Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[S:31][C:30]2[CH:32]=[C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=4)[CH:34]=[CH:35][C:29]=2[CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[S:31][C:30]2[CH:32]=[C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:63](=[O:65])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)=[N:38][CH:37]=4)[CH:34]=[CH:35][C:29]=2[CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(-c6cnc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]6)cc5s4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc5s4)ccc3c2[nH]1)C(C)C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To (S)-tert-butyl 2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.07 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (15 mg, 0.07 mmol), COMU (36 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.35 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (14.8 mg). LCMS-ESI+: calc'd for C47H48N8O6S: 853.00 (M+); Found: 853.22 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)c1

Procedure:
3-(4′-Trifluoromethoxy-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 4-(trifluoromethoxy)benzeneboronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=389.
Reaction SMILES: B(O)(O)[C@H]1[N:6](C([C@@H](N)C(C)C)=O)CCC1.[CH3:16][S:17]([OH:20])(=[O:19])=[O:18].[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]OS(C)(=O)=O.N>CO>[S:17]([O-:20])(=[O:19])(=[O:18])[CH3:16].[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34][NH3+:6]
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Reactant: CS(=O)(=O)O
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: N
Solvent: CO
Product: CS(=O)(=O)[O-]
Product: Cc1oc(-c2ccccc2)nc1CC[NH3+]
Temperature: 20 °C
Yield: 78 %

Procedure:
A 1500 mL double jacketed stainless steel autoclave equipped with a mechanical stirring bar and a Pt-100 thermometer was charged under nitrogen with 100 g (355 mmol) of methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester and 900 mL of methanol. The autoclave was closed and ammonia (200 g, 11.74 mol) was transferred into the suspension at −20° C. to 20° C. while stirring and cooling. The mixture was then heated to 75° C.-80° C. and the pressure rose to 10 bar. The mixture was stirred for 2-3 h at this temperature and then cooled down to 20° C. The pressure was relieved and the clear solution was transferred with the aid of 100 mL of methanol to a 1000 mL double jacketed glass reactor equipped with a mechanical stirrer, a Pt-100 thermometer, a reflux condenser, a dropping funnel and a nitrogen inlet. The solvent was completely removed by distillation under vacuum. The resulting suspension was twice treated with 500 mL of methylenechloride that was subsequently completely removed by distillation under normal pressure. The residue was again treated with 500 mL of methylenechloride and the resulting suspension was cooled to 0° C. within 1 h and stirred for another 2 h at this temperature. The precipitate was filtered with suction, the filter cake was washed with 200 mL of methylenechloride and dried under vacuum (50° C., 50 mbar) to afford about 85.8 g (yield 78%, 96% (m/m) purity based on HPLC assay) of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylammonium mesylate as a colorless solid. The HPLC analysis was performed with an external standard of pure 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylammonium mesylate. Conditions for HPLC: Column XTerra RP8 Waters, 4.6×150 mm, 3.5 μm; UV detector 205 nm; solutions for gradient: water (A), acetonitrile (B), pH 6.5 buffer KH2PO4/K2HPO4 (C); flow 1.2 mL/min, 40° C.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:2]=2[F:1])[CH2:13][CH2:12]1
Reactant: O=Cc1cccc(F)c1F
Reactant: NC1CC1
Product: Fc1cccc(CNC2CC2)c1F

Procedure:
Synthesized according to typical procedure J from 2,3-difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Br:60][C:61]1[CH:62]=[C:63]([CH2:67][NH2:68])[CH:64]=[CH:65][CH:66]=1>ClCCl>[Br:60][C:61]1[CH:62]=[C:63]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[CH:65][CH:66]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: NCc1cccc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromophenyl)methyl]amine hydrochloride (464 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (962 mg, 1.476 mmol, 73.8% yield) as a white solid. LC-MS m/z 633.6 (M+H)+, 0.97 min (ret time); mp 116-118° C.
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.CON(C)[C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:20]>O1CCCC1>[OH:20][C:19]1([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[O:10][N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:2]1
Reactant: CC(=NO)c1ccccc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2(O)CC(c3ccccc3)=NO2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acetophenone oxime (180 mg, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL). Mixture was cooled to 0° C. 2.0M Butyllithium in pentanes (1.35 mL, 2.7 mmol) was added to the mixture drop-wise. Reaction stirred at 0° C. for 1 hour. A solution of tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (360 mg, 1.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture drop-wise. Reaction stirred at 0° C. for 1 hour. Reaction was quenched with aqueous ammonium chloride. Mixture was extracted 2× ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as clear colorless oil in 71% yield. MS m/e (M−H)−=345.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[Mg]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[N:5]1[CH:6]=[CH:7][C:2]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: c1csc(-c2ccncc2)c1

