Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:8][C:9]1[N:22]=[C:21]([NH2:23])[C:12]2[N:13]=[C:14]3[CH2:20][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]=1[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)c2nc3n(c2c1C)CCCNC3
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc3n(c2c1C)CCCN(S(C)(=O)=O)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Methanesulfonyl chloride (198 mg, 1.73 mmol) was added to a solution of 3,4-dimethyl-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine dihydrochloride (400 mg, 1.31 mmol) and triethylamine (350 mg, 3.46 mmol) in DMF (250 mL) and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and adsorbed onto silica gel. The material was purified by column chromatography on silica gel, concentrated under reduced pressure, dissolved in dimethyl sulfoxide (DMSO), and purified by reverse phase prep HPLC (eluting with 0.5% formic acid in water/0.5% formic acid in acetonitrile in a 10-minute gradient from 5:95 to 95:5) using a HPLC purification system obtained from Shimadzu corporation (based in Kyoto, Japan) to afford 135 mg of 3,4-dimethyl-9-(methylsulfonyl)-7,8,9,10-tetrahydro-6H-pyrido[3′,4′:4,5]imidazo[1,2-a][1,4]diazepin-1-amine. HRMS (EI) calcd for C13H19N5O2S 310.1338, found 310.1346.
Reaction SMILES: [C:1]([C:9]([OH:11])=[O:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:15][CH2:16][CH:17](O)[CH2:18][OH:19])[CH:13]=[CH2:14]>>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH:17]([CH2:16][O:15][CH2:12][CH:13]=[CH2:14])[CH2:18][O:19][C:9](=[O:10])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: C=CCOCC(O)CO
Reactant: O=C(O)C(=O)c1ccccc1
Product: C=CCOCC(COC(=O)C(=O)c1ccccc1)OC(=O)C(=O)c1ccccc1

Procedure:
The compound of Example A.8 is prepared by the method described in Example A.7 using 2.2 mole equivalents of benzoylformic acid (glyoxalic acid) and 1 mole equivalent of 3-allyloxy-1,2-propanediol.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9]
Reactant: OCCO
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of n-butyllithium in hexanes (14 ml, 2.5 M) was added drop-wise under a nitrogen atmosphere to ethylene glycol (28 ml) at 0° C. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1,1-bis(2-methyl-phenyl)-1-propene (10.5 g, 35 mmol, prepared in a similar way to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 12 h and at 70° C. for 24 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts was dried (MgSO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (250 g) using a mixture of n-heptane and ethyl acetate (10:1) as eluent provided 3.0 g (30%) of 2-(3, 3-bis(2-methylphenyl)-2-propen-1-yloxy) ethanol.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:20][CH2:19][C@@H:14]([O:15]C(=O)C)[C@@H:9]([O:10]C(=O)C)[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:20][CH2:19][C@@H:14]([OH:15])[C@@H:9]([OH:10])[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: O[C@@H]1CO[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
An ethanolic solution of 2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimidazole (0.13 g, 0.28 mmol) was deprotected in a modification of General Procedure VI with 0.077 g (0.73 mmol) of sodium carbonate in 1 ml of water. After stirring overnight at ambient temperature, the mixture was treated as described in General Procedure VI. The crude product was triturated in dichloromethane and hexane to give 0.06 g (0.16 mmol, 56% yield) of 2-bromo-5,6-dichloro-1-(2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimidazole. 1H NMR (DMSO-d6) δ8.01 (s, 1H), 7.92 (s, 1H), 5.96-5.94 (d, 1H), 5.02 (s, 1H), 4.90-4.89 (d, 1H), 4.01 (s, 1H), 3.94-3.86 (m, 1H), 3.74-3.72 (d, 2H), 2.42-2.39 (m, 1H—partially underneath residual DMSO signal), 1.90-1.87 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH:7]1[CH3:16])[CH3:2].[H][H]>[Pd].C(O)C>[CH3:15][O:14][C:12]([N:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[C@H:7]([CH3:16])[CH2:8]1)=[O:13]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC)CC1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CCN(C(=O)OC)C[C@H]1C
Yield: 99 %

Procedure:
A mixture of 56.9 parts of methyl 4-(2-ethoxy-2-oxoethylidene)-3-methyl-1-piperidinecarboxylate and 400 parts of ethanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 57 parts (99%) of ethyl cis-1-(methoxycarbonyl)-3-methyl-4-piperidineacetate (int. 19).
Reaction SMILES: CS(O[C@H:6]1[C:23]2[C@:18]([CH3:25])([CH:19]=[CH:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([C:6]1[C:23]2[C@:18]([CH3:25])([CH:19]=[CH:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:33]=[N-:34]
Reactant: C[C@]12C=CC(=O)C=C1[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
In a manner similar to that described in Example 1D, treat 6β,7β-dimethanesulfonyloxy-1,4-androstadiene-3,17-dione with sodium azide in dimethylformamide. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-1,4,6-androstatriene-3,17-dione.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
5-Fluoro-2-nitrophenylamine (1.0 eq) and morpholine (3.0 eq) were dissolved in NMP and heated at 100° C. for 1 hour. The solution was cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to yield 5-morpholin-4-yl-2-nitrophenylamine. The resulting solid was recrystallized from EtOH to afford pure product as a bright yellow solid. LC/MS m/z 224.1 (MH+), Rt 1.89 minutes.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15](O)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:19]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([Cl:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: [Cl-]
Product: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Yield: 99.5 %

