Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1CC#N.C[Al](C)C.[CH2:19]([NH2:22])[CH2:20][NH2:21].[C:23]1(C)C=CC=C[CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[C:6]([CH:7]=1)[CH2:23][C:24]1[NH:21][CH2:20][CH2:19][N:22]=1
Reactant: N#CCc1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccccc1
Reactant: NCCN
Agent: C[Al](C)C
Product: Fc1ccc(C(F)(F)F)c(CC2=NCCN2)c1

Procedure:
2-(5-Fluoro-2-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-fluoro-5-trifluoromethyl-phenyl)-acetonitrile and the complex of trimethylaluminium with ethylene diamine in toluene at reflux for 18 hours in analogy to M. P. Wentland et al., J. Med. Chem. 30, 1482 (1987): brown solid; MS (ISP): 247.0 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1([CH3:25])[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:24][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([CH3:25])([OH:1])[CH2:3]1
Reactant: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (28 mg, 0.080 mmol) in DCM (6 mL) was added to a 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol). The mixture was stirred at room temperature for 4 hours. A 4.0M HCl solution in dioxane (1.4 mL, 5.63 mmol) from a different bottle was added. The resulting mixture was stirred for 18 hours. The solvents were removed in vacuo to give (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. DIPEA (41.5 mg, 0.321 mmol) was added to a suspension of this (5R)-5,7-dimethyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (25.8 mg, 0.0803 mmol), 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid (32.9 mg, 0.0964 mmol), and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (36.6 mg, 0.0964 mmol) in CH2Cl2 (6 mL) at room temperature. The resulting mixture was stirred for 1 hour. The solvent was removed in vacuo. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (46 mg, 100%) as a gel. LCMS (APCI+) [M−Boc+H] +472.2; Rt: 3.51 min.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C:15]([CH2:17][C:18]([CH3:21])(C)C)=[CH2:16].[CH3:22][C:23](=C)[CH3:24]>>[CH2:22]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:23][CH2:24][CH2:21][CH2:18][CH2:17][CH2:15][CH3:16]
Reactant: C=C(C)CC(C)(C)C
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C=C(C)C
Product: CCCCCCCCN(c1ccccc1)c1ccccc1
Temperature: 160 °C

Procedure:
In a 50 gallon (about 189 L) reactor, 144 pounds (about 65.5 kg) of diphenylamine and 5.9 pounds (about 2.7 kg) of Filtrol™ clay (Engelhard Corp., Iselin, N.J.) were mixed in a reactor and heated to 160° C. for 20 minutes to drive off moisture. About 124.3 pounds (about 56.5 kg) of diisobutylene at room temperature was then added to the reactor at a rate of about 60 pounds (about 27 kg) per minute. The reaction temperature dropped to 140° C. and then climbed back to an initial set point temperature of 160° C. Within about 10 minutes of first adding the diisobutylene, 37.4 pounds (about 17 kg) of isobutylene was charged in the reactor over one hour. The temperature during this period reached a maximum of about 190° C. due to the exothermic nature of the reaction. Based on experience and Examples illustrated in U.S. Pat. No. 5,750,787, it is believed that the initiation of the addition of isobutylene occurred before the reactive composition of diisobutylene and diphenylamine formed at least 50 wt. % monooctyldiphenylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:11])=[CH:4][CH:3]=1.[O-]CC.[Na+].O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]2[S:11][C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1ccc(Br)nc1Cl)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(Br)nc2s1)c1ccccc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of N-(6-bromo-2-chloropyridin-3-ylcarbamothioyl)benzamide (1.5 g, 4.0 mmol) and sodium ethoxide (0.54 g, 8.0 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was heated to 120° C. for 8 hours. After cooling the reaction mixture to room temperature the mixture was poured into water. The resulting solid was collected by filtration, then washed sequentially with water and diethyl ether. The filter cake was dried to give N-(5-bromothiazolo[5,4-b]pyridin-2-yl)benzamide (1.02 g, 76%). 1H NMR (400 MHz, d6-DMSO): 13.2 (br s, 1H), 8.16-8.10 (m, 3H), 7.72 (d, 1H), 7.70 (t, 1H), 7.59 (t, 2H). MS (EI) for C13H8BrN3OS: 336 (MH+).
