Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]4[NH:32][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[N:25]=4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: Nc1ccccc1N
Product: c1ccc2[nH]c(C3(c4ccc(OCCCN5CCCC5)cc4)CCOCC3)nc2c1
Temperature: 130 °C
Yield: 0.7 %

Procedure:
A mixture of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (400 mg, 1.20 mmol), 1,2-diaminobenzene (129 mg, 1.20 mmol) and polyphosphoric acid (2 g) was heated at 130° C. for 2 days. The cooled reaction mixture was partitioned between dichloromethane (20 ml) and aqueous ammonia (20 ml). The aqueous layer was further extracted with dichloromethane (2×50 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC on Fraction-Lynx® eluting with water:acetonitrile:TFA (95:5:0.1) to provide the title compound (3.5 mg, 1%). 1H NMR (400 MHz, CDCl3) δ 1.92-1.96 (m, 2H), 2.06-2.21 (m, 4H), 2.40-2.46 (m, 2H), 2.96-3.00 (m, 4H), 3.05-3.09 (m, 2H), 3.16-3.20 (m, 2H), 3.57-3.65 (m, 4H), 3.93 (d, 2H), 5.45 (d, 2H), 7.06 (d, 2H), 7.45 (d, 2H), 7.71-7.74 (m, 2H). LCMS ESI+ m/z 406 [MH]+.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].O.[NH2:30][NH2:31]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:31][NH:30][C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Solvent: O
Product: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 57 using 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 90.1) and hydrazine hydrate. The crude material was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2) and triturated in Et2O. tR: 0.75 min (LC-MS 2); ESI-MS: 393 [M+H]+ (LC-MS 2); Rf=0.23 (7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H) 2.46 (s, 3H) 2.64 (s, 3H) 6.48 (s, 1H) 7.19-7.46 (m, 5H) 8.47 (s, 1H) 13.49 (br. s., 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][CH:13]2[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]2)[CH:7]=1
Reactant: N#CC1CC(N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Yield: 67.3 %

Procedure:
2,4-Difluoro-1-nitrobenzene (0.38 g, 2.4 mmol), 3-aminocyclobutanecarbonitrile (0.23 g, 2.4 mmol) and then DIPEA (0.425 mL, 2.4 mmol) were added to acetonitrile (10 mL) and the resultant mixture stirred at 20° C. for 16 hours under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (Si—PPC; eluting with ethyl acetate in cyclohexane 0-50%) to give the title compound as a yellow solid (0.38 g, 68%). 1H NMR (CDCl3) δ: 8.23 (1H, dd, J=9.2, 5.8 Hz), 8.20 (1H, br s), 6.41-6.49 (1H, m), 6.29 (1H, dd, J=11.0, 2.7 Hz), 4.30-4.43 (1H, m), 3.20-3.31 (1H, m), 2.87-2.98 (2H, m), 2.42-2.55 (2H, m)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N1CCOCC1
Yield: 76 %

Procedure:
To a stirred solution of the above (2-morpholin-4-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.44 g, 1.8 mmol) in 1,4-dioxane (4.0 mL), HCl (4.0 mL of a 4 M solution in 1,4-dioxane) was added at room temperature. After one h, the precipitated product was collected via filtration and washed with EtOAc. The solid was dried under high vacuum to give 0.23 g (76%) of 2-amino-1-morpholin-4-yl-ethanone hydrochloride which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH2:22]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:34]3[CH:33]=[N:32][C:31]([O:30][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][CH:35]=3)=[CH:7][N:6]=2)=[CH:9][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cnc(-c2ccc(OCc3ccccc3)cc2)cn1
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)cc3)cn2)cn1

Procedure:
In accordance with scheme D, 14 g (47.2 mmol ) of 2-chloro-5-(4-benzyloxyphenyl)pyrazine are reacted analogously to Example 4a with 11.8 g (47.2 mmol) of 2-octyloxypyridine-5-boronic acid to give 2-(4-benzyloxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrazine.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[NH:36]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:36]([C:29]4[C:28]5[C:33](=[CH:34][CH:35]=[C:26]([F:25])[CH:27]=5)[N:32]=[CH:31][CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]2)=[CH:3]1>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCc2coc3ccccc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCN(CCc2coc3ccccc23)CC1
Reaction time: 3 h