Procedure:
To a 500 ml three-necked roundbottom flask was added 200 ml dry THF, 0.54 gr (1 mmol) Ni(dppp)Cl2 and 87 mmol of P-Br, fleshly prepared from 17 gr of the hydrochloride. To this was added T-MgBr, prepared from 14 gr (87 mmol) of T-Br and 2.5 gr (103 mmol) of magnesium. The mixture was refluxed for 20 hours and subsequently quenched with aqueous ammoniumchloride/HCl. About 100 ml of hexane was added and the organic layer extracted three times with dilute hydrochloric acid. Hereafter, the water layers were combined and made mildly alkaline with a strong sodium hydroxide solution. The product was extracted with three portions of 100 ml of chloroform. The chloroform solution was boiled shortly with a small amount of active coal and filtrated, whereafter the chloroform was removed on a rotation evaporator. Trituration of the remaining brown solid in boiling hexane yielded a clear yellow solution and a black unsoluble residue. After decanting the yellow solution, the solvent was evaporated and the remaining yellow solid dried in vacuo. The product was once recrystallized from 100 ml of hexane (a few hours standing at room temperature and overnight standing at 4° C.). The resulting yellow crystals were filtrated off, washed with cold pentane twice and dried in vacuo, (fraction I). From the collected pentane supernatants a second fraction of product with a lesser purity was obtained, by evaporating the solvent on a rotation evaporator and drying the remaining solid in vacuo. Yield: fraction I: light yellow powder of PT, 3.88 gr (24 mmol, 28%), fraction II: yellow powder of PT 6.00 gr (37.2 mmol, 43%), still containing some P-Br. M.p. (fraction I): 90°-91° C. (litt.: 92.5°-93.5° C.). Elemental analysis: found% (theory%) C 66.87 (67.05), H 4.38 (4.38), N 8.90 (8.69), S 18.7 (19.9). 1H-NMR (300 MHz, CDCl3): ∂=8.59 (2H, dd, J=4.6 and 1.7 Hz), ∂=7.52 (1H, dd, J=3.8 and 1.1 Hz), ∂=7.49 (2H, dd, J=4.6 and 1.7 Hz), ∂=7.43 (1H, dd, J=5.0 and 1.1 Hz), ∂=7.14 (1H, dd, J=3.8 and 5.0 Hz). M/z: 161 D (M.W.=161).
Reaction SMILES: CS([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12]2[N:13]=[C:14]([CH2:24]OS(C)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[N:6]1)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36]>>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:24][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36])=[N:13][C:12]([NH:11][C:7]1[CH:8]=[C:9]([CH3:10])[NH:5][N:6]=1)=[CH:21]2
Reactant: COc1ccc2c(COS(C)(=O)=O)nc(Nc3cc(C)n(S(C)(=O)=O)n3)cc2c1
Reactant: O=C1CCCCN1
Product: COc1ccc2c(CN3CCCCC3=O)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in the example 369d was used, starting from Methanesulfonic acid 3-(1-methanesulfonyl-5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-ylmethyl ester and Piperidin-2-one to give 5 mg of 1-[6-Methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylmethyl]-piperidin-2-one as a yellow solid. LC-MS m/e 366 (MH+).
Reaction SMILES: [Cl-].[CH3:2][N:3]([NH+]=C[Cl:7])[CH3:4].Cl.[NH2:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:19]/[O:20][CH3:21])/[C:16]([Cl:18])=[O:17])[N:14]=1.O1CCC[CH2:23]1>>[ClH:7].[CH3:2][N:3]([CH:4]=[N:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:19]/[O:20][CH3:21])/[C:16]([Cl:18])=[O:17])[N:14]=1)[CH3:23]
Reactant: CN(C)[NH+]=CCl
Reactant: C1CCOC1
Reactant: CO/N=C(\C(=O)Cl)c1csc(N)n1
Agent: Cl
Agent: [Cl-]
Product: CO/N=C(\C(=O)Cl)c1csc(N=CN(C)C)n1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 47 %

