Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[N:4]=1.[CH:38]([N:41]([CH:52]([CH3:54])[CH3:53])[CH2:42][CH2:43][NH:44][C:45](N1C=CN=C1)=[O:46])([CH3:40])[CH3:39]>>[CH3:30][C:26]1[CH:25]=[C:24]([CH:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH2:22][NH:21][C:5]2[N:4]=[C:3]([CH2:2][NH:1][C:45]([NH:44][CH2:43][CH2:42][N:41]([CH:52]([CH3:54])[CH3:53])[CH:38]([CH3:39])[CH3:40])=[O:46])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccc(C(CNc2nc(CN)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cccc(C)c2)c1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Product: Cc1cccc(C(CNc2nc(CNC(=O)NCCN(C(C)C)C(C)C)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cccc(C)c2)c1

Procedure:
The title compound was prepared from (2R,3R,45,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(3-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 65) and N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 27) using a similar procedure to that used in Example 36.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:24])(=[O:23])[C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:25])[C:7]([CH:26]([CH3:28])[CH3:27])=[N:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31]([NH2:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:24])(=[O:23])[C:15]3[CH:21]=[C:20]([O:22][CH2:30][C:31]([NH2:33])=[O:32])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:25])[C:7]([CH:26]([CH3:27])[CH3:28])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(O)cc3S(=O)(=O)N2)c1=O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(OCC(N)=O)cc3S(=O)(=O)N2)c1=O
Temperature: 80 °C
Yield: 49.2 %

Procedure:
To a solution of 2-Butyl-5-hydroxy-4-(7-hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-6-isopropyl-2H-pyridazin-3-one (5f) (38.7 mg, 95.2 μmol) in anhydrous DMF (4 mL), 2-Bromo-acetamide (14.5 mg, 104.7 μmol) was added followed by K2CO3 (39.5 mg, 285.6 μmol). The resulted mixture was heated at 80° C. overnight with stirring. The reaction mixture was concentrated under reduced vacuum and the residue was purified by flash chromatography on silica gel to give the desired product (5g) (21.7 mg) in 49.2% yield. 1H NMR (400 MHz, DMSO-d6): δ7.63-7.66 (m, 1H), 7.62 (br, 1 H), 7.40 (br, 1H), 7.34-7.39 (m, 2 H), 4.58 (s, 2H), 4.10 (m, 2H), 3.23 (m, 1H, J=6.8 Hz), 1.72 (m, 2H, J=7.2 Hz), 1.32 (m, 2H. J=7.2 Hz), 1.21 (d, 6H, J=6.4 Hz), 0.91 (t, 3H, J=7.2 Hz); LC-MS (ESI+): m/e=464.1-[M+1]+ (exact MS: 463.15).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24](Cl)[C:23]=2[N:22]=[CH:21]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[CH2:1]([NH:8][C:24]1[C:23]2[N:22]=[CH:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C:32]=2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2c(Cl)nc3ccccc3c21
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)NCCCn1cnc2c(NCc3ccccc3)nc3ccccc3c21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
One ml of benzylamine was added to 30 mg (0.0831 mmol) of 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]quinoline and the mixture was stirred at 150° C. for 3 hours. Excess benzylamine was distilled off under reduced pressure and 1N hydrochloric acid and brine were added thereto. The mixture was extracted twice with methylene chloride. The organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=150:1 (v/v)) to obtain 35 mg (0.0811 mmol) of 4-benzylamino-1-[3-(tert-butoxycarbonylamino)propyl]-1H-imidazo[4,5-c]quinoline shown below as white powder (mp: 171-172.5° C.). ##STR39## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3330, 1700, 1590, 1540. 1H-NMR (CDCl3) δ (ppm) :1.46 (9H, s), 2.18 (2H, m), 3.25 (2H, m), 4.57 (2H, t, J=7.0 Hz), 4.64 (1H, br), 4.95 (2H, d, J=5.2 Hz), 6.05 (1H, br), 7.26~7.36 (4H, m), 7.47 (2H, d, J=7.6 Hz), 7.51 (1H, t, J=7.6 Hz), 7.82 (1H, s), 7.92 (2H, t, J=8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>C(O)(=O)C.O>[Br:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: COc1cccc(C=O)c1O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
The solution of 2-hydroxy-3-methoxybenzaldehyde (10.0 g, 65.79 mmole) in acetic acid (50 mL) was cooled to 0° C. (ice bath). Bromine (12.55 g, 78.95 mmole) was added dropwise to above solution, which was allowed to stir for 2 hours. The reaction was warmed to room temperature and diluted with water (100 mL). A light brown precipitate was formed. The solid was filtered and washed with water (50 mL). The filtrate was dried on high vacuum to give a light brown solid (12.2 g, 80.0%): GCMS m/z 231.0 (M+). 1H NMR (CDCl3/400 MHz) 10.97 (s, 1H), 9.82 (s, 1H), 7.29 (s, 1H), 7.15 (s, 1H), 3.89 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:28])([F:27])[C:15]1[CH:26]=[CH:25][C:18]([O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:17][CH:16]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:28])[F:27])=[CH:26][CH:25]=3)[CH2:21]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Yield: 66 %

