Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])[C:20]([Cl:39])=[CH:19][N:18]=1>>[Cl:39][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:37][CH3:38])=[N:22][C:17]([NH:1][C:2]2[C:13]([O:14][CH3:15])=[CH:12][C:5]3[CH2:6][C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCNC(=O)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCNC(=O)C2

Procedure:
The title compound was prepared from 7-Amino-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.012 g, 15%). MP: 208-213° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.14-8.10 (m, 2H), 8.03-8.02 (m, 1H), 7.44 (s, 2H), 6.64-6.62 (m, 1H), 6.58-6.56 (m, 1H), 6.54-6.49 (m, 1H), 5.70 (br s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.56-3.50 (m, 2H), 3.23-3.18 (m, 4H), 3.00-2.96 (m, 2H), 2.64-2.59 (m, 4H), 2.38 (s, 3H). MS: 538 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16]CC)=O)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[NH4+:25].[OH-]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([NH2:25])=[O:16])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1csc(-c2cccc(Br)c2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)Cc1csc(-c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
Ethyl 2-(3-bromophenyl)-4-thiazolylacetate prepared by the process in Example 2 (10 g) in 75 ml of 28% NH4OH was stirred at room temperature. About 10 ml of dioxane was added to facilitate mixing. After 10 days, the crystalline product was filtered. The yield of product was 8.3 g, mp 150°-152° C. When recrystallized from alcohol, it melted 152°-154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][CH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reaction time: 24 h

Procedure:
2-Methyl-4-nitro-1-pentafluoroethyl-benzene (2.55 g) was dissolved in CCl4 (30 ml) and AIBN (164 mg) and NBS (1.96 g) were added. The reaction was heated to reflux and stirred for 24 h. The mix was diluted with CH2Cl2, washed with sat'd NaHCO3, dried over MgSO4 and concentrated to give the compound as an oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH2:9]>CS(C)=O.C(OCC)C>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:9])=[CH:3][CH:4]=1
Reactant: O
Reactant: Oc1ccc(S)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: Oc1ccc(SSc2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 96 %

Procedure:
25.0 g of para-hydroxy thiophenol (Wako Pure Chemical Industries, Ltd.) was dissolved in 100 ml of dimethyl sulfoxide (Kanto Chemical Co., Ltd.) at 0 degree C. The reaction solution was stirred for 24 hours at 65 degree C. and cooled to 0 degree C. after the completion of the reaction. Then the mixture was diluted with 100 ml of diethyl ether (Wako Pure Chemical Industries, Ltd.). Water was added to this solution and the aqueous phase was extracted with 50 ml of diethyl ether three times. Then the organic phase was dried by using sodium sulfate (Wako Pure Chemical Industries, Ltd.) and recrystallized in chloroform (Wako Pure Chemical Industries, Ltd.). 4,4′-disulfanediyldiphenol was obtained (23.8 g, yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:20][C:14]1[CH:13]=[C:12]([F:11])[C:17]([F:18])=[C:16]([F:19])[CH:15]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cc(F)c(F)c(F)c1
Product: O=Cc1ccc(Oc2cc(F)c(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3,4,5-trifluorophenol.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[N:22]=1)([CH3:19])[CH3:18].N#N>CN(C=O)C.[Cu]I.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>[CH:17]([O:20][C:21]1[N:22]=[C:23]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][N:14]=[C:13]([NH2:16])[N:12]=4)[CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC(C)C)n1
Reactant: Nc1noc(-c2ccc3[nH]cc(I)c3c2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4nc(N)no4)cc23)n1
Temperature: 90 °C
Yield: 3.2 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.3 g, 0.92 mmol) and 2-isopropoxy-6-(tributylstannyl)pyridine (0.471 g, 1.1 mmol) in DMF (10 mL) was bubbled with N2 gas for 15 min. To the mixture was added CuI (0.140 g, 0.73 mmol) and Pd(PPh3)4 (0.100 g, 0.092 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The reaction mixture was cooled to RT, and quenched with water (100 mL) and extracted in EtOAc (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified with preparative HPLC (eluent: 30-70% MeCN in water with 0.01% TFA) to afford 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.01 g, 7%) as a white solid. MS (ESI, pos. ion) m/z: 336.2 (M+1); 1H-NMR (400 MHz, CD3OD): δ 9.36 (s, 1H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.64 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 5.65 (m, 1H), 1.51 (d, J=6.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[CH:15].C(N(CC)CC)C.I.C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]#[C:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#Cc1ccc(S(=O)(=O)Oc2ccc(C)cc2)cc1
Reactant: CCOC(=O)c1cc(I)ccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Oc3ccc(C)cc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-hydroxy-5-iodobenzoate (58.5 g, 0.2 mol), 4-methylphenyl 4-ethynylbenzenesulfonate (54.4 g, 0.2 mol) and triethylamine (40 g, 0.4 mol) were dissolved in tetrahydrofuran (100 g). The solution was heated to 50° C. and dichlorobis(triphenylphosphine)palladium (0.5 g, 0.72 mmol) and copper(I)iodide (1 g, 5.2 mmol) were) added simultaneously with stirring. The reaction mixture turned dark and triethylamine hydroiodide started to precipitate after about 10 min. After keeping at 45° C. for 45 min, the suspension was poured into dilute hydrochloric acid and the mixture was extracted with toluene. The toluene solution was evaporated to dryness. The residue was triturated with acetonitrile, filtered off and dried. Yield 73 g, (84%). The pooled material from several batches (270 g) was recrystallized from acetonitrile (1.2 l). Yield 250 g.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].[CH3:11][O:12][CH:13](OC)[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1.B(F)(F)F.CCOCC.ClC1C=CC(O)=CC=1C(OC)=C1C2CC3CC(CC1C3)C2>>[CH3:11][O:12][CH:13]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([O:23][CH3:24])[CH:15]=1)[P:1]([O:2][CH2:3][CH3:4])(=[O:5])[O:8][CH2:9][CH3:10]
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Reactant: CCOP(OCC)OCC
Agent: COC(=C1C2CC3CC(C2)CC1C3)c1cc(O)ccc1Cl
Agent: FB(F)F
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(OC)c1cc(OC)cc([N+](=O)[O-])c1
Yield: 86.8 %

