Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]([CH3:34])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:32][CH3:33])[CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:34])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:32][CH3:33])[CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 85.4 %

Procedure:
A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (Intermediate 101, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH4Cl (17.32 mg, 0.32 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (175 mg, 85%) as a beige foam; 1H NMR: 2.17 (6H, s), 2.36 (2H, t), 2.63 (3H, s), 2.88 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.58 (2H, br s), 6.76 (1H, s), 7.12-7.19 (2H, m), 7.21-7.27 (1H, m), 7.48 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.27 (1H, d), 8.30 (1H, s), 8.42 (1H, d); m/z: ES+ MH+ 446.32.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=2)[CH:13]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2cc([N+](=O)[O-])ccc2n1

Procedure:
Operations similar to Production Example 1-(2) were conducted using ethyl bromopyruvate and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate to provide the title compound as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([O:18]CC)=[O:17])=[N:7][C:6]=2[CH:21]=1.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]3[C:16]([OH:18])=[O:17])=[N:7][C:6]=2[CH:21]=1
Reactant: CCOC(=O)[C@@H]1CCCCN1c1nc2cc(F)ccc2o1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCCN1c1nc2cc(F)ccc2o1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from ethyl (2S)-1-(5-fluoro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate [see Preparation 19] and 1N aqueous lithium hydroxide to afford (2S)-1-(5-fluoro-1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.[OH-].[Na+].[CH3:12]I>C(O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:12])[N:3]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,6-Dimethyl-pyrimidine-2-thiol (20 g, 142 mmol) is added slowly to a solution of sodium hydroxide (6.3 g, 156 mmol) in ethanol (120 ml) and water (60 ml). Methyl iodide (9.8 ml, 156 mmol) is added dropwise and the mixture is stirred at room temperature for 1 hour. The solvents are removed in vacuo and the residue is partitioned between diethyl ether (200 ml) and water (200 ml). The organic extract is dried (MgSO4) and the solvent is removed to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(I)nc1Br
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
2-Bromo-6-iodo-pyridin-3-ol (2.98 g) is dissolved in N,N-dimethylformamide (140 ml) and thereto are added cesium carbonate (16.3 g) and methyl iodide (1.25 mL) and the mixture is stirred at room temperature overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give 2-bromo-6-iodo-3-methoxy-pyridine (2.45 g). MS (m/z): 314/316 [M+H]+
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-valine (217.1 mg, 1.00 mmol) was added 2.5 mL CH2Cl2, and pyridine (81 μL, 1.00 mmol). The solution was cooled to −15 C, and to the reaction was added cyanuric fluoride (450 μL, 5.0 mmol). The reaction remained clear, but turned yellow green. The reaction was stirred at −15° C. for 60 minutes, with the gradual formation of a precipitate and transition to pale yellow. Without warming, the crude reaction was poured over ice and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with ice-cold water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 222.2 mg of 25f as a white solid. FTIR (neat) 1844 cm−1.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].O.O[N:13]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O>[NH2:1][C@H:2]([C:8]([NH2:13])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: NCCCC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
L-Lysine, N-e-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl)-butyl]phenyl]acetyl]-L-(O-benzyl)-seryl]-, (150.0 mg, 0.21 mmol), 1-hydroxy-benzotriazole hydrate (31.1 mg, 0.21 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40.1 mg, 0.21 mmol) were mixed in dimethylformamide (2.0 mL) at 0° C. for 15 minutes. N-Methylmorpholine (60.0 mg, 0.60 mmol) and methyl (R,S)-3-amino-3-cyclohexylpropionate (46 mg, 0.21 nmol) were added, and the solution was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure, and the residue taken up in methanol (1.00 mL). The product was isolated as a waxy solid by preparative HPLC to give 136 mg (73%) of L-lysinamide, N-[1-cyclohexyl-2-carbomethoxyethyl]-N-ε-(carbobenzoxy)-[N-α-[N-[4-[4-(2-methyl-1H-imidazol-1-yl)-butyl]phenyl]-acetyl]-L-(O-benzyl)-seryl]-, ±. HRMS calcd for C50H67N6O8 (M+H) 879.5020, found 879.5030.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[O:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCO2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution cooled to r.t. and concentrated under reduced pressure to give a white solid which was dissolved in methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to afford 4-chloro-2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([C:14](=[O:16])[CH3:15])([NH2:13])[N:10]([CH3:17])[CH2:9][CH:8]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)C.[CH2:28]([NH2:30])[CH3:29].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35]>CCOCC>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35].[CH2:28]([NH:30][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([C:14](=[O:16])[CH3:15])([NH2:13])[N:10]([CH3:17])[CH2:9][CH:8]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CCN
Reactant: CC(=O)C1(N)c2c(Cl)cccc2C(c2ccc(C)cc2)CN1C
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CCNc1cccc2c1C(N)(C(C)=O)N(C)CC2c1ccc(C)cc1
Temperature: 70 °C
Yield: 65.4 %

