Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][NH2:16])=[O:14])=[CH:9][CH:8]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23](Cl)=O)[CH3:18].O>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[O:14][C:13]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)=[N:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Reactant: NNC(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOc1ccc(-c2nnc(-c3ccncc3)o2)cc1OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH2Cl2 was added SOCl2 at room temperature; the reaction was refluxed for 1.5 h and the mixture concentrated under reduced pressure to yield 3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of the 3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirred for 12 h at room temperature. The mixture was poured into 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuum. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured into an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH2Cl2:MeOH (9:1) to yield the product as white solid in 67% yield (150 mg). 1H NMR (400 MHz, CDCl3): δ 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1350.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH2:9]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH:4]([CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1)[C:23]#[N:24])=[O:5]
Reactant: N#CCc1ccc(Cc2ccccc2)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a suspention of sodium methoxide (64.26 g) in toluene (2.5 l) was added dropwise at 0° C. a mixture of ethyl formate (88.14 g) and 4-benzylphenylacetonitrile (189.69 g) with stirring. After 30 minutes, ice bath was removed. After 20 hours, ice water (2.6 l) was added to the reaction mixture, and the aqueous layer was separated. The organic layer was washed with 0.5N sodium hydroxide aqueous solution (500 ml×5). The aqueous layer and the washings were combined, adjusted to acid with conc. hydrochloric acid, and stirred at 0° C. for 30 minutes. The precipitate was separated by filtration, washed, and dried to give the title compound (152.22 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([CH2:23]Br)[CH:16]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:23]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In 70 ml of N,N-dimethylformamide was suspended 3.97 g of sodium hydride (purity: 60%), and 50 ml of an N,N-dimethylformamide solution containing 8.49 g of p-toluenesulfonamide was added thereto, after which the resulting mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added a solution of 17.0 g of 1-bromo-3,4-di(bromomethyl)benzene in 50 ml of N,N-dimethylformamide at 60° C., and the resulting mixture was stirred at 60° C. for one hour. The reaction mixture obtained was added to 500 ml of ice water and the precipitate was collected by filtration, and purified by a column chromatography (eluent: chloroform), to obtain 15.2 g of colorless, crystalline 5-bromo-2-(p-toluenesulfonyl)isoindoline.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:13][OH:14]
Reactant: NO
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1c(F)ccc(F)c1Cl

Procedure:
A solution of 2-chloro-3,6-difluoro-benzaldehyde (16.5 g, 93 mmol) in ethanol (80 ml) was treated with hydroxylamine HCl (7.80 g, 112 mmol) and sodium acetate (9.20 g, 112 mmol). The mixture was heated under reflux for 16 h, then the solvent was evaporated, and the residue stirred with water. The precipitate was filtered and dried to afford 2-chloro-3,6-difluoro-benzaldehyde oxime. It was dissolved in acetic anhydride (140 ml) and refluxed for 16 h, then the mixture was evaporated to afford 2-chloro-3,6-difluoro-benzonitrile as a light brown liquid (10.6 g, 65%). In analogy to example 5a, this compound was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. Aqueous workup, extraction with Ethyl acetate followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 6%). MS: m/e=336.1 [M+H]+.
Reaction SMILES: [CH3:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH3:19][C:20]1[NH:21][CH2:22][CH2:23][CH:24]=1>C(Cl)Cl>[CH3:19][C:20]1([CH2:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5])[CH2:24][CH2:23][CH2:22][NH:21]1
Reactant: CC1=CCCN1
Reactant: CCO[PH](C)=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[PH](=O)CC1(C)CCCN1
Temperature: 0 °C