Procedure:
Triethyl phosphite (0.98 ml, 5.7 mmol) was added dropwise to a solution of dimethyl acetal 27 (1.08 g, 4.7 mmol), boron trifluoride etherate (1.2 ml, 9.8 mmol) and CH2Cl2 (10) at 0° C. After warming the reaction to room temperature overnight, the solution was partitioned with 3N HCl and the aqueous layer was washed with CH2Cl2 twice. The organic layers were washed with dilute NaHCO3, dried over Na2SO4, decanted and evaporated. The crude residue was purified on a silica gel column, eluting with 0-80% EtOAc/hexanes, to give 1.36 g (86%) phosphonate 28 as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 6 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 137 mg (0.70 mmol) of 3-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH:25]([CH3:27])[CH3:26])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (7.0 ml), 4′-chloro-4-ethyl-2′-nitrobenzenesulfonanilide (1.00 g (2.93 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (0.70 ml (7.01 mmol)) was added dropwise and heated at 130° C. for 2 hours with stirring. After being allowed to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with 1% aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent to give 0.41 g (37%) of the title compound as pale red crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[N:24]1([CH2:29][CH2:30]O)[CH:28]=[CH:27][N:26]=[CH:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:30][CH2:29][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: OCCn1ccnc1
Product: Fc1cccc(-c2nn(CCn3ccnc3)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound IIs was synthesized from 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-imidazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:19])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1.[N-:20]=[N+]=[N-].[Na+]>CO>[CH3:6][O:7][C:8]1[C:9](=[O:19])[NH:20][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: COC1=CC(=O)C2=C(CCCC2)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c([nH]c1=O)CCCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (10 mL, Baker), there was added 2-methoxy-5,6,7,8-tetrahydronaphthalene-1,4-dione (600 mg, 3.12 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (406 mg, 6.24 mmol, Aldrich) was added in portions. The reaction was allowed to slowly attain rt with stirring under N2. Gas evolution was noted. After 16 h, the reaction was judged complete by TLC analysis (10% MeOH/90% CHCl3). The reaction was added to crushed ice (100 mL) to give a yellow/brown solution. This was extracted with 30% MeOH/70% CHCl3 (4×30 mL) and CHCl3 (2×30 mL). The extract was washed with water (1×20 mL), saturated NaHCO3 (1×20 mL) and brine (1×20 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (280 mg). An additional portion was obtained in exactly the same manner (350 mg). The combined solids were subjected to vacuum chromatography (silica gel, 2.5×25 cm, initial CHCl3 elution to remove mobile impurities, 2% EtOH/98% CHCl3 elution to remove product) to yield a pink solid. Crystallization from 95% EtOH (dissolved in 20 mL, hot filtered, concd to 8 mL, allowed to cool to rt) yielded a pink solid (242 mg, 19%, >95% pure by 1H NMR, mp 227.5°-228.5° C.). A sample was further purified by recrystallization from 95% EtOH (25 mg dissolved in 2 mL, allowed to cool to rt, yielded a pale pink solid, 14 mg, 56% recovery); mp 228.5°-229.5° C.; 1H NMR (DMSO-d6) δ1.55 (m, 4H), 2.28 (m, 2H), 2.43 (m, 2H), 3.72 (s, 3H), 6.23 (s, 1H), 10.57 (s, 1H); MS m/z 207 (M+, 85).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:1]1([CH2:7][O:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Cyclohexyl methanol (2.0 g, 17.5 mmol), ethyl 3-hydroxybenzoate (2.6 g, 15.8 mmol), tri-n-butyl phosphin (5.3 g, 26 mmol), and ADDP (6.6 g, 26 mmol) were dissolved in dry THF (100 ml) and stirred overnight at 20° C. under N2. Water (100 ml) is added, and the resulting solution is extracted with DCM (3×100 ml). The combined organic layers were washed with water (100 ml), dried (MgSO4) and evaporated. The crude mixture was purified by preparative HPLC to give 1.8 g of the title compound. LC-MS (m/z): 264 (M+2).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:32][CH2:33]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C4CC4)c3N3CCNCC(F)(F)C3)c(N)s2)c1
Yield: 53 %

