Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[C:38]([O:40][CH3:41])[C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:39]=[C:38]([O:40][CH3:41])[C:19]3[N:20]([CH3:37])[C:21]([C:23]4[N:31]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC(F)(F)F)n(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(C(=O)N2CCC[C@@H](N)C2)cc2nc(-c3cc4cccnc4n3CC(F)(F)F)n(C)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
To a solution of (R)-tert-butyl(1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (4.31 g, 7.35 mmol) in dichloromethane (DCM) (20 ml) at 0° C. was added TFA (9 ml, 118 mmol) dropwise. The reaction mixture was stirred for 5 minutes and allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was concentrated under vacuum to afford an oil. The oil was dissolved in methanol and split into two equal batches. These were passed through two separate 70 g SCX cartridges. The columns were washed with MeOH (2CV) and the product collected from both columns as the free base with 2M ammonia in methanol (3CV). The product was concentrated and dried under vacuum to afford the title compound as a white solid (2.53 g).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6](N(OC(C)C(O)C)OC(C)C(O)C)=[C:5](CCC)[CH:4]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C1(P(Cl)(Cl)=O)C=CC=CC=1.[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:69]=[CH:68][C:67]([O:70][CH2:71]CCCCCCCCCCC)=[CH:66][CH:65]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])(C2C=CC=CC=2)[O:57]1)[CH2:51][CH2:52][CH3:53]>ClCCl>[CH2:50]([O:54][CH2:55][CH:56]1[CH2:63][N:62]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH3:71])=[CH:68][CH:69]=2)[CH2:61][CH:60]([CH2:83][O:84][CH2:85][CH2:86][CH2:87][CH3:88])[O:59][P:58](=[O:95])([O:2][C:3]2[CH:21]=[CH:20][CH:6]=[CH:5][CH:4]=2)[O:57]1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCOc1ccc(N2CC(COCCCC)OP(=O)(c3ccccc3)OC(COCCCC)C2)cc1
Reactant: CCCc1cc(OC)ccc1N(OC(C)C(C)O)OC(C)C(C)O
Agent: CN(C)c1ccccn1
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOCC1CN(c2ccc(OC)cc2)CC(COCCCC)OP(=O)(Oc2ccccc2)O1
Yield: 16 %

Procedure:
It is prepared from 4-methoxy-N,N-di(2-hydroxy-3-butoxy)-propyl aniline (1.91 g, 5 mmol), pyridine (1.2 g, 15 mmol), dimethylaminopyridine (0.2 g) and phenylphosphonic dichloride (1.1 g, 5.1 mmol) in dichloromethane as described for compound 200 to obtain a pale yellow liquid 0.4 g (16%) and its isomer 0.5 g (19% a pale yellow liquid).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.FC(F)(F)S(O)(=O)=O.[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:17]([C:5]1[C:6]([OH:7])=[C:1]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[C:3]([CH3:8])[CH:4]=1)=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1cc(C=Cc2ccccc2)c(O)c(C=Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
This example illustrates a reaction system comprising two reactors and providing for a two tiered temperature profile for forming styrenated p-cresol. 50 Kg (110.2 lb, 462.2 moles) p-cresol was pumped from a preheated drum into a 50 gallon glass lined steel jacketed reactor equipped with an agitator, thermowell, and a pump around loop for sampling and acid injection. The p-cresol was heated to about 60° C. followed by the addition of 1.6 to 8.3 g (5.53e-05 to 1.07e-02 moles) of trifluoromethane sulfonic acid via a syringe in an injection port of the pump around loop. 93.9 Kg (2071b, 901.6 moles) styrene was fed through a mass flow meter at a constant rate over a 3 to 4 hour reaction time where the reactor temperature was maintained at 70° C. The molar ratio of styrene to p-cresol fed was maintained at 1.95. After the completion of the styrene feed, the reactor contents were pumped to a second 50 gallon glass lined steel jacketed reactor and heated to 90° C. Approximately 1.5 lb (0.7 Kg) of acid-leached bentonite clay (Filtrol 20×) was added through a man hole to the second reactor and agitated for 15 minutes. The product was then pumped to a bag filter and into product drums. The typical sample result from this production, based on total GC area, are provided below in TABLE 10.