Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].[OH2:29].N.[OH2:31]>C(O)(=O)C>[Cl:11][C:7]1[CH:8]=[CH:9][C:10]([N:2]([CH3:1])[C:3](=[O:29])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[C:5]([C:4](=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1
Reactant: Cn1c(NC(=O)OCc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc21
Reactant: O
Agent: N
Solvent: CC(=O)O
Product: CN(C(=O)NC(=O)OCc1ccccc1)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
To a suspension of 1.0 g of benzyl 1-methyl-3-phenyl-5-chloroindole-2-carbamate in 10 ml of acetic acid, a solution of 1.0 g of chromic anhydride in 1 ml of water was added dropwise with stirring below 25° C. The resulting mixture was stirred at room temperature for 6 hours, and then 25 ml of water was added to the reaction mixture. The resulting reaction mixture was neutralized with concentrated ammonia water and extracted with ether. The extracted ether layer was washed with water and dried over Glauber's salt. The solvent was removed by distillation under reduced pressure to give 0.94 g of oily benzyl 4-(4-chloro-2-benzoylphenyl)-4-methylallophanate. After dissolving the oily material in 9 ml of ethanol and adding 3 ml of concentrated hydrochloric acid thereto, the resulting mixture was refluxed for 1 hour. After removing the solvent by distillation under reduced pressure, the obtained residue was neutralized with concentrated ammonia water. The obtained crystals were collected by filtration, washed with water and recrystallized from ethanol to give 1-methyl-4-phenyl-6-chloro-2(1H)-quinazolinone having a melting point of 220° - 221° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][N:3]=1.Cl.ClC1C=C(N2C(=O)C=C(OC3CCNCC3)C(C#N)=N2)C=CC=1Cl.ClC1N=CC(CCC)=CN=1.Cl.[C:47]([C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:60](=[O:61])[CH:59]=[C:58]([O:62][CH:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)[C:57]([C:69]#[N:70])=[N:56]2)=[CH:51][C:50]=1[F:71])#[N:48]>>[C:47]([C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:60](=[O:61])[CH:59]=[C:58]([O:62][CH:63]3[CH2:64][CH2:65][N:66]([C:2]4[N:3]=[CH:4][C:5]([CH2:8][CH2:10][CH3:9])=[CH:6][N:7]=4)[CH2:67][CH2:68]3)[C:57]([C:69]#[N:70])=[N:56]2)=[CH:51][C:50]=1[F:71])#[N:48]
Reactant: Clc1ncc(C2CC2)cn1
Reactant: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Agent: CCCc1cnc(Cl)nc1
Agent: Cl
Agent: N#Cc1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(C#N)c(F)c4)nc3C#N)CC2)nc1
Yield: 56 %

Procedure:
Example 38 was prepared in 56% yield according to procedures described in Example 21 substituting 2-chloro-5-cyclopropylpyrimidine and 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl for 2-chloro-5-propylpyrimidine and 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt. 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.25 Hz, 3H) 1.48-1.67 (m, 2H) 1.82-2.01 (m, 2H) 2.01-2.17 (m, 2H) 2.41 (t, J=7.69 Hz, 2H) 3.60-3.91 (m, 2H) 3.98-4.27 (m, 2H) 4.48-4.87 (m, 1H) 6.32 (s, 1H) 7.52-7.70 (m, 2H) 7.70-7.81 (m, 1H) 8.17 (s, 2H). MS (ESI) 460 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: O=C(O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=401.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:24]1[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccccc1NC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.4 %

Procedure:
A mixture of 15.5 g of 2-(tert-butoxycarbonylaminomethyl)aniline, 15 g of N-t-butyloxycarbonyl-4-piperidone, 250 mL of 1,2-dichloroethane, 4.2 mL of glacial acetic acid and 25 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Drying overnight under vacuum gave 30.1 g of tert-butyl (2-(tert-butoxycarbonylaminomethyl)anilino)piperidine carboxylate as a solid: 1H NMR (400 MHz, CDCl3) 7.19 (t, 1H), 7.0 (d, 1H), 6.6 (dd, 2H), 4.94 (br s, 1H), 4.75 (br s, 1H), 4.23 (br m, 2H), 4.0 (br m, 2H), 3.45 (br m, 1H), 3.0 (br m, 2H), 2.0 (br m, 2H), 1.82 (br m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].[Ru](=O)=O>[C:7]([OH:2])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: OCc1ccccc1
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a stirred suspension of 20 g (94 m mol) sodium periodate in 200 cc of 1 molar sodium hydroxide there was added 0.1 g (0.75 m mol) ruthenium dioxide and 4.32 g (40 m mol) benzyl alcohol. After two hours the reaction was stopped. The mixture was then filtered and the filtrate washed with ether obtaining a neutral fraction comprising benzaldehyde and unreacted benzyl alcohol. The aqueous alkali phase was acidified with sulfuric acid and extracted with ether. There was obtained 4.32 grams of benzoic acid (89% yield).