Procedure:
A mixture of 5.2 g (0.0145 mole) of 8-chloro-acetyl-amino-2-methyl-4-p-tolyl-1,2,3,4-tetrahydro-isoquinoline-hydrochloride, 100 ml of ethanol and 30 ml (20.8 g, 0.45 mole) of ethyl amine is heated in a bomb tube at 70° C. for 5 hours. The reaction mixture is evaporated, the residual orange oil is dissolved in 50 ml of ethanol and reacted with 1.8 g (0.0155 mole) of maleic acid. The solution is diluted with 150 ml of ether in portions, cooled, and the precipitated product is filtered off and washed with a mixture of acetone and ether. The product 5.7 g, [white powder, mp.: 157° C. (decomposition)] is recrystallized from a mixture of ethanol and ether. Thus 4.3 g of the title compound are obtained. Yield 66%, mp.: 176° C. (decomposition).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:19]S(C)(=O)=O)[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[ClH:2].[C:31]([NH:19][C:5]1[C:6]2[O:10][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:18]=[C:3]([Cl:2])[CH:4]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)cc2nc(N3CCCNCC3)oc12)c1ccccc1
Reaction time: 3 h

Procedure:
The compound of Example 14 (a) (7-amino-5-chloro-2-[1-(4-tert-butyloxycarbonyl) homopiperazinyl]benzoxazole, 48 mg, 0.130 mmol) was dissolved in methylene chloride (2 ml), and the solution was successively added with triethylamine (0.056 ml) and benzoyl chloride (0.031 ml) at 0° C. After the reaction mixture was stirred for 3 hours, the reaction was stopped by using saturated aqueous solution of sodium hydrogencarbonate. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solution was added with 4 N hydrochloric acid in ethyl acetate (1 ml), and the deposited solids were collected by filtration to obtain the title compound (20 mg).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.C([O:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]=2[N:21]=[CH:20]1)C1C=CC=CC=1.CO.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[O:32]([C:23]1[C:22]2[N:21]=[CH:20][N:19]([CH2:18][CH2:17][OH:16])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(COCCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Yield: 81.3 %