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5].FC(F)(F)C([O-])=O.[CH2:28]([O:35][C@H:36]([CH3:39])[CH:37]=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)[C@@H](C)O)C>>[CH2:28]([O:35][C@H:36]([CH3:39])[CH2:37][NH:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8]1=[O:18])=[O:5])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: C[C@H](C=O)OCc1ccccc1
Agent: CCOC(=O)[C@@H](C)O
Agent: O=C([O-])C(F)(F)F
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate (Example 107, Step C) and (R)-2-benzyloxypropanal (prepared from ethyl-D-lactate according to the procedure of Hanessian and Kloss, Tetrahedron Lett. 1985, 26, 1261-1264.) by the procedure described in Example 86, Step A. 1H NMR (200 Mhz,CD3OD): 1.31 (d,6 Hz,3H), 1.40 (s,3H), 1.43 (s,3H), 2.17 (m,1H), 2.30 (m,1H), 2.6-3.1 (m,5H), 3.22 (dd;3,12 Hz;1H), 3.86 (m,1H), 4.48 (dd;7,12 Hz;1H), 4.50 (d,12 Hz,1H), 4.70 (d,12 Hz,1H), 7.11 (d,8 Hz,1H), 7.15-7.45 (m,8H). FAB-MS: calculated for C25H33N3O3 423; found 424 (M+H,100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.[CH3:19][O:20][N:21]=[C:22]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:23]([O-])=[O:24].[Na+].N1CCC1=O>O1CCOCC1>[C:11]([O:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:23](=[O:24])[C:22](=[N:21][O:20][CH3:19])[C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:17](=[O:18])[N:4]2[C:5]=1[C:14]([OH:16])=[O:15])(=[O:13])[NH2:12]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CON=C(C(=O)[O-])c1cccs1
Agent: O=C1CCN1
Agent: [Na+]
Solvent: C1COCCO1
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccs1
Yield: 50.4 %

Procedure:
Following the procedure of Example 2, the title compound (888 mg., 50%) was prepared from (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylic acid (1.09 g., 4 mmole) and sodium 2-methoxyimino-2-(thien-2-yl)acetate (syn -isomer) (923mg., 4.8 mmole). Its properties are: m.p. 157° to 163°, [α]D20° + 57.3° (c 1.0 in dioxan), RPAC 0.8* Solvent system A*,λmax. (pH6 buffer) 262.5 nm (ε 15,550), and inflexion at 235 nm (ε 10,350), τ (DMSO-d6) 0.20 (d, J 8 Hz, NH), 2.29 (dd, J 2 and 5 Hz, thienyl C5 -H), 2.7 to 2.9 (m, thienyl C3 -H and C4 -H), 3.40 (s, CONH2), 4.13 (dd, J 5 and 8 Hz, C7 -H), 4.75 (d, J 5 Hz, C6 -H), 5.01 and 5.34 (AB-q, J 13 Hz, C3 -CH2), 6.08 (s, NOCH3), and 6.42 (collapsed AB-q, C2 -H2), νmax. (Nujol) 3700 to 2100 (CO2H), 3480, 3440, 3365, and 3255 (NH and NH2), 1760 (azetidin-2-one), 1722 (CO2H), 1709 (OCONH2) and 1652 and 1530 cm-1 (amide).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:11]=1)=[O:5].N1C=CC=CC=1.[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40]([C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](Cl)=[O:46])=[O:41]>ClCCl.C(OCC)(=O)C>[CH3:38][N:39]([CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[C:40](=[O:41])[C:42]1[CH:50]=[CH:49][CH:48]=[C:44]([C:45]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:11]=2)=[O:46])[CH:43]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1nc(-c2cccc(C(F)(F)F)c2)cs1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide (287 mg, 0.64 mmol, 1.00 equiv) in dichloromethane (3 mL), and pyridine (406 mg, 5.13 mmol, 8.00 equiv). This was followed by dropwise addition of a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride (300 mg, 0.97 mmol, 1.50 equiv) in dichloromethane (2 mL) with stirring. The resulting solution was stirred for 1 h at room temperature, then diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of hydrogen chloride (1 N) and 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (300 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 120 mg (20%) of as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.89(s, 1H), 10.93(s, 1H), 9.79(s, 1H), 8.26 (m, 2H), 8.00(m, 4H), 7.69(m, 4H), 7.53(s, 1H), 7.27(d, J=8.7 Hz, 1H), 4.01(s, 2H), 3.85(s, 2H), 3.63(s, 4H), 3.44(s, 2H), 3.17(m, 6H), 2.99(s, 3H), 1.70(m, 6H). MS (ES, m/z): 721 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22](Cl)(Cl)=[O:23].C1(C)C=CC=CC=1.[CH3:33][NH:34][C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)[N:38]=[CH:37][N:36]=1>O1CCOCC1.CCOCC>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:3][C:2]=1[NH:1][C:22]([N:34]([CH3:33])[C:35]1[CH:40]=[C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)[N:38]=[CH:37][N:36]=1)=[O:23]
Reactant: O=C(Cl)Cl
Reactant: CNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)N(C)c1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (preparation 3, 62 mg, 0.21 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (110 μl, 0.21 mmol, 1.25 eq.) under argon. The reaction mixture is stirred for further 22 h at room temperature under argon. Then, the solvent is evaporated and the residue is taken up in dry toluene (2 ml). After the addition of N-Methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (50 mg, 0.168 mmol, 1.0 eq.) the suspension is refluxed for 24 h under argon. After cooling ether (2 ml) is added and the mixture is stirred for 30 min. The precipitated product is filtered off, washed (1× toluene/ether 1:1, 1× ether) and vacuum dried at 60° C. overnight to afford the title compound as colorless crystals: M.p. 189.5-191° C., HPLC: tR=6.02 min (purity: >99%, gradient A), ESI-MS: 619.6 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][NH2:20])[CH3:15]>O1CCOCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:21][CH3:22])[CH2:14][CH3:15])=[O:9]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CCN(CC)CCCN
Solvent: C1COCCO1
Product: CCN(CC)CCCNC(=O)c1cc(Cl)ccc1N

Procedure:
A solution containing 4.00 grammes (20.3 mmoles) of 5-chloroisatoic anhydride in 25 ml of dioxane at room temperature is joined by 4.80 ml (30.4 mmoles) of 3-diethylamino- 1-propylamine.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].Cl>O1CCOCC1.C(O)(C)C>[CH:10]([NH:13][C:14]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[O:15])([CH3:12])[CH3:11]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)NC(=O)N1CCc2[nH]cnc2C1

Procedure:
A solution of 2.46 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 6.8 g of isopropyl isocyanate in 50 ml of dry dioxane is refluxed for 2 h. After evaporation to dryness, the residue is dissolved in 25 ml of methanol and treated with 12.5 ml of 2N sodium hydroxide for 2 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue (2.21 g, oil) that is treated with one equivalent of hydrogen chloride in isopropanol. After cooling, 1.7 g of 5-(N-isopropyl-carbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine hydrochloride, m.p. 190°, are collected.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]([NH2:14])=[S:13].[O-]CC.[Na+].[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20].S(=O)(=O)(O)O>CCO.O>[NH2:20][C:19]1[N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:12](=[S:13])[NH:14][C:22](=[O:23])[CH:21]=1
Reactant: NC(=S)NCc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(=O)[nH]c(=S)n1Cc1nc2ccccc2[nH]1
Reaction time: 7 h
Yield: 30.3 %