Reaction SMILES: C([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[Cl:20][C:18]1[C:17]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:16][C:14]2[NH:15][C:11]([S:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[N:12][C:13]=2[CH:19]=1
Reactant: CCOP(=O)(CSc1nc2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CSc1nc2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1

Procedure:
Compound 1-1 was stirred with TMSBr (0.41 mL, 3.2 mmol) and 2.7 mL of CH2Cl2 for 5 hours before concentrating in vacuo to afford compound 1-2 as an oil. The oil was redissolved in 2 to 3 mL of MeOH and re-concentrated, then triturated with acetonitrile and EtOAc to afford title compound 1-2 as a white powder. mp 210-215° C.; LRMS (API-ES) m/e for C16H12ClN2O3PS (M+H)+, calcd 378.77. found 379.4; Anal. Calcd for C16H12ClN2O3PS+1 HBr: C, 41.81; H, 2.85; N, 6.09. Found: C, 42.11; H, 2.66; N, 6.21.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[C:16]#[N:17].[CH3:18][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:18])[N:7]=1
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 210 mg (0.87 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.16 ml (0.87 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.11 ml (1.73 mmol) methyl iodide and stirring continued for 90 minutes at room temperature. The reaction mixture was then poured onto 100 ml ice-water and the resulting crystals collected by filtration and dried in vacuo to afford 135 mg (61%) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyridine-3,5-dicarbonitrile as a light brown crystalline solid. EI-MS m/e (%): 256 (M+, 49), 255 ([M—H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: CC(O)CN
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(O)CNC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 36 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 1-amino-2-propanol as for example 34. After workup, the residue was triturated with hexane then dried, affording 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (36%) as a white solid; m.p. (EtOAc/Hexane) 161-166° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 10.13 (br s, 1H), 8.31 (t, J=1.7 Hz, 1H), 7.73 (br s, 1H), 7.66-7.58 (m, 2H), 7.37-7.31 (m, 1H), 5.75 (dd, J=5.2, 0.9 Hz, 1H), 3.96-3.88 (m, 1H), 3.46-3.39 (m, 1H), 3.42 (s, 3H), 3.25-3.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0371. HPLC 96.8% (254 nm).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:33]=[CH:32][N:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:37]([CH2:39][C:40](O)=[O:41])#[N:38].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:37]([CH2:39][C:40]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:33]=[CH:32][N:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1)=[O:41])#[N:38]
Reactant: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1ccc(Nc2cc(N[C@H]3CC[C@H](NC(=O)CC#N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Example 48 and 2-cyanoacetic acid (4.01 mg, 0.047 mmol) in DCM (1 mL) was added DIEA (0.035 mL, 0.200 mmol) and BOP (20.87 mg, 0.047 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated. The crude reaction mixture was purified by reversed-phase preparative HPLC to give the title compound (8.1 mg, 61%) as white solid. HPLC Rt=2.981 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=560.
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[CH:7]=1.O>ClCCl>[I:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1
Reactant: COc1ccc2cc(I)ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2cc(I)ccc2c1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
BBr3 (102 g, 407 mmol) is added dropwise over 30 min to a slightly cloudy solution/suspension of 2-iodo-6-methoxy-naphthalene (45.4 g, 160 mmol) in dichloromethane (dried over 3 {acute over (Å)} molecular sieves) (1 L) at −8° C. The mixture is warmed to 20° C. and stirred at this temp for 1.5 h. Water (400 mL) is carefully added (slow dropwise addition at the start) and the biphasic mixture vigorously stirred for 20 min. The layers are separated and the aqueous layer extracted with dichloromethane (250 mL) with additional water (400 mL) being added. The combined organic fractions are washed with water (500 mL), dried (Na2SO4), filtered and solvent removed in vacuo to give a colourless solid with silvery purple patches (44.7 g). This is recrystallised from IMS/water (initially dissolved in 100 mL IMS) washing with water and dried in a vacuum oven to give an off-white solid (40.3 g, 94%).
Reaction SMILES: [OH:1][CH:2]([CH3:10])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C1COCC1>[OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C#CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C(C)O
Temperature: -70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
NaAlH2[O(CH2)2OMe]2 (68.6% m/m, 82.2 g, 0.270 mol) is dissolved in THF (750 ml) and cooled to −70° C. 20 (rac-Ethyl 4-hydroxypent-2-inoate) (crude, HPLC: ˜90 area %, 21.33 g, 0.135 mol) in THF (500 ml) is added dropwise over 1.25 h at ≦−65°. After stirring for 2 hours at ≦−68° C. the reaction mixture is quenched with 2 M HCl (540 ml). Then water (250 ml) is added and the mixture is extracted with tBuOMe (1.5 and 1 l). The organic phases are washed with saturated NaHCO3 (250 ml) and brine (2×100 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is purified by flash chromatography (AcOEt:heptane fraction 20:80 to 40:60) and yields 21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (15.56 g, 80%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[C:10]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1C=C(OC)NN(OC)N=1.Cl.[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH2:46]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:53])[C@H:45]([CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[NH:46][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:10]2[C:5]3[C:4](=[O:22])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: COC1=CC(Cl)=NN(OC)N1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OC
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To 2.00 g (6.74 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid, prepared in Preparation 4, in 23 ml dimethylformamide under nitrogen was added 1.40 g (13.8 mmol) of N-methylmorpholine and 1.17 g (6.70 mmol) of 4-chloro-2,6-dimethoxytriazine. The formation of the active ester was monitored by the HPLC analysis of aliquots. After 40 minutes at room temperature 0.70 g (6.9 mmol) of N-methylmorpholine was added followed by 1.56 g (7.37 mmol) L- glutamic acid dimethyl ester hydrochloride. After 30 minutes HPLC analysis indicated substantially complete consumption of the active ester and formation of N-[4-[2-[2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl]glutamic acid dimethyl ester. The reaction mixture was filtered and the above product concentrated and purified by silica chromatography (elution 1:4 methanol:methylene chloride). The pure fractions were pooled and provided 1.30 g of the above product in a yield of 43 percent. 1H NMR (DMSO-d6) δ2.01 (m, 2H), 2.40 (t, J =7.4 Hz, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 3.53 (s, 3H), 3.59 (s, 3H), 4.40 (m, 1H), 5.99 (s, 2H),6.26 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 8.62 (d, J=7.5 Hz, 1H), 10.15 (s, 1H), 10.57 (d, J =1.9 Hz, 1H ).