Procedure:
The title compound (D91) (230 mg) was prepared according to the experimental procedure described in Description 62 starting methyl 2,5-dichloronicotinate (180 mg, 0.87 mmol) and 3-(4-(trifluoromethyl)phenoxy)pyrrolidine (D57) (242 mg, 1.05 mmol).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([O:23][CH:24]=[CH2:25])(=[O:22])[CH3:21].[C:26]([OH:31])(=[O:30])[CH2:27][CH2:28]C>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>[C:26]([OH:31])(=[O:30])[CH:27]([CH3:28])[OH:22].[C:20]([O:23][CH:24]=[CH2:25])(=[O:22])[CH3:21]
Reactant: CCCC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=COC(C)=O
Product: CC(O)C(=O)O

Procedure:
A 300 ml autoclave is charged with 0.692 g. of Pd(Ph3P)4 (0.6 mmole Pd), 3.15 g. of Ph3P (12 mmole), 83 ml of butyric acid as solvent, and 37 ml of vinyl acetate (0.4 mole). The autoclave was flushed, heated-up, and operated in a procedure similar to that described in Example 1. Several 1-ml increments of water were added, and then additional water to make a total of 9 ml. was added and the reaction continued overnight. After 23 hours of reaction time at 150° C. and 700 psig the reaction was terminated and analyzed by gas chromatography. The product mixture contained both 60-acetoxypropionic and lactic acids, the amount of lactic acid being 67-100% of the α-acetoxypropionic acid. The presence of lactic acid in this mixture was confirmed by nuclear magnetic resonance and mass spectroscopy. Thus lactic acid was produced in this experiment in one-step from vinyl acetate.
Reaction SMILES: [C:1](=[C:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.C[Mg]I.[OH2:18]>C1COCC1.C(OCC)C>[OH:18][C:3]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=C=O)C1
Reactant: O
Agent: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17 g, 0.06 mol) in THF (45 mL) was slowly added to a solution of MeMgI (21.41 g, 0.129 mol) in diethyl ether. The reaction was conducted at −20° C. under stirring for 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to produce a crude product of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate. The above crude product was dissolved in 20 mL 1,4-dioxane. To the resulting solution was introduced an HCl gas. The resulting mixute was stirred overnight and filtered by suction to produce the title product as a red solid (1.67 g) in a yield of 20% (two steps).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:12]2)=O)(C)(C)C.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[CH:13]12[NH:8][CH:9]([CH2:15][CH2:14]1)[CH2:10][N:11]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:12]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)C(F)(F)F)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC2CCC(C1)N2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (212 mg, 1.0 mmol) in DCM (4 mL) were added triethylamine (208 μL, 1.5 mmol) and trifluoroacetic anhydride (169 μL, 1.2 mmol) at 0° C. and the mixture stirred at 0° C. for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by column chromatography to give 3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a colourless oil. To a solution of 3-(2,2,2-trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in DCM (4 mL) was added TFA (1 mL) and the solution stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a colourless oil (212 mg, 66%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:25]#[N:26])=[C:11]([O:17]C(C1OC=CC=1)=O)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1.[OH-].[K+].O.Cl>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:11]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[OH:17])[C:25]#[N:26]
Reactant: N#CC(=C(OC(=O)c1ccco1)c1ccco1)c1nc2ccccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC(=C(O)c1ccco1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of furan-2-carboxylic acid 2-benzothiazol-2-yl-2-cyano-1-furan-2-yl-vinyl ester (660 mg, 1.82 mmol) and KOH (108 mg, 1.93 mmol) in ethanol (20 mL) was stirred first at room temperature overnight and then at 50° C. for 2 hours. The resulting suspension was poured into water (200 mL), and the solution was adjusted to pH 7 using 5% HCl solution. The solids were isolated by filtration, washed with water, and air-dried to yield 474 mg (97%) of crude 2-benzothiazol-2-yl-3-furan-2-yl-3-hydroxy acrylonitrile which was used in the next step without further purification. MS (m/z, ES+): 268.98 (M+1, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Oc1ccc2ccccc2c1
Solvent: CO
Product: CN(CCOc1ccc(CC(Oc2ccc3ccccc3c2)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 162-4° C. (methanol), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-napthyloxy)propanoate in a manner analogous to that described for Example 2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.CN([CH:26]=[O:27])C.Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH:6]=1)[CH:26]=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc(F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(F)c(C=O)c1
Temperature: -45 °C
Reaction time: 5 h