Procedure:
To a solution of N-(1H-benzimidazol-2-ylmethyl)thiourea (0.85 g, 4.1 mmol, obtained from Example 8(a)) in EtOH (10 mL) was added, dropwise, in portions during 7 h, sodium ethoxide (1M, 16.6 mL, 16.6 mmol) and a solution of ethyl cyanoacetate (1.76 mL, 16.6 mmol) in EtOH (10 mL) while the reaction was stirred at 80° C. After cooling to r.t. water (200 mL) was added followed by 2M sulphuric acid, the mixture was concentrated until precipitation occurred. The formed solid was collected by filtration, washed with water and dried to give the title compound (0.34 g, 30%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 920 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 9,600 ml of toluene 460 g of triethylamine are added during 5 minutes, followed by 618 g of p-fluorophenylisocyanate. The mixture is stirred under nitrogen overnight at room temperature, cooled to 10° and combined with 5,000 ml of 1 N aqueous sodium hydroxide. The mixture is stirred for 15 minutes, the organic phase separated and extracted twice with 2,000 ml of 1 N aqueous sodium hydroxide again. The combined aqueous solutions are washed twice with 2,000 ml of diethyl ether each, cooled to 5° and acidified with 900 ml of concentrated hydrochloride acid during 30 minutes. The resulting suspension is stirred for 1 hour, filtered and the residue washed 6 times with 2,000 ml of water each. 1,364 g thereof are dissolved in 55,000 ml of boiling ethanol, the solution filtered hot and the filtrate stirred under nitrogen overnight at room temperature. The precipitate formed is filtered off, washed twice with 1,000 ml of cold ethanol each and recrystallized from ethanol again, to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one melting at 255°-257° with decomposition; it is identical with that obtained according to Example 6.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1.[CH3:50][C:51]1([CH3:65])[C:55]([CH3:57])([CH3:56])[O:54][B:53]([C:58]2[CH:59]=[C:60]([CH:62]=[CH:63][CH:64]=2)[NH2:61])[O:52]1>CN(C=O)C.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:61][C:60]4[CH:62]=[CH:63][CH:64]=[C:58]([B:53]5[O:54][C:55]([CH3:57])([CH3:56])[C:51]([CH3:65])([CH3:50])[O:52]5)[CH:59]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2cccc(NC(=O)c3ccc4cc5n(c4c3)CCCNC5=O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 2.3 g, 9.2 mmol) in DMF (30 mL) are added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.7 g, 9.7 mmol) and N-methylmorpholine (2.5 mL, 22.5 mmol). The reaction mixture is stirred for 1 h at room temperature and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.4 g, 11.1 mmol) is added. The reaction mixture is stirred for 16 h at room temperature and is poured into water (200 mL). The resulting solid is collected by filtration, rinsed with water and dried to afford the title compound (3.8 g, 92%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH:7]([CH2:11][C:12]#[N:13])[C:8]([OH:10])=[O:9].[OH-].[Na+].Cl>C1COCC1>[C:12]([CH2:11][CH:7]([NH:6][C:2]([O:4][CH3:5])=[O:3])[C:8]([OH:10])=[O:9])#[N:13]
Reactant: COC(=O)Cl
Reactant: N#CCC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)NC(CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 19.6 %

Procedure:
Methyl chloroformate (0.81 mL, 10.51 mmol) was added dropwise to a stirred suspension of 2-Amino-3-cyano-propionic acid (1.00 g, 8.76 mmol) and NaOH (5 N in H2O, 4.2 mL, 21.0 mmol) in THF (20 mL). After stirring at room temperature for 7 h, the reaction mixture was poured into 10% HCl and the aqueous phase was extracted 3× with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated to afford 3-Cyano-2-methoxycarbonylamino-propionic acid (295 mg, 20%).