Reaction SMILES: CN1CCN([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)CC1.[OH2:21].NN.[CH3:24][CH2:25]O>[Ni]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[CH2:10][CH2:9][CH:8]([OH:21])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1
Reactant: CCO
Reactant: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Reactant: O
Agent: [Ni]
Agent: NN
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A 50 mL round bottom flask was charged with [3-(4-Methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine (0.742 g, 3.34 mmol) and dissolved into EtOH (20 mL). Hydrazine Hydrate (0.642 mL, 20.04 mmol) was then added. Excess RaNi was then added in dropwise until the solution stopped bubbling. The suspension was then allowed to stir for an additional 15 minutes at 65° C. The suspension was cooled to rt and then filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo. The crude oil was then purified over silica (3% Chloroform/Hexanes to 10% Chloroform/Hexanes) affording pure 1-(4-amino-phenyl)-piperidin-4-ol as a light brown oil in 51% yield (0.327 g, 1.71 mmol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([C:20]([OH:22])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([C:20]([O:22][CH3:23])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To O-benzyl-N-(tert-butoxycarbonyl)homoserine (5.8 g, 18.9 mmol) in 20% methanol/benzene (72 mL) is added 2M trimethylsilyldiazomethane in hexane (12.3 mL, 24.5 mmol), and the reaction stirred at room temperature 1.5 h. The solution is concentrated under reduced pressure to give the title compound in pure form. ESI MS m/z 324.2 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][CH:11]1[CH:16]([CH3:17])[NH:15][CH:14]([CH3:18])[CH:13]([CH3:19])[NH:12]1.[CH:20]1([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH3:37])[C:29]([C:38]([Cl:40])=[O:39])=[CH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl>[ClH:40].[CH:20]1([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][C:34]=3[O:36][CH3:37])[C:29]([C:38]([N:12]3[CH:13]([CH3:19])[CH:14]([CH3:18])[NH:15][CH:16]([CH3:17])[CH:11]3[CH3:10])=[O:39])=[CH:28]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC1NC(C)C(C)NC1C
Reactant: COc1cccc2c(C(=O)Cl)cn(CC3CCCCC3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(C(=O)N3C(C)C(C)NC(C)C3C)cn(CC3CCCCC3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of diisopropylethylamine (0.83 ml, 4.90 mmol) and 2,3,5,6-tetramethylpiperazine (0.35 g, 2.45 mmol) in dichloromethane (5 ml) was added a solution of 1-(cyclohexylmethyl)-7-methoxyindole-3-carbonyl chloride (0.33 g, 1.08 mmol, prepared following the method in Example 1) in dichloromethane (5 ml). The mixture was stirred at room temperature for 6 h, evaporated under reduced pressure and the residue purified by flash chromatography eluting with 5-10% (v/v) methanol in dichloromethane to afford the title compound (free base) as a colourless oil (0.43 g). The free base (0.1 g, 0.24 mmol) was dissolved in dichloromethane (1 ml), treated dropwise with 2 M hydrochloric acid in diethyl ether (0.3 ml) and diethyl ether (3 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (15 ml) and dried under reduced pressure to afford the title compound (1:1 hydrochloric acid salt) as a white solid (0.09 g, 0.20 mmol). 1H NMR (400 MHz, CD3OD) δH 0.98-1.39 (8H, m), 1.42 (6H, d, J 7.0), 1.64-1.89 (9H, m), 3.44-3.70 (3H, m), 3.95 (3H, s), 4.21-4.34 (3H, m), 6.77 (1H, d, J 7.7), 7.11 (1H, t, J 8.2), 7.38 (1H, d, J 8.2), 7.58 (1H, s); EIMS: m/z 412.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example J18) (180 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (206 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:25])=[CH:28][CH:29]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoic acid (1.0 g, 2.85 mmol) in DMF (20 mL) was added 4-aminophenol (0.31 g, 2.85 mmol), HBTU (1.1 g, 2.85 mmol), DIEA (2 mL, 11.4 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (100 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then the resulting residue