Procedure:
0.8 g (7.4 mmol) of ethyl methylphosphinate of formula (CH3)(H)P(O)OC2H5 and 488 mg (8 mmol) of triethylamine are dissolved in 20 ml of anhydrous methylene chloride and cooled to 0° C. 0.87 g (8 mmol) of trimethylsilyl chloride is then added. The formation of the intermediate P(OSiMe3)(OEt)(Me) is virtually instantaneous. 0.63 g (7.6 mmol) of 2-methylpyrroline of formula:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][N:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([NH:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[C:16]2=[O:36])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][N:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([NH:24][CH:25]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[C:16]2=[O:36]
Reactant: CC(C)(C)OC(=O)NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (+/−)-3-{[8-(2-tert-butoxycarbonylamino-ethylamino)-4-oxo-4H-quinolizine-3-carbonyl]-amino}-3-phenyl-propionic acid (20.5 mg, 0.042 mmol) in dichloromethane (1 ml) at room temperature was added trifluoroacetic acid (1 ml). The resulting mixture was stirred at room temperature for 45 min. The solvent was removed under vacuum and the resulting residue was subjected to a silica gel chromatography (EtOH:H2O: NH4OH, 90:5:5) to give desired product which was further lyophilized to afford a yellowish solid (30 mg, 73%) which was characterized by 1HNMR (400 MHz, D2O) δ: 2.58-2.65 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 2H), 5.21 (m, 1H), 6.0-8.7 (m, 10H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[F:22]/[C:23](/[C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)=[CH:24]\[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:39]3[CH:40]=[C:35](/[C:23](/[F:22])=[CH:24]/[C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=4)[CH:36]=[CH:37][CH:38]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(/C=C(\F)c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(/C=C(\F)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Yield: 41.6 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol) and (Z)-methyl 4-(2-fluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)vinyl)benzoate (150 mg, 0.39 mmol) in 25 mL of 1,4-dioxane were added Na2CO3 (64 mg, 0.6 mmol) and 3 mL of water at room temperature. Then the mixture was degassed with nitrogen for 15 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added in one portion and the reaction mixture was stirred at reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was purified by silica gel chromatography (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate=1:1) to give (Z)-methyl 4-(2-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)phenyl)-2-fluorovinyl)benzoate (70 mg, 42%) as a yellow sold. 543 [M+H]+, tR=1.88 min.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O.COC1C=CC(/[CH:36]=[C:37]2/[C:38]([NH:40][C:41]([S:43]/2)=[NH:42])=[O:39])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:42][C:41]1[S:43]/[C:37](=[CH:36]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)/[C:38](=[O:39])[N:40]=1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC1CCOCC1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(N)=NC3=O)cc2c1OC1CCOCC1

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile (example 76b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[OH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:41][CH:42]1[CH2:47][CH2:46][N:45]([C:4](=[O:5])[CH2:3][S@:7](=[O:8])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:9][C:10](=[O:11])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)[CH2:44][CH2:43]1
Reactant: OC1CCNCC1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CC(=O)N3CCC(O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and 4-hydroxypiperidine were reacted to give the title compound.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:66][CH2:65][CH2:64][C@H:42]1[C:43]([NH:45][C@H:46]([C:50]([NH:52][C@H:53]([C:61]([NH2:63])=[O:62])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:51])[CH:47]([CH3:48])[CH3:49])=[O:44])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(N)=O)C(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
25 g (43.3 mmol) of Z-Val-Val-MeVal-Pro-OH and 15.59 g (43.3 mmol) of H-Pro-Val-Phe-NH2 were suspended in 430 ml of dry dichloromethane. After cooling to 0° C., 5.81 ml (52 mmol) N-methylmorpholine, 1.97 g (15 mmol) of HOBt and 8.33 g (43.3 mmol) of EDCI were added and the reaction mixture stirred overnight at room temperature. The solvents were evaporated, the residue dissolved in 640 ml of dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (4×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 33.04 g of the product. The crude product was chromatographed on a silica gel column with 20% MeOH/hexane. 18.32 g of the desired product were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and sodium sulphate (56 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (89.0 g).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44](O)=O)=[CH:31][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[ClH:28].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44]2[NH:13][C:14]3[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=3[N:20]=2)=[CH:31][N:30]=1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cc2c(CC(=O)O)cnc(Cl)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(Cl)c2cc1OC
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.6M aqueous solution, 0.33 ml, 1.85 mmol) is added to a suspension of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.327 g, 1.54 mmol), (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.414 g, 1.54 mmol) and 1-hydroxybenzotriazole (0.251 g, 1.85 mmol) in CH2Cl2 (2 ml). Water (2 ml) is added, the biphasic mixture is shaken for 18 hours and the the resultant solid is collected by filtration. This intermediate is suspended in methanol (10 ml), 4M aqueous NaOH (5 ml) is added and the mixture heated to reflux for 4 hours. After evaporation of the methanol, the residue is acidified to pH2 with concentrated hydrochloric acid and the resultant solid collected by filtration and purified by preparative HPLC to afford 8(1-chloro-6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione hydrochloride, [M]+ 458.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CO.C(Cl)Cl.O>[N:17]1([C:22]([NH:1][C:2]2[CH:16]=[N:15][C:5]3[NH:6][C:7]4[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)N1CCCC1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(N)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc2c(cn1)[nH]c1ncc(NC(=O)N3CCCC3)cc12
Temperature: 60 °C
Yield: 11.4 %