Procedure:
235 ml of a 2.9N ethanolic hydrogen chloride solution are added to a solution of 21 g of the product obtained in Step A in 786 ml of ethanol. After 3 hours at 70° C. and then 16 hours at room temperature, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 150 ml of water. The expected product is precipitated by the addition of 20% sodium hydroxide solution.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C([N:10]([CH2:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=O)C.Cl.[OH-].[Na+]>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[NH:10][CH2:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1
Reactant: COc1cccc(N(CC2CNCCO2)C(C)=O)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: COc1cccc(NCC2CNCCO2)c1
Temperature: 0 °C

Procedure:
A mixture of 2-(N-acetyl-3-methoxyanilino)methylmorpholine oxalate (2 g.) and concentrated hydrochloric acid (25 ml.) is heated under reflux for 24 hours. The solution is cooled, diluted with ice (25 g.) basified with sodium hydroxide solution and then extracted with ether (2 × 100 ml.). The ethereal extract is dried over anhydrous sodium sulphate, filtered and concentrated to about 25 ml. On addition of an ethereal solution of oxalic acid there is obtained 2-(3-methoxyanilino)methylmorpholine oxalate, m.p. 156°-157°C. The corresponding maleate at 145°-147°C. (decomposition).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:49]=[C:48]([NH:50][NH2:51])[CH:47]=[CH:46][N:45]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:10]2[N:50]([C:48]3[CH:47]=[CH:46][N:45]=[C:44]([Cl:43])[CH:49]=3)[N:51]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Br)c1
Reactant: NNc1ccnc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
600 mg (1.30 mmol) of the compound of Example 2A is reacted analogously to the synthesis of the compound of Example 20A with 257 mg (1.43 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 175 mg (34% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:9]([N:11]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: CCNCC
Reactant: Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(C)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
20 mmol of p-chlorotoluene (2.53 g), 24 mmol of diethylamine (1.75 g), 28 mmol of KOtBu (3.13 g) and 44 mg of trans-di-μ-acetatobis[2-[bis(1,1-dimethylethyl)-phosphino]-2-methylpropyl-C,P]dipalladium(II) (0.3 mol %) are suspended in 50 ml of toluene and refluxed for 24 hours. After cooling to room temperature, the salts are filtered off and washed with petroleum ether. The solvents are removed from the filtrate on a rotary evaporator. Distillation via a bulb tube (100° C./12 torr) gives 4-(N,N-diethylamino)toluene as a colorless liquid in a yield of 87%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:11]1([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)=[CH:21][CH:22]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.5 %

Procedure:
Following procedure A, 4-fluoronitrobenzene (325 mg, 2.30 mmol, 1.00 eq) and 4-cyclohexylphenol (519 mg, 2.94 mmol, 1.28 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (513 mg, 3.72 mmol, 1.61 eq) was added and the reaction mixture was stirred at room temperature for 48 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100 to 1:50) to afford the title compound as pale yellow solid (640 mg, 2.15 mmol, 93% yield). Rf=0.55 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C18H20NO3+ [M+H]+ 298.1438. found: 298.1442. 1H NMR (400 MHz, CDCl3) δ 8.31-8.11 (m, 2H, aromatic H), 7.26 (d, J=2.3 Hz, 2H, aromatic H), 7.13-6.92 (m, 4H, aromatic H), 2.57-2.50 (m, 1H, cyclohexyl H), 2.09-1.67 (m, 5H, cyclohexyl H), 1.59-1.18 (m, 5H, cyclohexyl H). 13C NMR (101 MHz, CDCl3) δ 163.89, 152.61, 145.58, 142.57, 128.66, 126.04, 120.49, 116.99, 44.14, 34.72, 26.99, 26.23.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:21])[N:13]([CH2:15][CH:16](OC)[O:17]C)[CH3:14])=[N:8][N:7]=1)([CH3:5])[CH3:4].Cl>O>[CH3:1][O:2][C:3]([C:6]1[S:10][C:9]([N:11]2[CH:16]([OH:17])[CH2:15][N:13]([CH3:14])[C:12]2=[O:21])=[N:8][N:7]=1)([CH3:5])[CH3:4]
Reactant: COC(CN(C)C(=O)Nc1nnc(C(C)(C)OC)s1)OC
Agent: Cl
Solvent: O
Product: COC(C)(C)c1nnc(N2C(=O)N(C)CC2O)s1
Yield: 71.6 %

