mL) was added and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The organic layer was concentrated under vacuum to obtain the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1CO
Reaction time: 8 h
Yield: 106.9 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol) in THF (150 mL) was added BH3-THF (1 M, 231 mL) at room temperature, and the reaction mixture was stirred overnight. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. The reaction was quenched with water (150 mL) and extracted with EtOAc (3×500 mL). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (10 g, crude), which was directly used in the next step without further purification. MS (ES+) C7H8BrNO requires: 201. Found: 202, 204 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:33].[NH4+]>C(Cl)Cl.C(O)C>[ClH:27].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:33])[NH2:2]
Reactant: [NH4+]
Reactant: N#Cc1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)c1cccc(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 150 %

Procedure:
5 To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl)methoxy]phenyl ester (280 mg, 0.7 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (15 mL) at 0° C. The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (10 nL) and ammonium carbonate (300 mg, 3.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (150 mL), washed with 10% K2CO3 (2×50 mL), and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and then concentrated in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white foam (238 mg, 75%). 1H-NMR (300 MHz, DMSO-d6) δ 5.15 (s, 2H), 6.67 (d, 1H, J=4.0 Hz), 6.81 (s, 1H), 7.03 (d, 1H, J=4.0 Hz), 7.32 (t, 1H, J=8.3 Hz), 7.58 (t, 1H, J=7.5 Hz), 7.65 (t, 1H, J=7.7 Hz), 7.75-7.94 (m, 6H), 9.27 (br s, 2H), and 9.45 (br s, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H17N2ClO4S: 417.1 (M+H), 439.0 (M+Na). Found: 417.4, 439.1.
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:3]1=2.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.P(Cl)(Cl)([Cl:41])=O>O>[Cl:41][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(=O)[nH]cnc23)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)ncnc23)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
tert-Butyl 4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (466 mg, 1.38 mmol) was dissolved in phosphorus oxychloride (2 mL) and stirred at 100° C. for 5 hours. The reaction liquid was concentrated under a reduced pressure, a 2 N aqueous sodium hydroxide solution (pH=14) was added, and then di-tert-butyl dicarbonate (602 mg, 2.76 mmol) was added to the aqueous solution, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The obtained residue was purified by using silica gel chromatography (chloroform:methanol=10:1) to give tert-butyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (201 mg, 43.1%) as a pale yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:19])[NH:13][CH:14]=[C:15]([Cl:18])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].Br[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24](C(OC(C)(C)C)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:19])[N:13]([CH2:21][C:22]3[C:30]4[C:25](=[N:26][CH:27]=[CH:28][CH:29]=4)[NH:24][N:23]=3)[CH:14]=[C:15]([Cl:18])[C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)c[nH]c2=O)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)c(Cl)cn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-[(4,5-dichloro-2-oxo-1,2-dihydropyridin-3-yl)oxy]benzonitrile (49 mg, 0.155 mmol) in DMF (1 mL) was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (48.5 mg, 0.155 mmol) and potassium carbonate (21.46 mg, 0.155 mmol) and the mixture heated at 55° C. for 30 minutes. After this time, the reaction mixture was allowed to cool to room temperature and the mixture was filtered through a Gelma Acrodisc. The filtrate was purified on Gilson LC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) eluting with a gradient of 20-95% ACN/water (0.5% TFA). The desired fractions were combined and evaporated in vacuo. This residue was dissolved in TFA (3 mL) and allowed to stand at room temperature for 15 minutes and then the solvent was evaporated in vacuo to give a white solid. This solid was suspended in ACN (10 mL) and the solvent removed in vacuo to give the title compound. 1H NMR (DMSO-d6) δ=8.52 (d, 1H, J=3.8 Hz), 8.41 (s, 1H), 8.19 (d, 1H, J=7.9 Hz), 7.74 (s, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.19 (dd, 1H, J=4 and 8.9 Hz) and 5.49 (s, 2H) ppm. HRMS (M+1): 445.9991.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: Cc1cccc(C)c1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C)cccc1C
Reaction time: 8 h

Procedure:
