Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[Br:10]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: COc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1nc(N)ncc1Br
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 4-methoxypyrimidine-2-ylamine (1.84 g, 14.7 mmol) in chloroform (600 mL) was added N-bromosuccinimide (2.62 g, 14.7 mmol). After stirring in the dark for 5 hours, the solution was added to CH2Cl2 (200 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 2.88 g (96%) of 5-bromo-4-methoxypyrimidine-2-ylamine. LCMS (m/z): 204/206 (MH+). 1H NMR (CDCl3): δ 8.10 (s, 1H), 4.93 (bs, 2H), 3.96 (s, 3H).
Reaction SMILES: [NH:1]([C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C@H:2]([C:10]([NH:12][C@H:13]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65](OC)=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:55])[CH2:50][C:51](=[O:53])[NH2:52])=[O:47])[CH2:41][CH2:42][C:43](=[O:45])[NH2:44])=[O:38])[C@@H:30]([CH3:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[O:11])[C@@H:3]([CH3:9])OC(C)(C)C.[OH2:79].[NH2:80][NH2:81]>CO>[NH:1]([C:69]([O:71][CH2:72][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)=[O:70])[C@H:2]([C:10]([NH:12][C@H:13]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:46]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([NH:80][NH2:81])=[O:66])[CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:55])[CH2:50][C:51](=[O:53])[NH2:52])=[O:47])[CH2:41][CH2:42][C:43](=[O:45])[NH2:44])=[O:38])[C@@H:30]([CH3:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[CH:17][CH:16]=1)=[O:11])[C@@H:3]([CH3:9])[O:79][C:15]([CH3:20])([CH3:16])[CH3:14]
Reactant: O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Reactant: NN
Solvent: CO
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN)[C@@H](C)OC(C)(C)C

Procedure:
2.0 g of Z-Thr(tBu)-Tyr(tBu)-Thr(tBu)-Gln-Asn-Phe-OCH3 are dissolved in 150 ml of methanol and caused to react with 10.7 ml of hydrazine hydrate for 6 hours at room temperature. The precipitate is filtered off, washed with methanol, and dried in a high vacuum over concentrated sulfuric acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[S:1]1[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: c1csc(-c2cccs2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)c1ccc(-c2cccs2)s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a suspension of 2,2′-bithiophene (1.0 g) in tetrahydrofuran (10 ml) was added a solution of n-butyl lithium in n-hexane (1.54 M, 4.3 ml) at −25° C. under nitrogen atmosphere. The mixture was stirred at −60° C. for 30 minutes. To the solution dry-ice (1.0 g) was added and the mixture was stirred at ambient temperature for 30 minutes. To the resultant suspension hydrochloric acid (1N, 10 ml) and ethyl acetate were added. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether. The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried to give [2,2′]bithiophenyl-5-carboxylic acid (952 mg, 75.6%).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[NH2:8][C:9]1[N:10]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29][CH2:28]2)[CH:2]=[CH:13][C:14]=1[C:15](=[O:16])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and propionyl chloride (Aldrich 98%) using the procedure described in Example 24. HRMS, observed: 401.1988, Calcd for (M+H)+: 401.1984.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[I:1][C:2]1[C:7]([C:8]([O:10][CH3:13])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1c(I)ccnc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Iodo-2-methoxynicotinic acid (800 mg, 2.87 mmol) is dissolved in MeOH (7 mL) and cooled at 0° C. Trimethylsilyldiazomethane (9 mL, 2M in hexane, 4.5 mmol) is added slowly over 20 minutes. The reaction mixture is brought to room temperature and stirred for 16 hours. The reaction mixture is concentrated and purified by silica gel column chromatography using hexane:ethyl acetate as eluent to afford the desired compound. 1H NMR 400 MHz (DMSO-d6) δ 7.88 (d, 1H, J=5.6 Hz), 7.34 (d, 1H, J=5.6 Hz), 4.12 (s, 3H), 3.84 (s, 1H); MS m/z 294.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18](=[O:19])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2ccc(-c3ccncc3)c3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)naphth-1-ylacetic acid (D2) and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) following a similar procedure to Example 1.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[S:16])=[C:10]([CH3:20])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:2](=[O:3])[C:1](=[O:5])[N:17]([CH2:18][CH3:19])[C:15]2=[S:16])=[C:10]([CH3:20])[CH:9]=1
Reactant: CCNC(=S)Nc1ccc(Cl)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN1C(=O)C(=O)N(c2ccc(Cl)cc2C)C1=S
Yield: 62.2 %