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][NH:5][C:6](=[O:12])[C:7]([O:9]CC)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:4]([NH:5][C:6](=[O:12])[C:7]([NH:27][CH2:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)=[O:9])/[CH:3]=[C:2](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])\[CH3:1]
Reactant: CCOC(=O)C(=O)NCC=C(C)CCC=C(C)C
Reactant: NCCc1ccccn1
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CNC(=O)C(=O)NCCc1ccccn1
Yield: 66.7 %

Procedure:
The ethyl 2-(3,7-dimethylocta-2,6-dienylamino)-2-oxoacetate (1.5 g, 5.92 mmol) was mixed with 2-(pyridin-2-yl)ethanamine (1 g, 8.19 mmol) in ethanol (20 ml) to give a yellow solution. The reaction mixture was stirred at reflux for 1.5 hour. Then the solvent was removed by evaporation. The remaining residual solid was washed with ethanol/pentane to provide the target compound as white crystals (1.3 g; 65% yield). The product is ca. 97% pure according to NMR analysis.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](O)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[I-].[Na+].[C:18](=[O:21])([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:18][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:8]([N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1
Yield: 199.8 %

Procedure:
A mixture of N-(5-acetyl-2-hydroxyphenyl)methanesulfonamide (31) (0.30 g, 1.32 mmol), sodium iodide (0.20 g, 1.32 mmol), potassium carbonate (0.91 g, 6.58 mmol), and benzyl bromide (0.39 mL, 3.28 mmol) in acetone (10 mL) was stirred under reflux for 66 h. After removal of solvent by rotary evaporation, the resulting residue was diluted with dichloromethane and insoluble inorganics were vacuum filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by flash silica gel column chromatography eluting with a mixture of ethyl acetate (0-3%) in dichloromethane to give benzyl ether 32 as a yellow solid (0.54 g, 99%): 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.85 (s, 3H), 4.75 (br, 2H), 5.18 (s, 2H), 7.05 (d, 1H), 7.23 (m, 5H), 7.42 (m, 5H), 7.62 (d, 1H), 7.89 (dd, 1H); m/z (ESI) 410 [C23H23NO4S+H]+.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[C:32]3[N:31]=[CH:30][N:29]=[C:23]([N:24]=CN(C)C)[C:22]=3[N:21]=[CH:20]2)[CH2:6]1)[CH:2]=[CH2:3]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[C:32]3[N:31]=[CH:30][N:29]=[C:23]([NH2:24])[C:22]=3[N:21]=[CH:20]2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cnc3c(N=CN(C)C)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of 57 (875 mg; 1.90 mmol) in anhydrous THF (45 mL), 1 M TBAF in THF solution (2.09 mL; 2.09 mmol) was added and the reaction was stirred at room temperature for 1 h. After evaporation, the residue was dissolved in 7 M ammonia in methanol solution (34 mL). The mixture was then stirred in a sealed flask at 50° C. for 9 h. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 58 as white solid (548 mg; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H, 2-H), 8.17 (s, 1H, 8-H), 6.38 (dd, J=5.8, 8.6 Hz, 1H, 1′-H), 5.91-6.01 (m, 1H, CH2CH═CH2), 5.30-5.37 (dm, J=17.3 Hz, 1H, one of CH2CH═CH2), 5.17-5.22 (dm, J=10.6 Hz, 1H, one of CH2CH═CH2), 4.36 (m, 1H, 3′-H), 4.21 (m, 1H, 4′-H), 4.04-4.15 (m, 2H, CH2CH═CH2), 3.85 (dd, J=3.2, 12.3 Hz, 1H, one of 5′-H), 3.74 (dd, J=3.2, 12.3 Hz, 1H, one of 5′-H), 2.75-2.83 (ddd, J=5.7, 8.6, 13.6 Hz, 1H, one of 2′-H), 2.52-2.58 (ddd, J=1.8, 5.8, 13.6 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 157.1, 153.1, 149.5, 141.2, 135.6, 120.6, 117.0, 87.5, 87.2, 80.9, 71.0, 63.9, 38.7; HRMS (FAB+) calcd for C13H18O3N5 (M+H+): 292.1410, found: 292.1426.