Procedure:
Dimethylaminochloromethyleneammonium chloride (496 mg, 3.87 mmol) was dissolved in 10 ml of tetrahydrofuran, followed by cooling to -10° C. Added to the solution were 870 mg (3.4 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl chloride hydrochloride and the resulting mixture was stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure. Deposited crystals were collected by filtration under a nitrogen gas stream and then dried at room temperature, whereby 497 mg of the title compound were obtained (yield: 47%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNc2ccc3nc(NCc4ccccc4OC)ccc3c2)c1

Procedure:
The title compound, MS: m/e=400.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3-methoxybenzylamine.
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Ca+2:6].P(=O)(O)(O)[OH:8].[S:12](=[O:16])(=[O:15])([OH:14])[OH:13].OP(O)(O)=O>>[P:1](=[O:2])([OH:5])([OH:4])[OH:3].[OH2:8].[S:12]([O-:16])([O-:15])(=[O:14])=[O:13].[Ca+2:6]
Reactant: O=S(=O)(O)O
Reactant: O=P([O-])([O-])O
Agent: O=P(O)(O)O
Agent: [Ca+2]
Product: O
Product: O=S(=O)([O-])[O-]

Procedure:
In the meantime, the other portion of the clarified monocalcium phosphate/phosphoric acid solution from intermediate storage 19 is passed by line 30 to crystallizer 31 and reacted with at least a stoichiometric amount of sulfuric acid from line 32. The sulfuric acid reacts with the MCP/H3PO4 solution to produce phosphoric acid and calcium sulfate hydrate and this slurry is passed by line 33 to thickener 34 wherein concentration of the slurry is achieved and the underflow slurry is then passed by line 35 to filter 36. The solid calcium sulfate hydrate in substantially pure form is recovered by line 37.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[NH:6][C:5]2=O.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=CC=2N=N1.N12CCCN=C1CCCCC2.CN.C1COCC1>O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)[N:6]=[C:5]2[NH:26][CH3:30]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=c1[nH]c(-c2cnccn2)nc2ccc(I)cc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CNc1nc(-c2cnccn2)nc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
In a 100 mL round-bottomed flask was added 6-iodo-2-(pyrazin-2-yl)quinazolin-4(3H)-one (0.500 g, 1.428 mmol), BOP (0.821 g, 1.857 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.426 ml, 2.86 mmol) in DMT (10 mL) to give a colorless solution. Methylamine, 2M in THF (2.142 ml, 4.28 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and then a precipitate formed. The resulting solid was collected by filtration and dried to give 0.515 g of 6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale brown solid in a 99% yield. LCMS m/z=364 (M+1) (Method D) (retention time=1.25 min). 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 8.89-8.65 (m, 3H), 8.65-8.48 (m, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 3.11 (d, J=4.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH2:46]([O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:47].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:52]([CH:53]([CH3:55])[CH3:54])[NH:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 321 mg (0.60 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 21b) and 182 mg (1.8 mmol) of NMM in 5.8 ml of DMF are added to 136 mg (0.72 mmol) of N-ethoxycarbonyl-(L)-valine and 178 mg (0.60 mmol) of TPTU in 3 ml of DMF and the mixture is stirred at room temperature for 15 hours. The reaction mixture is poured into ice-water, stirred for 30 min and filtered. Crystallisation from THF with DIPE and hexane yields the title compound: m.p.: 209-211 ° C.; HPLC20-100: tRet =15.2; FAB MS (M+H)+ =711.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1OCCOC)[N:15]=[CH:14][C:13]([C:24]#[N:25])=[C:12]2Cl)C1C=CC=CC=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CN1CCCC1=[O:40]>>[CH3:1][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)[NH:15][CH:14]=[C:13]([C:24]#[N:25])[C:12]2=[O:40]
Reactant: CN1CCNCC1
Reactant: CN1CCCC1=O
Reactant: COCCOc1cc2ncc(C#N)c(Cl)c2cc1OCc1ccccc1
Product: COc1cc2c(=O)c(C#N)c[nH]c2cc1N1CCN(C)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.92 mmol) of 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (Reference Example 24) and 551 mg (5.50 mmol) of N-methylpiperazine in 1 mL of 1-methyl-2-pyrrolidinone is heated at 90° C. for 8 hours, then at 105° C. for a further 16 hours. The solvents are removed in vacuo. To the resulting oily residue was added 2 mL of water and 5 mL of methanol. The solvents are again removed in vacuo. The crude product is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol (9:1 to 4:1) to yield 152 mg of 6-methoxy-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carbonitrile as a yellow solid, dec.>235° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.C([N:17]([CH2:20]C)CC)C.ClC([O:26]C(Cl)=O)(Cl)Cl>C(Cl)Cl>[N:17]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])=[C:20]=[O:26]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1ccccc1N1CCOCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 307.4 %