65 g of 2,6-dimethylphenol are dissolved in 200 ml of dry DMF and, under N2, 23.2 g of a 55% suspension of sodium hydride in mineral oil are added in portions. Then 50.4 ml of methyl bromoacetate are added dropwise with stirring, and the mixture is left to stand overnight. The precipitated salt is filtered off with suction, and the filtrate is concentrated. The residue is taken up in ethyl acetate, and the solution is extracted with water. The organic phase is dried over magnesium sulfate and concentrated. An oily liquid remains and is used directly in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>>[C:12]([NH:11][S:8]([C:6]1[CH:5]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:3]=[C:2]([NH:1][C:35]2[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)[CH:7]=1)(=[O:10])=[O:9])([CH3:14])([CH3:15])[CH3:13]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Product: CC(C)(C)NS(=O)(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Cl)c1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 2,4,5-trichloropyrimidine as the starting materials in 35% yield. LCMS for C27H33Cl2N5O4SNa (M+Na)+: m/z=616.2, 618.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:21]>N1CCCCC1.C(O)C>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][NH:25][C:26]([C:28]1[C:32]([CH3:33])=[C:31]([CH:34]=[C:18]2[C:11]3[C:10]([NH:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)=[N:15][CH:14]=[N:13][C:12]=3[NH:16][C:17]2=[O:19])[NH:30][C:29]=1[CH3:36])=[O:27])[CH3:38]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (66 mg, 0.24 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (63.7 mg, 0.24 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 78.5 mg (62%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.33 (br s, 1H, NH), 11.61 (br s, 1H, NH), 9.17 (br s, 1H), 8.29 (s, 1H), 7.69 (dd, J=2.5 & 6.5 Hz, 1H), 7.35 (m, 4H), 3.29 (m, 2H, CH2), 2.5 (m, 6H, N(CH2CH3)2 & CH2), 2.45 (s, 3H, CH3), 2.25 (s, 3H, CH3), 0.96 (t, J=7 Hz, 6H, N(CH2CH3)2). MS 526 [M++1].
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[C@@H:29]([CH2:33][CH:34]=[CH2:35])[C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:1]([N:8]([C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11])[C:30](=[O:31])[CH:29]([N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]1=[O:18])[CH2:33][CH:34]=[CH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: C=C[C@H](NCc1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCC(C(=O)N(Cc1ccccc1)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-N-benzyl-1-phenylprop-2-en-1-amine (5a) (240 mg) in DCM (5 mL) at RT under N2 was added (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (4b) (263 mg) and EDAC.HCl (224 mg). The mixture was stirred overnight at RT, then diluted with 30% hexanes/EtOAc and washed with H2O, 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and concentrated to a white foamy solid (233 mg, 48%). 1H NMR (300 MHz) The NMR of this compound in both CDCl3 and DMSO-d6 (with elavated temperatures) was complex, thus limiting interpretation. MS APCI, m/z=451 (M+1). LC/MS 3.13 min., Method A.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.[H-].[Na+]>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([OH:5])[N:6]=2)=[CH:14][CH:15]=1
Reactant: CN(C)C=CC(=O)c1ccc(F)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
2-Cyanoacetamide (4.31 g) and 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (9.00 g) were added in this order to a mixture of sodium hydride (60% oil, 4.10 g) and DMF (90 mL), and the resultant mixture was stirred at 105° C. for 2 hours. The solvent was distilled off. Water was added to the obtained residue, and then, the mixture was rendered acidic by the addition of acetic acid and stirred at 70° C. for 15 minutes. Methanol was added to the reaction mixture for suspension, and the deposited solid was washed with ethyl acetate to obtain the title compound (9.98 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15][CH:14]3[C:12]2([C:27](Cl)=[O:28])[CH2:13]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.CC(C)=O>[C:5]1([CH:11]2[N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:15][CH:14]3[C:12]2([C:27]([N:1]=[N+:2]=[N-:3])=[O:28])[CH2:13]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)Cl)C2c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(C(=O)N=[N+]=[N-])C2c2ccccc2)cc1
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred solution of sodium azide (5.63 g, 86.62 mmol) in 17 mL of water was added in a dropwise fashion to a solution of racemic 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl chloride (5.0 g, 13.3 mmol) (Intermediate 3) in 30 mL of acetone. 3 mL of water was then added to the reaction and the reaction mixture was stirred for 16 hours. The acetone was removed at reduced pressure and the reaction diluted with both methylene chloride and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carbonyl azide (5.1 g, 100% crude yield).