Procedure:
A mixture of 26.2 g (106 mmol) of (4-benzylpiperidin-1-yl)oxoacetic acid and 50 ml of thinyl chloride is refluxed for 2 h, then cooled and concentrated to yield 28.0 g (99.5%) of the title compound as an oil.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=[O:36])[CH2:34][CH:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:32][C:31]=2OCC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8].O>C(#N)C>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][CH:13]=2)[C:30]2[C:35](=[O:36])[CH2:34][CH:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:32][C:31]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cccs2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(c2cccs2)C3)cc1
Temperature: 25 °C

Procedure:
Sodium tert-butoxide (108 mg, 1.13 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(thiophen-2-yl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)-urea (intermediate 21, 507 mg, 0.94 mmol) in acetonitrile (6 mL) and the mixture is stirred at room temperature over night. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified two times by reversed phase HPLC (first purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 31 mg; ESI mass spectrum [M+H]+=494, Retention time HPLC: 1.18 min, 1.20 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH2:16])[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=2)=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:29]1([CH2:35][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([C:10]3[N:15]=[C:14]([NH2:16])[C:13]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)=[CH:12][N:11]=3)=[N:2]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1nc(-c2n[nH]c3ncccc23)ncc1-c1ccncc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(CC3CCCCC3)c3ncccc23)ncc1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.691 mmol) of 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(pyridin-4-yl)pyrimidine-4-amine (preparation: see WO 03/097063, Example 35A) were dissolved in 5 ml of DMF, and 248 mg (0.760 mmol) of cesium carbonate and 136 mg (0.760 mmol) of cyclohexylmethyl bromide were added. The mixture was stirred at RT overnight. Water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was fractionated by preparative HPLC (Method 5). The product-containing fractions were combined and concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 29 mg (11% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH:26]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[CH2:27].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[C:31]1([S:28]([CH:26]=[CH:27][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)(=[O:30])=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2cnc3cc(C=CS(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Temperature: 100 °C
Yield: 49.4 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (1.00 g, 2.46 mmol), phenyl vinyl sulfone (0.852 g, 5.06 mmol), palladium(II) acetate (12 mg, 0.05 mmol), and tris(2-tolyl)phosphine (32 mg, 0.10 mmol) were added to a pressure tube. Triethylamine (1.37 mL, 9.84 mmol) and acetonitrile (5 mL) were added. The tube was flushed with nitrogen, sealed with a TEFLON plug and heated at 100° C. for 96 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was initially purified by flash column chromatography (silica gel, eluting with a gradient of 50%-100% ethyl acetate in hexanes, followed by a gradient of 2%-6% methanol in ethyl acetate). Recrystallization of the resulting solid from acetonitrile provided 0.600 g 7-(2-benzenesulfonylvinyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline as a yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH3:21]>C(O)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH3:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 42, 1 g, 3.30 mmol) in ethanol (25 mL), 1-bromobutan-2-one (0.337 mL, 3.30 mmol) was added, and the reaction mixture was heated to 80° for 4 h, then cooled to room temperature, concentrated under reduced pressure, and the resulting solid was washed with acetonitrile to give the title compound as an off-white solid (431 mg). MS (ESP): 356 (M+1) for C13H15BrN4OS; NMR: 1.09 (t, 3H); 1.29 (t, 3H); 2.84 (q, 2H); 3.15-3.20 (m, 2H); 7.34 (br s, 1H); 7.66 (s, 1H); 8.38 (s, 1H); 8.50 (s, 1H); 9.36 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[N:16][C:17]3[N:18]([C:24](=[O:26])[NH2:25])[CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=2)[CH:13]=1)C.[Li+].[OH-].CCO>O>[C:24]([N:18]1[C:17]2[N:16]=[CH:15][C:14]([C:12]3[CH:13]=[C:8]([CH2:7][O:6][CH2:5][C:4]([OH:27])=[O:3])[CH:9]=[N:10][CH:11]=3)=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1)(=[O:26])[NH2:25]
Reactant: CCOC(=O)COCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCCc2cc(-c3cncc(COCC(=O)O)c3)cnc21
Yield: 86.5 %