Procedure:
Oxalyl chloride (10.5 g; 0.082 mol) was added dropwise to the stirring solution of N-(4-chloro-2-methylphenyl)-N′-ethylthiourea (17 g; 0.075 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N hydrochloric acid (500 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethyl acetate/hexane to give 13.2 g of 1-(4-chloro-2-methylphenyl)-3-ethyl-2-thioxo-4,5-imidazolidinedione, m.p. 161–162° C. Mass spectrum; FAB (M+H)+ m/z 283. 1H-NMR (DMSO-d6; 300 MHz): δ 7.49 (d, 1H), 7.39 (m,1H), 7.33 (d, 1H), 3.91 (m, 2H), 2.16 (s, 3H), and 1.23 ppm (t, 3H).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:9][CH:8]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:15]=[C:16]([C:22]5[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:32][NH:33][CH3:34]>>[CH:27]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([CH:8]5[CH2:7][N:6]([S:3]([CH2:1][CH2:2][N:33]([CH3:34])[CH3:32])(=[O:5])=[O:4])[CH2:9]5)[CH:31]=[CH:30][C:13]=4[C:14]=3[N:15]=2)=[N:26][CH:25]=[N:24]1)([CH3:28])[CH3:29]
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)CCN(C)C)C3)ccc1-2
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a suspension of 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (75 mg, 0.17 mmol) in IMS (2 mL) was added dimethylamine (2M in MeOH, 158 μL, 0.32 mmol) and the reaction mixture was stirred for 72 hours. The mixture was concentrated in vacuo to low volume and partitioned between DCM and water. The layers were separated and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was combined with a previous batch of the desired compound and purified by flash chromatography (SiO2, 0-2% MeOH in DCM) to give 455 as a white solid (43 mg, 34%). LCMS: RT=8.51 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.36 (1H, d, J=8.20 Hz), 7.90 (1H, s), 7.16 (1H, dd, J=8.24, 1.92 Hz), 7.03 (1H, d, J=1.88 Hz), 5.93-5.83 (1H, m), 4.39 (2H, t, J=5.04 Hz), 4.26 (2H, t, J=8.23 Hz), 4.10 (2H, t, J=7.33 Hz), 3.81-3.74 (1H, m), 3.40 (2H, t, J=5.05 Hz), 3.22-3.14 (2H, m), 2.81 (2H, t, J=7.47 Hz), 2.29 (6H, s), 1.61 (6H, d, J=6.63 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([C:12]2[CH:17]=[CH:16]C(Cl)=[CH:14][CH:13]=2)[NH:10][CH3:11])[CH:3]=1.Cl[C:20]([Cl:30])(OC(=O)OC(Cl)(Cl)Cl)Cl.C1C[O:34][CH2:33]C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:33](=[O:34])[N:10]([CH3:11])[CH:9]2[C:12]1[CH:13]=[CH:14][C:20]([Cl:30])=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCOC1
Reactant: CNC(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Bromo-2-[(4-chloro-phenyl)-methylamino-methyl]-phenylamine (4.0 g, 0.012 mol) dissolved in THF (100 mL) is added triphosgene (4.4 g, 0.015 mol). The mixture is stirred at RT for 1 hours. The reaction is quenched with H2O, extracted with ethyl acetate, dried over NaSO4 and concentrated. This produces the desired compound.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[F:40])[NH:36][CH2:35][CH2:34]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[F:40])[N:36]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=1)=[O:29])[CH2:35][CH2:34]2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: Fc1cc2c(cc1F)NCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)c(F)cc21

Procedure:
0.10 g (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 50 mg (0.26 mmol) 5,6-difluoro-2,3-di-hydro-1H-indole, 0.10 mL (0.72 mmol) TEA and 80 mg (0.25 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[C:1]1([NH:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CNc1cccc2ccccc12