Reaction SMILES: O[CH:2]([CH3:17])[C:3]#[C:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]([C:44]([NH:46][O:47][C:48]([O:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:49])=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>[O:50]([C:48]([O:47][N:46]([CH:2]([CH3:17])[C:3]#[C:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:6]1)[C:44]([O:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:45])=[O:49])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Reactant: CC(O)C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
trans-2-(3-Hydroxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (205, 210 mg, 0.89 mmol), triphenylphosphine (288 mg, 1.1 mmol) and N,O-bis(phenoxycarbonyl)hydroxylamine (283 mg, 1.1 mmol) were dissolved in dry THF (5 mL). The solution was cooled to 0° C. under dry argon, and diisopropylazodicarboxylate (216 mL, 1.1 μmol) was added dropwise. Stirring was continued for 1 hour at the same temperature. The solvent was evaporated and the residue was purified via flash column chromatography (eluent, 30% ethyl acetate in hexane) to yield 250 mg (57%) of trans-2-{3-(N-phenoxycabonyloxy-N-phenoxycarbonyl-amino)-but-1-ynyl}-5-(4-fluorophenyl) tetrahydrofuran (206). 1H-NMR (CDCl3) δ 7.15-7.45 (12H, m), 7.02 (2H, t, J=8.6 Hz), 5.32 (1H, q J=7.0 Hz), 5.07 (1H, t, J=6.8 Hz), 4.96 (1H, t, J=5.7 Hz), 2.25-2.50 (2H, m), 2.05-2.20 (1H, m), 1.70-1.85 (1H, m), 1.66 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[CH2:21])=[CH:16][N:15]=2)=[CH:3][CH:2]=1>[Pd].[Pt].CCO>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=2)=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccc(-c2cccc3c2oc2ccccc23)nc1
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1ccc(-c2cccc3c2oc2ccccc23)nc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-(Dibenzo[b,d]furan-4-yl)-5-(prop-1-en-2-yl)pyridine (7.5 g, 26.3 mmol) was added to a hydrogenator bottle containing EtOH (150 mL). The reaction mixture was degassed by bubbling nitrogen for 10 min Pd/C (0.28 g, 2.63 mmol) and Pt/C (0.26 g, 1.3 mmol) were added to the reaction mixture. The reaction mixture was placed on the Parr hydrogenator for 1 h. The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane to yield 7.5 g (99%) of the desired product. The product was confirmed by GC/MS and NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C(OC)(OC)OC>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC1CC(=O)N(CNc2ncccc2N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: CCCC1CC(=O)N(Cn2cnc3cccnc32)C1
Yield: 302.4 %

Procedure:
A solution of 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78 (1 eq, 1.6 mmol, 300 mg), and para-toluenesulfonic acid (0.32 mmol, 0.2 eq, 42 mg) in trimethyl orthoformate (15 ml) is allowed to react at room temperature for 3 days. After hydrolysis (20 ml of saturated NaHCO3), extraction with AcOEt (2×10 ml), drying of the cumulated organic layers over MgSO4, and filtration, the volatiles are removed under reduced pressure and the crude material is purified by preparative chromatography affording 250 mg of 1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one 268.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[OH:24][B:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[CH2:27][O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:34][C:31]3[CH:32]=[CH:33][C:28]4[CH2:27][O:26][B:25]([OH:24])[C:29]=4[CH:30]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc2c(c1)B(O)OC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A 8-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (20 mg, 0.052 mmol, 1.05 eq.), 1-hydroxy-3H-2,1-benzoxaborol-6-amine (7.5 mg, 0.05 mmol, 1 eq.) and DMSO (0.5 ml). The mixture was stirred at 90° C. under Ar for 2 hr. After cooling to room temperature, the mixture was added to water (5 ml). The precipitate was collected by filtration and washed with water. After dried, the mixture was purified by prep. TLC using 10% of ethyl acetate in dichloromethane as a mobile phase to give the title compound as a solid (10 mg, 52% yield). MW=385.68. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.92 (d, J=4.0 Hz, 1H), 6.58 (brs, 1H), 5.15 (s, 1H), 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH:1]([C:8]1[C:9]([C:18](O)=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:8]2[C:9]=1[CH:10]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=[CH:17]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Product: Clc1c2ccccc2nc2cc3ccccc3cc12

Procedure:
treating 3-anilino-2-naphthoic acid with phosphorous oxychloride to produce 12-chloro-benz[b]acridine;