was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.N1C2C(=CC=CC=2)C=C(B(O)O)[CH:17]=1.Br[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32]1([C:44]3=[CH:45][C:46]4[O:50][CH2:49][O:48][C:47]=4[CH:51]=[C:43]3[O:42][CH2:41]1)[C:33](=[O:40])[N:34]2[CH3:39]>>[CH3:39][N:34]1[C:35]2[C:31](=[C:30]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:38]=[CH:37][CH:36]=2)[C:32]2([C:44]3[C:43](=[CH:51][C:47]4[O:48][CH2:49][CH2:17][O:50][C:46]=4[CH:45]=3)[O:42][CH2:41]2)[C:33]1=[O:40]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3cnn(C)c3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (58%) as a colorless solid: mp 220-222° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.9, 7.9 Hz, 1H), 7.16 (s, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.48 (d, J=9.1 Hz, 1H), 4.23-4.09 (m, 4H), 3.75 (s, 3H), 3.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.6, 144.8, 144.2, 138.7, 138.0, 130.8, 129.3, 129.1, 127.8, 125.2, 122.7, 119.0, 111.5, 107.0, 99.4, 76.7, 64.6, 64.0, 58.3, 38.9, 26.8; MS (ES+) m/z 390.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:15][S:16]([C:19]1[C:31]([CH3:32])=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][C:20]=1[CH3:33])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CC(C)(C)C(Cl)=O.Cl.[NH2:49][CH2:50][CH2:51][NH:52][C:53](=[O:62])[O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:31]([CH3:32])=[CH:30][C:22]([O:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[NH:49][CH2:50][CH2:51][NH:52][C:53]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:62])=[CH:21][C:20]=1[CH3:33])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)O)cc1C
Reactant: NCCNC(=O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude phenoxybutanoic acid (20) from the previous reaction (2.75 g) in CH2Cl2 (150 mL) cooled in an ice water bath was added 4-methylmorpholine (0.89 g, 8.8 mmol) and then trimethylacetyl chloride (1.06 g, 8.8 mmol). The reaction mixture was allowed to warm to rt. After 1 h, the reaction mixture was concentrated in vacuo then DMF (100 mL) was added and this was also removed in vacuo (to remove any unreacted trimethylacetyl chloride, bp 105-106° C.). The crude product was redissolved in CH2Cl2 (150 mL) and a solution of benzyl N-(2-aminoethyl)carbamate hydrochloride, 21 (1.52 g, 6.6 mmol) and 4-methylmorpholine (1.11 g, 11.0 mmol) in DMF was added. After 1 h, the reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. After separation of the layers, the EtOAc solution was washed with dilute NaHCO3 and water. The EtOAc solution was concentrated in vacuo to give the crude product. This material was purified by chromatography (97:3 EtOAc/MeOH) to give 2.80 g of product 22.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:22]N(C)C=O.[H-].[Na+].CI>O>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (847 mg, 3.00 mmol) and N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 120 mg, 3.00 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of MeI (426 mg, 3.0 mmol) and N,N-dimethylformamide (5 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 553 mg (62%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.Cl[CH:18](C1C=CC=C(CC)C=1)[C:19]1[N:23]([CH3:24])[N:22]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1.CCN([CH2:44][CH3:45])CC>C(#N)C>[CH2:15]([C:16]1[CH:2]=[C:3]([N:1]([CH2:18][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:20]=2)[C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:4][CH:3]=2)[CH:4]=[CH:44][CH:45]=1)[CH3:5]
Reactant: CCc1cccc(C(Cl)c2nc(-c3ccccc3)nn2C)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCc1cccc(N(Cc2nc(-c3ccccc3)nn2C)c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-aminobenzylcarbamate (31 mg, 0.14 mmol) was added to a solution of intermediate 370.3 (43 mg,) and Et3N (0.1 mL) in acetonitrile (1 mL) and stirred at 80° C. for 16 h. The mixture was concentrated and purified by flash chromatography (EtOAc/hexanes) to yield 43 mg of intermediate 372.1 as a white solid. LCMS 498.38 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH2:39][CH3:40]>C1COCC1>[C:38]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:41])[CH2:39][CH3:40]