Procedure:
Under an atmosphere of nitrogen to a suspension of 25.9 g of 4-(4-amino-phenyl)-morpholin-3-one (APMO) (MW=192.22; 1 eq.) and 27.2 g of triethylamine (MW=101.19; 2 eq.) in 390 mL of methylene chloride was added at room temperature a solution of 14.6 g chloroformic acid trichloromethyl ester (MW=197.83; 0.55 eq.) in 390 mL of methylene chloride within 10 minutes. The reaction was slight exothermic and the temperature rose to 35° C. After stirring at room temperature for two hours the resulting suspension was filtered and the filtrate was concentrated in vacuo at 45° C. to afford 49.5 g of the title compound. The resulting material was used in the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][CH:21]=[CH2:22])[C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[CH2:27]CN.Cl.[CH3:35][N:36](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[CH2:27][N:36]([CH3:35])[C:10](=[O:12])[C@@H:9]([N:8]([CH2:20][CH:21]=[CH2:22])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccccc1CCN
Reactant: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1OC

Procedure:
Combine (S)-2-[N-(t-butoxycarbonyl)-allylamino]-3-phenyl-propioic acid (1.59 g, 5.20 mmol), (2-methoxybenzyl)methylamine (0.79 g, 5.20 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.12 g, 5.72 mmol), 1-hydroxybenzotriazole (0.38 g, 2.52 mmol), and diisopropylethylamine (1.34 mL, 6.5 mmol) in dichloromethane (50 mL) and stir for 18 hours. Dilute with ethyl acetate and extract with 1M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. Dry the separated organic layer over MgSO4, filter and evaporate in vacuo. Chromatograph on silica gel eluting sequentially with 5% ethyl acetate/hexane and 10% ethyl acetate/hexane to give the title compound: TLC Rf =0.55 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[C:15](=N)(OCC)[CH3:16]>C(O)C>[CH3:15][C:16]1[NH:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]=2[N:1]=1
Reactant: CCOC(C)=N
Reactant: CCOC(=O)c1cccc(N)c1N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc2[nH]c(C)nc12
Reaction time: 19 h
Yield: 98.6 %

Procedure:
(a-1) A mixture of 17 parts of ethyl 2,3-diaminobenzoate, 14 parts of ethyl ethanimidate hydrochloride and 240 parts of ethanol was stirred for 19 hours at reflux temperature. After evaporation, the residue was taken up in a potassium carbonate solution 10% and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 19 parts (98.6%) of ehtyl 2-methyl-1H-benzimidazole-4-carboxylate as a residue (int. 65).