Procedure:
In 5 ml of THF, 500 mg of 1-naphthylamine was added, then 168 mg of sodium hydride (60% in oil) was added and the resultant mixture was stirred for 30 min under ice cooling. To the reaction mixture, 0.46 ml of ethyl bromoacetate was added and the mixture was refluxed for 5 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was re-dissolved in ethyl acetate. The obtained solution was washed with 5% sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated. under reduced pressure and subjected to a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give 720 mg of ethyl 1-naphthylaminoacetate. In 10 ml of ethanol, 460 mg of the ester was dissolved, 3.78 ml of 1N-NaOH aqueous solution was added and the resultant mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and crystallized by the treatment with ether to give 188 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CN1C(=O)CCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.Br[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH:46]([CH3:50])[CH2:47][O:48][CH3:49])[CH:44]=1)[C:40]#[N:41]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45][CH:46]([CH3:50])[CH2:47][O:48][CH3:49])[CH:44]=1)[C:40]#[N:41]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COCC(C)Oc1cc(Br)cc(C#N)c1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCC(C)Oc1cc(C#N)cc(Oc2cc(F)cc(F)c2)c1
Temperature: 120 °C
Yield: 62.5 %

Procedure:
3,5-Difluorophenol (2.00 equiv; 51.8 mmol; 6.74 g) was charged to a 100 ml round-bottomed flask (3 necks, 2 stoppers, air condenser with argon inlet, magnetically stirred, oven dried) followed by NMP (471 mmol; 45.3 ml; 46.7 g) and cesium carbonate (51.8 mmol; 16.9 g). The mixture was sparged with argon for 10 minutes then cuprous monochloride (6.48 mmol; 641 mg), 2,2,6,6-tetramethyl-3,5-heptanedione, (1.30 mmol; 271 μl; 239 mg) and 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile (1.00 equiv; 25.9 mmol; 7.00 g) were charged sequentially. The mixture was sparged with argon for 5 minutes then heated to 120° C. and stirred for 24 hours. The reaction mixture was cooled and partitioned between HCl solution (1M, aqueous, 200 ml) and MTBE (200 ml). The layers were separated and the organic portion washed with NaOH solution (1M, aq, 200 ml), water (200 ml) and brine (200 ml). The resultant organic solution was dried over MgSO4, filtered and the solvent removed in vacuo affording a brown oil. This material was purified by flash column chromatography affording 3-(3,5-difluorophenoxy)-5-(2-methoxy-1-methylethoxy)benzonitrile as a pale yellow oil (5.17 g, 63%). 1H NMR (400 MHz, CDCl3) δ: 7.01 (s, 1H), 6.86 (m, 2H), 6.62 (m, 1H), 6.53 (m, 2H), 4.54 (m, 1H), 3.53 (m, 2H), 3.39 (s, 3H), 1.32 (d, 3H).
Reaction SMILES: COC1C=CC2C3C4C=CN=CC=4C(=O)C=3C(=O)NC=2C=1.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:39]3[C:38]4[CH:37]=[N:36][CH:35]=[CH:34][C:33]=4[C:32](=[O:40])[C:31]=3[C:30](=O)[NH:29][C:28]=2[CH:42]=1.P(Cl)(Cl)([Cl:45])=O>>[Cl:45][C:30]1[C:31]2[C:32](=[O:40])[C:33]3[CH:34]=[CH:35][N:36]=[CH:37][C:38]=3[C:39]=2[C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:42][C:28]=2[N:29]=1
Reactant: COc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccncc1-3
Reactant: O=P(Cl)(Cl)Cl
Agent: COc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1cnccc1-3
Product: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccncc1-3
Temperature: 60 °C
Reaction time: 72 h

Procedure:
The mixture of 3-methoxy-5H-5,9-diaza-benzo[c]fluorene-6,7-dione and 3-methoxy-5H-5,10-diaza-benzo[c]fluorene-6,7-dione (8.77 g) obtained above was suspended in phosphorus oxychloride (359 g) and stirred at 60° C. for three days. Excess phosphorus oxychloride was evaporated under reduced pressure. The residue was treated with ice water and saturated sodium hydrogen carbonate to adjust the pH to about 7. Black ppt was collected with suction and washed water. The ppt was purified by silica gel column chromatography developed by dichloromethane-methanol-trifluoroacetic acid (200:2:1) and by dichloromethane-methanol-trifluoroacetic acid (200:4:1). This chromatography gave two yellow bands. The first band was collected and evaporated. The residue was treated with methanol to give a less polar isomer (1.72 g), 6-chloro-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one (Example 1c-1) as a yellow powder. The second band was collected and evaporated. The residue was treated with methanol to give a more polar isomer (1.86 g), 6-chloro-3-methoxy-5,9-diaza-benzo[c]-fluoren-7-one (Example 1c-2) as a yellow powder.
Reaction SMILES: C([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[CH2:21]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][NH:22]1.[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]>>[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39]([NH:8][C@H:9]([C:18]([N:22]2[CH2:23][CH2:24][C@H:25]3[C@H:30]([CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21]2)=[O:20])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Reactant: C1CC[C@@H]2CNCC[C@@H]2C1
Product: Nc1c(Cl)cc(S(=O)(=O)N[C@@H](CCc2ccccc2)C(=O)N2CC[C@@H]3CCCC[C@@H]3C2)cc1Cl