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)ONC(=O)CCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (2.8 g) in THF (40 ml) was added triethylamine (1.4 ml) followed by addition of propionyl chloride (669 mg) at 0° C. The reaction mixture was stirred for 1 hour and partitioned between water and ethyl acetate. The organic layer was dried and concentrated. The residue was purified with silica gel chromathography using hexane-ethyl acetate as an eluent to give the titled compound (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([F:8])=[CH:6][CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(Cl)c1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1c(F)ccc(Cl)c1F
Yield: 92.2 %

Procedure:
A solution of 1,1-dimethylethyl (3-chloro-2,6-difluorophenyl)carbamate (437 mg, 1.66 mmol) in methanol (2 mL) was treated with 4 N hydrochloric acid in dioxane (2 mL) and heated for 1 min with a heat gun. After cooling, the volatile materials were removed in vacuo. The resulting residue was taken up in ethyl acetate and washed with sodium bicarbonate (sat). The organic phase was dried over magnesium sulfate, filtered, and concentrated yielding 3-chloro-2,6-difluoroaniline as a white solid (250 mg, 1.53 mmol, 92%). MS (EI) for C6H4ClF2N: 164 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[C:22]([OH:24])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[C:22]([O:24][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: OCc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)cc1OCC(F)(F)F
Temperature: 100 °C
Yield: 13 %

Procedure:
Charged 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.62 g, 6.37 mmol), 5-chloro-2-(hydroxymethyl)phenol (1.01 g, 6.37 mmol, PREPARATION 7), K2CO3 (1.76 g, 12.74 mmol) and DMF (7 mL) to a flask; heated to 100° C. overnight. The reaction mixture was then poured into ice-water and extracted with EA twice, washed the organic phase with water twice, brine and dried with Na2SO4, concentrated for gel chromatograph to give the title compound (200 mg, 13%). 1H NMR (400 MHz, CDCl3): δ 4.39 (2H, q, J=8.0 Hz), 4.70 (2H, d, J=5.2 Hz), 6.83 (1H, d, J=1.6 Hz), 7.05 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.33 (1H, d, J=7.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14]
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1F
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10.0 mg, 0.0537 mmol, from Example 2, Step 5) in DMF (1.5 mL) was added sodium hydride (0.0065 g, 0.16 mmol, 60% in mineral oil). After stirring for 10 minutes, 1-(bromomethyl)-2-fluorobenzene (0.010 g, 0.054 mmol, Aldrich) was added. After stirring for 45 minutes, the reaction was quenched with water, diluted with MeCN and filtered, then was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (7 mg, 40%).
Reaction SMILES: [Br:1][CH:2]([NH:4][C:5](Br)=[O:6])[CH3:3].CC1C2C(C)(C)C(C2)CC=1>>[Br:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3].[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3]
Reactant: CC(Br)NC(=O)Br
Agent: CC1=CCC2CC1C2(C)C
Product: C=CN=C=O
Product: CC(Br)N=C=O
Yield: 10 %
Yield: 89 %

Procedure:
A mixture of 231 parts of 1-bromoethylcarbamic acid bromide and 475 parts of α-pinene is heated at from 23° to 120° C. in the course of 1.5 hours, whilst stirring, and the reaction mixture is then subjected to fractional distillation. A total of 14.6 parts (10% of theory) of 1-bromoethyl isocyanate of freezing point -27.5° C. (decomposition) and 61.5 parts (89% of theory) of vinyl isocyanate of boiling point 38.5° C./1013 mbar is obtained.
Reaction SMILES: [CH:1]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH:4]=[C:3]([C:14]([O:16]CC)=[O:15])[N:2]=1.[OH-].[K+].O.[ClH:22]>CCO>[ClH:22].[CH:1]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1
Reactant: CCOC(=O)c1cn2c(cn1)cc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(cn1)cc1ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 34 %

Procedure:
To a solution of ethyl pyrazino[1,2-a]indole-3-carboxylate (0.49 g, 2.0 mmol) in EtOH (30 mL) is added crushed potassium hydroxide (1.1 g, 20.0 mmol) followed by water (30 mL). The resulting dark colored solution is stirred at rt for 40 min and then neutralized with conc. HCl to pH ˜2. The acidic mixture is concentrated to dryness to afford pyrazino[1,2-a]indole-3-carboxylic acid hydrochloride. HRMS (FAB) calcd for C12H8N2O2+H 213.0664, found 213.0658.