Procedure:
To the 4.9 grams of the 3-[5-[1-methoxy-1-methylethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-(2,2-dimethoxyethyl)urea (prepared above) was added 150 milliliters of water and 1.5 milliliters of concentrated hydrochloric acid (HCl). The resulting solution was refluxed for 5 minutes, and the aqueous phase was extracted twice with 50 milliliters of chloroform (CHCl3). The 100 milliliter chloroform extract was dried over anhydrous MgSO4, filtered and topped on a roto-vac at 70° C. to yield 3.0 grams of a yellow oil of 3-[5-(1-methoxy-1-methylethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-4-hydroxy-2-imidazolidinone with an
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH2:10][C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:12])#[N:9].[S:23]1CC(O)S[CH2:25][CH:24]1O.O>CN(C)C=O.C(O)(=O)C.C(OCC)(=O)C>[NH2:9][C:8]1[S:23][CH:24]=[CH:25][C:10]=1[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Reactant: OC1CSC(O)CS1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C(=O)c2ccsc2N)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 118.7 %

Procedure:
Triethylamine (1.331 mL, 9.55 mmol) was added with stirring to a solution of methyl 4-(2-cyanoacetyl)benzoate (4.85 g, 23.87 mmol) and 1,4-dithiane-2,5-diol (1.817 g, 11.93 mmol) in dimethylformamide (10 mL), to give a yellow solution. After 15 min, the solution was heated to 60° C. for 2 hours and stirred at room temperature overnight. Water (50 mL), ethyl acetate (50 mL), and glacial acetic acid (ca. 1-3 mL) were added to the oily residue until the organic layer became clear. After separation of the organic layer and further extraction of the aqueous layer with ethyl acetate (50 mL), the combined organic layers were washed subsequently with 5% aqueous NaHCO3 and H2O, dried over anhydrous MgSO4. The solvent was removed and the residue was purified via ISCO (0-50% EtOAc/Hexanes; 80 g silica gel column) to afford title compound 491 (3.7 g, 59%) as a yellow solid. MS (m/z): 357.4 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:24]1([S:30]([NH:12][NH:11][C:9](=[O:10])[C:8]2[CH:13]=[CH:14][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)NN)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-tert-Butyl-benzoic acid hydrazide (0.5 g, 2.60 mmol) was dissolved in THF (29 mL). N,N-diisopropylethylamine (1.81 mL, 10.4 mmol) was added, and the reaction was cooled to 0° C. Phenylsulfonyl chloride (0.36 mL, 2.86 mmol) was added followed by DMAP (5 mg, 0.04 mmol). The reaction was allowed to warm to room temperature, and the reactants all dissolved. The solution went from a yellow color to a deep red over the course of 4 hours. The reaction was then concentrated down and purified by flash chromatography eluting with 3:1 hexanes/EtOAc. The desired product was isolated (0.32 g, 37.1%). MS: 333.1 (M+1 for C17H20N2O3S); mp 197-199° C.; TLC: SiO2 Rf=0.56 (1:1 hexane/EtOAc). Analysis C17H20N2O3S: (calc) C, 61.42; H, 6.06; N, 8.43. (found) C, 61.38; H, 6.09; N, 8.27. IR (KBr, cm−1) 3213, 2965, 1648, 1403, 1349, 1179. 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 7.39-7.55 (m, 8H), 7.92-7.93 (m, 2H), 8.06 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 33.1 %