Reaction SMILES: [Cl-].[NH4+].COCCOC.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:32][CH3:33])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1>O.[Zn]>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:32][CH3:33])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH2:29])[CH:27]=3)[CH2:22][CH2:21][CH2:20]2)(=[O:17])=[O:18])[CH:15]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(N)cc21
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A 27% solution of ammonium chloride in water (35.00 mL) was mixed with 1,2-dimethoxyethane (21.00 mL) and the mixture cooled to 15° C. 1-(5-Chloro-2-methoxy-benzenesulfonyl)-7-nitro-1,2,3,4-tetrahydro-quinoline (1.00 g, 26.10 mmol) was added under vigorous stirring, followed by zinc powder (2.22 g, 33.96 mmol). The mixture was warmed to room temperature and stirred for 1 hour. After filtering off the solids, the organic solvent was evaporated and the residual slurry extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylamine as a brown solid, 0.32 g (35%), MS (ISP): m/e=353.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CN(C=O)C>O>[CH2:35]([O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), potassium carbonate (95 mg), benzylbromide (81 μl) and DMF (5 ml) was stirred at room temperature for 3 hrs. After diluting with water, the mixture was extracted with ether. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate and n-hexane was added to the residue. The mixture was crystallized to give the title compound (152 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([NH:9][C:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:11])[C:6]([OH:8])=O.[C:19](OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([NH:9][C:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:11])[C:6](=[O:8])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC(NC(=O)c1ccc(C)s1)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)CC(NC(=O)c1ccc(C)s1)C(C)=O
Temperature: 90 °C

Procedure:
2-[(5-Methyl-thiophene-2-carbonyl)-amino]-succinic acid 4-methyl ester (12 g, 45 mmol), pyridine (60 mL) and acetic anhydride (50 mL) were combined in a 500 mL flask. The reaction mixture was heated at 90° C. for 2 h and then cooled to ambient temperature. After concentrating the reaction mixture under reduced pressure, DI water was added (100 mL). (Potential exotherm!). The reaction mixture was partitioned between water and CH2Cl2. The organic phase was washed with 1N HCl and then dried (MgSO4), filtered and concentrated under reduced pressure. The material was used without further purification. MS (EI) 270.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24]C(=O)OC(C)(C)C)[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:9][C:8]=12)#[N:2].[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[NH2:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[C:12](=[O:13])[C:7]4[C:8]([O:9][C:10]=3[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[C:3]([C:1]#[N:2])[N:4]=[CH:5][CH:6]=4)=[CH:19][CH:18]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#N)nccc4c3=O)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1nccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 1-(4-(8-cyano-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate (10 mg, 0.020 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (1.0 ml). The reaction mixture was stirred at RT for overnight. The solvent was evaporated and the crude product was washed several times with DCM and acetonitrile (3×1 ml). The product was dried to give the title compound as the HCl salt (5 mg, 71%). 1H NMR (500 MHz, CD3OD): δ 8.55 (d, 1H), 8.15 (d, 1H), 7.48-7.18 (m, 9H), 2.75-2.67 (m, 2H), 2.55-2.42 (m, 2H), 2.18-2.09 (m, 1H), 1.88-1.73 (m, 1H). LCMS (Method I): RT=4.39 min, [M+2]+=395.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[CH:20]=[N:19][CH:18]=1.CCOP(O)N(C(C)C)C(C)C>ClCCl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:26][CH2:25][CH2:24][NH:23][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([CH3:16])[N:22]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1cncc(NCCN)n1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cncc(NCCNC(=O)/C=C/C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (70 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (42 μl, 0.5 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of N-(6-methylpyrazin-2-yl)ethane-1,2-diamine (38 mg, 0.25 mmol) and EDIPA (175 μl, 1 mmol) in a mixture of anhydrous dichloromethane (2 ml) and anhydrous dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 19.9 mg of a solid (0.07 mmol, 14.5% yield)