Procedure:
A solution of 1-tert-butyl-4-fluoro-benzene (4.54 g, 30 mmol) in THF (100 mL) cooled at −78° C. was treated dropwise with a 2.5M solution of nBuLi in hexane (24 mL, 59 mmol). The reaction mixture was stirred for 5 h at −45° C. then DMF (3.5 mL, 44 mmol) was added at −75° C. and the reaction mixture was stirred for 0.5 h at −75° C. The reaction mixture was poured onto 1N aq. HCl and extracted with Et2O. Combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g silica gel, hexane to hexane-EtOAc 10:1) as a light yellow oil: TLC (hexane-EtOAc 10:1) Rf=0.48, HPLC RtA=2.10 min; 1H NMR (400 MHz, CDCl3): δ10.36 (s, 1H), 7.85 (dd, 1H), 7.62 (m, 1H), 7.08 (dd, 1H), 1.32 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[CH3:37][NH2:38]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH:33]=[C:32]([C:34]([NH:38][CH3:37])=[O:35])[CH:31]=[N:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-n5cc(C(=O)O)cn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CN
Product: CNC(=O)c1cnn(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)c1

Procedure:
Starting material: 1-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-1H-pyrazole-4-carboxylic acid (Example 186) and methyl amine (0.16 mL, 2.0M in THF, 0.320 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](I)[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][CH2:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1cc(I)ccn1
Reactant: Cc1ccc(CO)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(COc2ccnc(Cl)c2)cn1
Temperature: 105 °C
Yield: 74.6 %

Procedure:
(6-Methylpyridin-3-yl)methanol (3.25 g, 26.4 mmol), 2-chloro-4-iodopyridine (5.7 g, 24 mmol), cesium carbonate (10.1 g, 31.2 mmol), CuI (0.90 g, 4.8 mmol) and 1,10-phenanthroline (0.86 g, 4.8 mmol) were stirred in toluene (15 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 100% ethyl acetate) to provide the title compound (4.2 g, 75%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=2.0 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.65-7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.83-6.80 (dd, J=5.8, 2.2 Hz, 1H), 5.08 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([O:17][CH3:18])=[N:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[CH:13]=O)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=C(C2C(OC)=NC(C)=C(C=2)C#N)C=CC=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:19][CH2:13][C:12]1[C:11]([CH3:16])=[N:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: COc1nc(C)c(C#N)cc1-c1cccc(Cl)c1
Reactant: COc1nc(C)c(C=O)cc1-c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1nc(C)c(CCl)cc1-c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 72 %

Procedure:
5-(3-Chlorophenyl)-6-methoxy-2-methylnicotinaldehyde. To a cooled solution, −78° C., of 5-(3-chlorophenyl)-6-methoxy-2-methylnicotinonitrile (500 mg, 1.9 mmol) in DCM (15 mL), under nitrogen, was added diisobutylaluminium hydride (1 M in hexanes, 4.8 mL, 4.8 mmol) drop-wise, over 3 minutes. The reaction mixture was stirred at −78° C. for 1 h. The reaction was carefully quenched by addition of saturated sodium fluoride (1 mL). After stirring for 30 minutes the suspension was filtered and the filtrate concentrated under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (358 mg, 72%). [M+H]=262.05.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[I:6][C:7]1[CH:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[C:10](O)=[N:11][CH:12]=1>CN(C=O)C>[Cl:3][C:10]1[C:9]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([I:6])=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(I)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(I)cnc1Cl
Temperature: 110 °C
Yield: 62 %