Procedure:
Example 115 is prepared from Boc-(L)-homophenylalanine, (±)-cis-decahydroisoquinoline, and 4-amino-3,5-dichlorobenzenesulfonyl chloride in the same manner that Example 1 is synthesized. ESI MS: Calc: 523.2; Found: 524.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCCO1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (2.0 g, 11.1 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.46 g, 11.7 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound P, 2.62 g (78%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22]([O:24]C)=O.[NH3:26]>C1COCC1.[OH-].[NH4+]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:26]
Reactant: N
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Temperature: 35 °C
Yield: 54 %

Procedure:
A solution of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (480 mg, 1.43 mmol) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped and the mixture heated to 35° C. with stirring until tlc indicated complete consumption of starting material (20 hours). The THF was evaporated and the aqueous layer saturated with solid sodium chloride. The mixture was extracted three times with THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The foam was taken up in hot ethyl acetate and passed over a shoroom temperature column of silica gel using ethyl acetate as the eluent to afford 247 mg (54%) of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.46 (s, 1H), 8.81 (br s, 1H), 8.46 (d, 1H, J=5.8 Hz), 8.36 (br s, 1H), 7.8 (dd, 1H, J=2.9 and 6.4 Hz), 7.67-7.59 (m, 1H), 7.47-7.41 (m, 2H), 7.30-7.20 (m, 2H), 7.05 (d, 1H, J=7.9 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.57 (d, 1H, J=7.8 Hz), and 5.73 (s, 2H). IR (KBr, cm−1) 3404, 3051, 1652, 1618, 1595, 1582, 1567, 1559, 1450, 1436, 1334, 1266, 1226, 776, 763 and 647. MS (ES) m/e 318 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: Cc1cccc(C)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (22.2 g, 0.0136 mole), 15.0 g (0.124 mol) of 2,6-dimethyl-phenylamine 3, 300 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in 500 ml flask under a flow of nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2,6-dimethyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 1 was 12.86 g (39%) as a yellow solid. 1H NMR (500 MHz, CD2Cl2, TMS): δ2.00 (s, 6H, Me), 2.20 (s, 3H, Me), 2.70 (s, 3H, Me), 6.90 (t, 3JHH=8.1 Hz, 1H, Arom-H), 7.10 (d, 3JHH=8.1 Hz, 2H, Arom-H), 7.95 (t, 3JHH=8.0 Hz, 1H, Pyr-H), 8.10 (d, 3JHH=8.0 Hz, 1H, Py-H), 8.55 (d, 3JHH=8.0 Hz, 1H, Py-H). 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ167.1 (C═N), 200.1 (C═O). Anal. Calculated for C17H18N2O (Mol. Wt.: 266.34): C, 76.66; H, 6.81; N, 10.52, Found: C, 76.69; H, 6.84; N, 10.57.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([OH:34])[CH2:26][CH2:25]1)=[O:22].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:5]([O:34][C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]([NH:23][C:21](=[O:22])[C:20]([F:35])([F:36])[F:19])[CH2:25][CH2:26]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
tert-Butylchlorodiphenylsilane (4.4 mL) was added to a stirred solution of 2,2,2-trifluoro-N-((1R,4R)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (2.2 g) and imidazole (1.7 g) in DMF (35 mL). The reaction mixture was stirred at room temp overnight. The reaction mixture was diluted with EtOAc (150 mL), and washed with distilled water (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo and purified by column chromatography (eluting with 1:1 DCM/Hex), to give 4.0 g (95%) of the titled compound. 1H-NMR (300 MHz, CDCl3) □ 7.7 (d, 2H), 7.6 (d, 2H), 7.4 (m, 6H), 7.2 (m, 4H), 6.3 (broad s, 1H), 5.2 (q, 1H), 4.8 (t, 1H), 2.4 (m, 1H), 1.8 (m, 2H), 1.6 (m, 1H) ppm.