Procedure:
Methyl 2-{[2-(4-fluorophenyl)ethyl]thio}-3-[4-(2-{4-[(methylsulfonyl)oxy]-phenoxy}ethyl)phenyl]propanoate (77 mg, 0.14 mmol) was dissolved in 2.5 ml of a 4:1 mixture of THF and water and cooled on an ice-bath. Lithium hydroxide (6.9 mg, 0.29 mmol) was added. Water was added after 2 days of stirring at room temperature. The THF was evaporated under reduced pressure. The aqueous phase was acidified with 1M HCl and extracted with EtOAc three times. The organic phases were pooled, washed (water, brine), dried (MgSO4) and evaporated. The crude product was purified using preparative HPLC (eluent: CH3CN/5% CH3CN-waterphase containing 0.1M NH4Oac). 24 mg of the desired product (yield 30%) was obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.C([N:33]1[CH2:40][CH:39]([NH2:41])[C:35]2([CH2:38][O:37][CH2:36]2)[CH2:34]1)C1C=CC=CC=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:41][CH:39]3[C:35]4([CH2:38][O:37][CH2:36]4)[CH2:34][NH:33][CH2:40]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CN(Cc2ccccc2)CC12COC2
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CNCC34COC4)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 6-benzyl-2-oxa-6-azaspiro[3.4]oct-8-ylamine. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.11-8.08 (m, 2 H), 7.90-7.88 (d, J=7.2, 1 H), 7.75-7.70 (m, 2 H), 7.65-7.59 (m, 2 H), 6.36 (s, 1 H), 5.38-5.36 (d, J=8.8, 2 H), 5.20-5.10 (m, 1 H), 4.80-4.79 (m, 2 H), 4.74-4.72 (m, 2 H), 4.56-4.54 (d, J=7.2, 2 H), 3.90-3.87 (m, 1 H), 3.81-3.75 (m, 4 H), 3.60-3.50 (m, 1 H), 2.48 (s, 3 H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:23])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>C1COCC1>[CH2:3]([O:10][CH2:11][C:12]([CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:23])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(COCc1ccccc1)(COCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(COCc1ccccc1)(COCc1ccccc1)C(=O)O
Yield: 34.7 %

Procedure:
1 N Aqueous sodium hydroxide (2.6 mL) was added to a solution of benzyl 3-benzyloxy-2-benzyloxymethyl-2-methylpropionate obtained in Step A (350 mg, 0.87 mmol) in THF (2.6 mL), and the mixture was stirred under reflux for three hours. Water and ethyl acetate were added to the mixture to separate the aqueous layer. 1 N hydrochloric acid was added to the aqueous layer to make the aqueous layer acidic, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. From the resulting residue, crude 3-benzyloxy-2-benzyloxymethyl-2-methylpropionic acid (95 mg) was obtained as a colorless oil without purification. Condensation was carried out by a method similar to that of Example 3-1 using 3-benzyloxy-2-benzyloxymethyl-2-methylpropionic acid obtained above instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14, and deprotection was carried out by a method similar to that of Example 1-36 using a 10% Pd—C catalyst in a hydrogen atmosphere to synthesize the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[CH:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=2)O1>>[C:46]([C:43]1[N:44]=[CH:45][C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]2)=[CH:41][CH:42]=1)#[N:47]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(C#N)nc3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (47 mg, 0.093 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (26 mg, 0.200 mmol) to afford the crude product (47 mg) as a yellow solid: ESI MS m/z 514 [C30H35N5O3+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:17])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Solvent: O=CO
Product: CCOC(=O)C(=NO)c1csc(NC=O)n1
Yield: 76.7 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (126.4 g), formic acid (81.3 g) and acetic anhydride (180 g) were treated in a similar manner to that of Preparation 12 to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (109.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[CH2:9][C:10]3[C:11](=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)ccc1CNc1cccc(Br)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=O)N(c1cccc(Br)c1C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Step 3 A solution of methyl 2-((3-bromo-2-methylphenylamino)methyl)-5-methoxybenzoate (360 mg, 0.988 mmol) in THF (10 mL) was treated with sodium tert-butoxide (142 mg, 1.483 mmol) and stirred at rt overnight. The mixture was treated with water and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide 2-(3-bromo-2-methylphenyl)-6-methoxyisoindolin-1-one as a white solid (246 mg, 75%). 1H NMR (400 MHz, chloroform-d) δ 7.62 (1 H, dd, J=7.9, 1.1 Hz), 7.46 (1 H, d, J=2.4 Hz), 7.42 (1 H, d, J=8.4 Hz), 7.15-7.26 (3 H, m), 4.67 (2 H, s), 3.92 (3 H, s), 2.34 (3 H, s). Mass spectrum m/z 332, 334 (M+H)+.