Procedure:
To an ice-cold mixture of POCl3 (1.60 mL) and DMF (1 mL) in a microwave vial, 5-iodo-3-trifluoromethyl-2-pyridinol (1 g, 3.47 mmol) is added. The vial is sealed and heated 20 min at 110° C. The reaction mixture cooled at room temperature is poured into ice cold water. The product precipitates. The precipitate is filtered, washed with cold water and dried to afford 661 mg (62%) of a light brown powder.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].C(N(CC)CC)C.FC(F)(F)S(O[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=2)[N:41]=1)(=O)=O>CS(C)=O.O>[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=5)[N:41]=4)[CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: O=S(=O)(Oc1ccc2ccc(F)cc2n1)C(F)(F)F
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4ccc(F)cc4n3)CC2)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
To a RT solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (1.00 g, 3.18 mmol, prepared according to Step 2 of Example 1) and triethylamine (2.00 ml, 14.35 mmol) in DMSO (10 ml) was added a solution of 7-fluoroquinolin-2-yl trifluoromethanesulfonate (1.10 g, 3.73 mmol, prepared according to Step 3 of Example 2) in DMSO (2 mL). The reaction mixture was heated at 60° C. for 2.5 h. The reaction was cooled RT and diluted with water. The mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and the solution was evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→3:1). The fractions containing product were concentrated in vacuo and the residue was stirred vigorously over Et2O for 3 h. The solid was filtered, washed with Et2O and dried to give 674 mg (46%) of the desired product. m/z=460 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (d, J=2.34 Hz, 1H), 8.59 (d, J=2.34 Hz, 1H), 8.39 (br. s., 1H), 8.04 (d, J=9.21 Hz, 1H), 7.69-7.83 (m, 2H), 7.45-7.58 (m, 2H), 7.18-7.28 (m, 2H), 7.08 (td, J=8.77, 2.63 Hz, 1H), 4.66 (d, J=13.30 Hz, 2H), 3.13-3.29 (m, 1H), 2.86-3.03 (m, 2H), 2.82 (d, J=4.68 Hz, 3H), 1.72-1.97 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)[C:9]2[CH:22]=[CH:21][C:20]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(O)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N:30]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)[C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[CH:17]=4)[C:12]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)(O)[C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.[I-].[Na+].O.[PH2]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:44][C:41]1[CH:40]=[CH:39][C:38]([N:30]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]4[C:11]([C:12]=3[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[CH:10][C:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)=[CH:22][CH:21]=4)[CH:17]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(c2)C(O)(c2ccccc2)c2ccc(N(c4ccc(C)cc4)c4ccc(C)cc4)cc2C3(O)c2ccccc2)cc1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c(-c4ccccc4)c4cc(N(c5ccc(C)cc5)c5ccc(C)cc5)ccc4c(-c4ccccc4)c3c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
The crude N,N,N′,N′-tetrakis(4-methylphenyl)-2,6-diamino-9,10-dihydro-9,10-diphenyl-9,10-anthracenediol was dissolved in 65 ml acetic acid. Sodium iodide (10 g), and sodium hypophosphite hydrate (10 g) were added with stirring. The mixture was heated to reflux for 60 minutes, cooled to room temperature and poured into water. The precipitated solid was collected by filtration, washed with water, washed with a small amount of methanol (˜5 ml) and then dried. Purification by column chromatography yielded 2.3 g (76% yield) of pure N,N,N′,N′-tetrakis(4-methylphenyl)-9,10-diphenyl-2,6-anthracenediamine (Inv-B73) as an orange solid. At a pressure of 600 mTorr, Inv-3 sublimed at 290° C. using train sublimation. FD-MS (m/z): 720.
Reaction SMILES: Br[C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 5-bromo-2,4-dinitrotoluene (2.61 g, 10 mmol) and pyrrolidine (2.49 g, 35 mmol) was heated at 90°-100° C. for 2 hours. The resulting dark brown oil was combined with cracked ice and the precipitated solids filtered off, washed with water, and vacuum dried. Purification was carried out by flash chromatography of the solids on a silica gel column using chloroform/hexane (50:50) as eluant. Evaporation of the eluants afforded 17 as orange needles: 2.0 g (82%) yield; mp 142° C.; TLC (chloroform), Rf =0.82; IR (KBr pellet) 1606, 1566, 1510, 1369, 1350, 1334, 1301, 1276, 1130, 833 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ8.83 and 8 53 (2H, 2×s, aromatic protons), 3.27 (4H, m, methylenes adjacent to pyrrolidine N), 2.61 (3H, s, methyl), 1.99 (4H, m, other pyrrolidine methylenes); mass spectrum (EI mode) m/z 251 (P+), 234 (P+ -OH). Anal. Calcd for C11H13N3O4 : C, 52.58; H, 5.21; N, 16.72. Found: C, 52.51; H, 5 27; N, 16.64.