Procedure:
[5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-acetic acid ethyl ester (1.0 g, 2.7 mmol) and LiOH (0.10 g, 4.2 mmol) are mixed in H2O (10 mL) and EtOH (10 mL) and stirred at room temperature overnight. The reaction mixture is concentrated under vacuum and treated with 1 N HCl, and ethyl acetate. The organic layer is concentrated to give [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethoxy]-acetic acid (0.80 g).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.Cl.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH2:18].[Cl:28][C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:18][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[N:37][C:29]=1[Cl:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
EDC.HCl (2.11 g, 11 mmol) was added to a mixture of L-tyrosine methyl ester hydrochloride (2.32 g, 10 mmol), 2-chloronicotinic acid (1.58 g, 10 mmol), HOBT (1.49 g, 11 mmol) and NMM (2.31 ml, 21 mmol) in DMF (50 ml). The mixture was stirred overnight at room temperature. The solvent was removed in vacuo. the residue dissolved in EtOAc (300 ml) and washed with dilute HCl (100 ml), saturated aqueous NaHCO3 (100 ml), water (3×100 ml) and brine (50 ml), dried (Na2SO4) and solvent removed in vacuo to give the title compound as a yellow gum (3.27 g, 98%). δH (DMSO-d6, 300 MHz) 9.21 (1H, s, OH), 9.03 (1H, d, J 7.9 Hz, CONH), 8.45 (1H, dd, J 4.8, 1.9 Hz, pyrH), 7.67 (1H, dd, J 7.4, 1.9 Hz, pyrH), 7.47 (1H, dd, J 7.5, 4.8 Hz, pyrH), 7.05 (2H, d, J 8.5 Hz, ArH), 6.67 (2H, d, J 8.5 Hz, ArH), 4.58 (1H, ddd, J 9.6, 7.9, 5.4 Hz, CHα), 3.65 (3H, s, CO2Me), 3.01 (1H, dd, J 13.9, 5.4 Hz, CHAHBAr) and 2.85 (1H, dd, J 13.9, 9.6 Hz, CHAHBAr), m/z (ESI, 60V) 335 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Sn](Cl)(Cl)(Cl)Cl.[N:12]1([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13]1.O>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([C:13]1[N:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of isobutyryl chloride (5.4 ml) in DCM (250 ml) was added tin (IV) chloride (5.8 ml) at -10° C. under nitrogen. After stirring for 15 minutes in the cooling bath, 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (10.0 g) was added portion-wise. The reaction mixture was allowed to warm to room temperature, and stir for three days, at which time it was poured into cold water. The layers were separated and the organic phase was washed twice with water, once with 5% HCl (aq.), and subsequently dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, DCM) afforded 2.5 g of the product as a solid, m.p. 147°-149° C.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C.CC(=O)OCC>[N:34]1[NH:39][N:40]=[N:41][C:33]=1[C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:36][CH:35]=3)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[N:32][CH:31]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C#N)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(-c3nn[nH]n3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Yield: 12 %

Procedure:
Into a solution of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoate INT-18 (34 mg, 0.07 mmol) in DMF (2 mL) were added NH4Cl (7.5 mg, 1.4 mmol) and NaN3 (7 mg, 0.1 mmol). The reaction mixture was heated at 100° C. for 3 h then diluted with EA and washed with NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by preparatory HPLC to provide 4.6 mg (12%) of tert-butyl (S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate. LCMS-ESI (m/z) calculated for C29H33N7O3: 527.6; no m/z observed, tR=3.83 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 2H), 8.42 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 5.13 (dd, J=14.4, 7.1 Hz, 1H), 3.28 (ddd, J=21.0, 13.6, 6.7 Hz, 2H), 1.47 (d, J=6.8 Hz, 9H), 1.33 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[I-:19].[Na+].I>CC(C)=O>[I:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: [I-]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: Ic1nnc(Cc2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under exclusion of air, a suspension of 12.8 g (50 mMol) of 1-chloro-4-(4-pyridyl-methyl)-phthalazine (Example 67A.1 in WO 98/35958) and 25 g (166.8 mMol) of sodium-iodide in 0.3 l of acetone is mixed with 20 ml hydroiodic acid (55% Hl in water; 144 mMol) and stirred in the dark during 6 days at RT. Filtration and washing with acetone follow. The remaining solid is suspended in 1 l of water, neutralized with 100 ml of an 1 M Na2CO3 solution, stirred during 10 min, filtered and washed with water, yielding the title compound: An. calc. (C14H10N3I.0.05 H2O) C, 48.31%; H, 2.92%; N, 12.07%; I, 36.46%; H2O, 0.26%; An. meas. C, 48.60%; H, 3.10%; N, 12.08%; I, 36.28%; H2O, 0.28%; FAB-MS (M+H)+=348.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)c3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and benzenesulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 37%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1.O>[C:27]([C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccccc23)C1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.906 g, 10.18 mmol) in NMP (10 mL) at 0° C. was added NaH (0.339 g, 8.48 mmol). The mixture was stirred for 5 minutes and then 1-chloroisoquinoline-3-carbonitrile (1.6 g, 8.48 mmol) was added. The reaction mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently diluted with water and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane to give the title compound as a yellow solid (1.61 g, 55.9%). ESI-MS m/z [M+H-tert-butyl]+ 284.2.