Procedure:
Under a nitrogen atmosphere, triflic acid (29.0 g) was added dropwise to a solution of 1-[2-(benzyloxy)ethyl]-4-phenoxy-1H-imidazo[4,5-c]quinoline (7.65 g) in anhydrous dichloromethane (200 mL). When analysis by TLC (5% methanol in dichloromethane) indicated that the reaction was complete, the reaction mixture was concentrated under reduced pressure to provide an oil. This material was dissolved in ethyl acetate and then combined with triethylamine (10 eq.). The solution was diluted with additional ethyl acetate, washed with water, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to provide ˜4.8 g of 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol as a white fluffy solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl>CS(C)=O.C(OCC)C>[Cl:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH:3]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
5-Fluoro-3-chloro-benzonitrile (1 g, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition of K2CO3 (1.3 g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80° C. for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with 1N HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile (1.4 g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M+H]+ 236, acidic method).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22](O)=[O:23])=[CH:16][CH:17]=3)[N:12](C3CCCCO3)[N:11]=2)[CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>CC(OC)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22]([NH:42][CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)=[O:23])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH:3]=1
Reactant: NCc1ccccn1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Solvent: COC(C)(C)C
Product: Cc1ccnc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)NCc4ccccn4)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 and Example 7 above except using 2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol -6-ylamino]-benzoic acid and C-Pyridin-2-yl-methylamine. 1H NMR (DMSO-d6, 300 MHz) δ 12.91 (1H, s), 9.77 (1H, s), 9.19 (1H, t, J=5.8 Hz), 8.50 (1H, d, J=4.1 Hz), 8.45 (1H, d, J=5.0 Hz), 8.06 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=16.4 Hz), 7.82–7.70 (2H, m), 7.51–7.25 (7H, m), 7.10 (1H, d, J=4.6 Hz), 6.98 (1H, dd, J=8.8, 1.8 Hz), 6.96–6.91 (1H, m), 4.58 (2H, d, J=5.9 Hz), 2.35 (3H, s). ESIMS m/z 461 (M+H)+. Anal. Calcd. for C28H24N6O×0.3 MTBE: C, 72.71; H, 5.77; N, 17.25. Found: C, 72.38; H, 5.80; N, 16.88.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:17])[C:11]#[C:12][C:13](O)([CH3:15])[CH3:14])[CH:7]=[CH:6][C:5]=12.C(NCC)C.C([OH:25])C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:17][C:13]([CH3:14])([CH3:15])[C:12](=[O:25])[CH:11]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(O)C#CC(=O)c1ccc2nsnc2c1
Reactant: CCO
Solvent: CCNCC
Product: CC1(C)OC(c2ccc3nsnc3c2)=CC1=O
Reaction time: 3 h
Yield: 83 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.6 g, 2.597 mmol) in ethanol (10 mL), a solution of diethyl amine (0.189 g, 2.597 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 3 h. The ethanol was then removed, and the mixture further diluted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 83%) as a light yellow solid.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH2:11][Cl:12])=[O:9].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:16])[CH:14]=[CH2:15]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:14]=[CH2:15])[O:10][CH2:11][Cl:12]
Reactant: C=CC(=O)OCCCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)OCCl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of chloromethyl chloroformate (0.98 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.82 (4H, m, CH2 --CH2), 4.27 (4H, m, 2×CH2 --O), 5.77 (2H, s, Cl--CH2 --O), 5.8-6.7 (3H, m, CH=CH2)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.C(#N)C.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(OCCCCCCn2cncn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature, 300 mg. of the iodide prepared in Examples 2 or 3, 3 ml. acetonitrile, 225 mg. 1,2,4-triazole and 274 mg. cesium carbonate in a reaction flask. Work up the reaction mixture in methylene chloride with a water wash and elute on a silica column with methylene chloride and ethylacetate to recover the title compound.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[N:29][C:28]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[N:29]=[N:30][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=1
Reactant: CC(C)(C)OC(=O)NCc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnc(CN)n1)c1csc(N)n1)C(=O)O
Yield: 44.5 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-2H-tetrazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (185 mg, 0.234 mmol), DCM (2.34 mL) and TFA (1.08 mL, 14.06 mmol) for 1.5 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (55.5 mg, 45%) as a white powder. LCMS: Rt=0.30 min, m/z=533.0 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J=8.8 Hz, 1H), 8.55 (br s, 3H), 7.34 (br s, 2H), 6.73 (s, 1H), 5.37 (dd, J=8.7, 5.5 Hz, 1H), 5.19-5.13 (m, 1H), 5.01-4.94 (m, 1H), 4.62-4.57 (m, 1H), 4.43-4.37 (m, 2H), 1.38 (s, 3H) 1.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([O:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)[CH:26]=[CH:25][N:24]=1.CC(O)=O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:26]=[CH:25][N:24]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccnc(Cl)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a stirred solution of the 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 165 mg, 0.55 mmol) and tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate (164 mg, 0.55 mmol) in dioxane (2.7 ml) was added AcOH (66 μl, 1.15 mmol). The mixture was heated to 120° C. for 5 h, treated with additional portion of AcOH (66 μl, 1.15 mmol), and left to stir overnight. Additional AcOH (66 μl, 1.15 mmol) was then added and the resultant mixture was left to stir overnight. The mixture was then cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash. (ethyl acetate/hexanes) to afford 80 mg (0.14 mmol, 26% yield) of tert-butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1Br.CCCCCC.C([Li])CCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.Cl>C1COCC1>[C:14]1([C:5]2[CH:4]=[C:3]([B:32]([OH:37])[OH:33])[C:2]([Br:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Temperature: -100 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml Schlenk reaction vessel were added under a nitrogen atmosphere 755 mg (1.95=mol) of 1,2-dibromo-4,5-diphenylbenzene synthesized in 2) and 12 ml of THF. The solution was cooled to −100° C. and 1.3 ml (2.1 mmol) of a hexane solution of n-butyllithium (manufactured by Kanto Chemical Co., Ltd., 1.59M) was added dropwise. After 30 minutes of aging, 472 my (2.51 mmol) of triisopropyl borate (manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise. After the temperature was gradually raised to room temperature, 3N hydrochloric acid was added and phase separation was conducted. The organic phase was concentrated under reduced pressure to obtain 770 my of a white solid (2-phenyl-5-bromo-4-biphenylboronic acid).