Procedure:
A solution of 3-amino-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (47.9 mg, 0.229 mmol) in pyridine (6.1 mL) was treated with pyrrolidine-1-carbonyl chloride (83.4 μL, 0.755 mmol) and heated at 60° C. for 4 h. The cooled reaction mixture was treated with saturated aqueous sodium bicarbonate solution then diluted with 20% MeOH in DCM and water. The layers were separated, the aqueous phase extracted with 20% MeOH in DCM, and the combined organic phase was dried over sodium sulfate and concentrated in vacuo. The resultant residue was dissolved in DCM/methanol, absorbed onto silica gel, and purified by flash chromatography (silica, 4 g column, Biotage, 1-20% methanol in DCM containing 0 1% 7N ammonia in MeOH). Collecting appropriate fractions afforded a yellow solid which was further purified by preparative HPLC (5-85% MeCN in water (0.1% NH4OH) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (8.0 mg, 11%). 1H NMR (400 MHz, DMSO-D6): 12.92 (s, 1H), 8.78 (s, 1H), 8.70 (dd, J=4.7, 1.4 Hz, 1H), 8.60 (dd, J=7.9, 1.4 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 4.71 (dd, J=8.7, 4.6 Hz, 1H), 2.85 (m, 2H), 2.07 (m, 4H), 1.92 (m, 2H). LCMS (Method E): RT=3.36 min, M+H+=307.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:20](=[O:23])[CH2:21][CH3:22])[C:16](=[O:19])[CH2:17][CH3:18].B(Br)(Br)Br>>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:16](=[O:19])[CH2:17][CH3:18])[C:20](=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)C(CCCCCCc1ccccc1OC)C(=O)CC
Agent: BrB(Br)Br
Product: CCC(=O)C(CCCCCCc1ccccc1O)C(=O)CC

Procedure:
[I; Ar is 2-HOC6H4, R0 is H, R' and R" are CH3CH2CO, Y is CH2CH2CH2CH2 ] was prepared by demethylation of 4-[6-(2-methoxyphenyl)hexyl]-3,5-heptanedione (Example 46) with boron tribromide according to the procedure of Example 42f.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:14])=[C:5]([C:10]([F:13])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:14][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([F:13])[CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: COC(=O)c1c(F)ccc(CBr)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a room temperature solution of methyl 3-(bromomethyl)-2,6-difluorobenzoate (14.24 g, nominally 51.2 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (9.1 g, 50.24 mmol, 1.0 equiv) in DMF (50 mL) was added K2CO3 (27.8 g, 201 mmol, 4.0 equiv) as a solid. The resulting mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with H2O. The combined aqueous layers were washed once with EtOAc, and the combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10%-60% EtOAc/hexanes) provided tert-butyl 4-(2,4-difluoro-3-(methoxycarbonyl) benzyl)piperazine-1-carboxylate (7.70 g, 41.4% over two steps). LCMS m/z (APCI)=371.2 (M+H).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH:38]([C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)C1C=CC=CC=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: c1ccc(Nc2ccncc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccncc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.10 mL, 0.57 mmol) and 4-amiinopyridine (76 mg, 0.59 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (39 mg, 28% yield).