Procedure:
Following the procedure for Example 105, tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2-fluoro-5-methylphenylboronic acid was reacted to give 144 as a beige foam (75 mg, 53% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.92 (dd, J=7.2, 2.2 Hz, 1H), 7.84-7.79 (m, 1H), 7.16-7.11 (m, 1H), 7.10-7.00 (m, 1H), 6.09 (s, 2H), 3.69 (t, J=13.3 Hz, 2H), 3.51-3.35 (m, 5H), 3.09 (t, J=5.5 Hz, 2H), 2.39 (s, 3H), 2.05-1.80 (m, 1H), 1.29-1.19 (m, 2H), 1.09-0.98 (m, 2H). LCMS (ES+) m/z 492 (M+1).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1[O:10][C:11](=O)[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:32][C:11](=[O:10])[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 19.5 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 11.1 parts L-leucine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude dipeptide is then subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonylglycyl-L-leucine benzyl ester.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([OH:44])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1.CC(C)=O.CCN(CC)CC>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([O:44][CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)N[C@H](C(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1)C(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (37.4 mg, 167 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 mol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (8.2 mg). MS m/z [M+H]+ calc'd for C28H31ClFN5O9, 636.18. found 636.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[H-].[Na+].Br[C:11]1[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=[C:15]([Cl:17])[CH:16]=1.CO>CN(C=O)C>[Cl:17][C:15]1[CH:16]=[C:11]([NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:12]2[N:13]([C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[F:30])=[O:22])=[CH:19][N:20]=2)[N:14]=1
Reactant: Cn1ccc(N)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1ccc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (37.2 mg, 0.383 mmol) in DMF (0.8 mL) was added 60% NaH (14.10 mg, 0.353 mmol). The mixture was stirred for 10 min. Solid 8A (50 mg, 0.153 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3 h. Methanol (5 mL) was added and a solid precipitated that was collected by filtration and dried to give 18A (26 mg, 37%) as an off white solid. [M+H]=387. HPLC Peak Rt=2.753 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CN1CCCC1=O.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][Cl:29])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1cnc2ncc(NC(=O)CCl)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Yield: 76.4 %

Procedure:
To a solution of 0.74 g (2.2 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 0.7 g (5.44 mmol) of disopropylethyl amine in a 7 ml of N-methylpyrrolidone was added with stirring at 0° C. a solution of 0.29 g (2.6 mmol) of chloroacetyl chloride in 5 ml of tetrahydrofuran over 5 min. After 1 hr at 0° C. the mixture was warmed to room temperature. The mixture was poured into saturated sodium bicarbonate. Solid was collected and air dried. The solid was purified by chromatography on silica gel eluting with ethyl acetate-methanol mixtures giving 0.7 g of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 416.1, 418.1.
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17](CCCCN3C(=O)C4C=CC=CC=4S3(=O)=O)[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1.Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]1[C:46](=[O:47])[C:45]2[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=2[S:43]1(=[O:53])=[O:52]>>[ClH:1].[Cl:1][C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][N:17]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]3[C:46](=[O:47])[C:45]4[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=4[S:43]3(=[O:53])=[O:52])[CH2:16][CH2:15]2)[C:7]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCN1CCN(c2cc(Br)cc3c2OCCO3)CC1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCCBr
Agent: Cl
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCCN1CCN(c2cc(Cl)cc3c2OCCO3)CC1

Procedure:
This compound was prepared analogous to the method described for 2-(4-(4-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)-butyl)-1,2-benzisothiazole-3(2H)-one-1,1-dioxide, dihydrochloride (Example 3) using intermediate 2a (2.00 g, 6.9 mmol) and 2(5-bromopentyl)-1,2-benzisothiazole-3(2H)-one-1,1-dioxide (2.52 g, 7.6 mmol). Yield 1.40 g, m.p. 193°-5° C.