Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[O:19]1[CH2:23][CH2:22]NC1=O>O1CCCC1>[O:19]=[C:23]([N:9]1[C@@H:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:22][CH2:17][CH:16]1[CH:5]2[CH2:6][CH:1]3[CH2:2][CH:3]([CH2:14][CH:15]1[CH2:7]3)[CH2:4]2
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C1NCCO1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCC1C2CC3CC(C2)CC1C3)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (-78° C.) solution of tricyclo[3.3.1.1-3,7]decane-2-propanoic acid (9.63 mmol, 2.006 g) in tetrahydrofuran (25 mL) was added triethylamine (11.5 mmol, 1.170 g, 1.61 mL), and the resulting mixture stirred for 10 min. Dropwise addition of pivaloyl chloride (9.63 mmol, 1.161 g, 1.19 mL) to the carboxylate provided a thick suspension, which was stirred at low temperature (-78° C.) for 15 min and then warmed to 0° C. (30 min). In a separate flask, while the mixed anhydride was forming, was introduced a solution of (S)-4-(phenylmethyl)-2-oxazolidinone (9.44 mmol, 1.673 g) in tetrahydrofuran (25 mL). This mixture was cooled to -78° C. and n-butyl lithium (1.6M in hexanes, 9.44 mmol, 5.90 mL) was added over the course of 10 min. The oxazolidinone anion was allowed to form for 30 min at low temperature (-78° C.). The mixed anhydride was recooled to -78° C. (15 min) and the anion added dropwise via cannulae. The flask containing the anion was rinsed with tetrahydrofuran (5 mL) and the washings transferred via a cannulae to the reaction mixture. The reaction mixture was stirred at low temperature (-78° C.) for 15 min, warmed to 0° C. over the course of 45 min, and quenched by the addition of saturated aqueous ammonium chloride (20 mL). The heterogeneous mixture was concentrated in vacuo and partitioned with CH2Cl2 (100 mL) and water (25 mL). The aqueous phase was extracted with CH2Cl2 (3×100 mL), and the combined organic layers dried (Na2SO4) then concentrated in vacuo. This pale yellow oil was purified by flash chromatography, eluting with hexanes/EtOAc (6:1), to provide (S)-3-[1-oxo-3-(tricyclo[3.3.1.1-3,7]dec-2-yl)propyl]-4-(phenylmethyl)-2-oxazolidinone as a colorless glass that crystallized upon standing overnight at room temperature (93%, 3.234 g). mp 82°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[CH3:27][C@H:28]1[O:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:30]3[CH2:29][C@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Temperature: 50 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of 6-bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (1.7 g, 3.75 mmol) in dichloromethane (50 ml) was added (2R,6S)-2,6-dimethylmorpholine (0.863 g, 7.49 mmol) and the mixture stirred at 50° C. for 18 hr. The crude product was purified by silica (100 g) cartridge on Flashmaster II using a gradient of dichloromethane and methanol to give the title compound as a pale yellow solid (1.79 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[C:18]([CH:23]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(N)sc2cc(C)ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Yield: 71.2 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methylbenzo[b]thiophene-3-carboxylate (4.5 g), 2,4-difluoronitrobenzene (3.1 g) and dimethyl sulfoxide, ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (5.1 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9](=[O:15])[N:8]([OH:16])[C:7]1=[O:17].[NH:21]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:22]([CH3:24])=[O:23]>>[OH:16][N:8]1[C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][C:11]=2[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:21][C:22](=[O:23])[CH3:24])[CH:30]=3)[CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:17]
Reactant: O=c1c2sccc2n(Cc2cccc(Br)c2)c(=O)n1O
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cccc(Cn3c(=O)n(O)c(=O)c4sccc43)c2)c1

Procedure:
The title compound was prepared from 1-(3-Bromo-benzyl)-3-hydroxy-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) and 3-acetamino-phenyl boronic acid via general procedure C. The crude product was purified by mass-triggered preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)=[CH:4][C:3]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](O)=[O:48])=[CH:43][CH:42]=2)[S:35]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[C:11]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]([OH:19])=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:14]=4)=[CH:4][C:3]=3[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:48])=[CH:50][CH:51]=2)[S:35]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 82.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.55 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.42 g), diethyl cyanophosphonate (0.24 g), triethylamine (0.15 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.72 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:15]2[C:16]([O:22]C)=[N:17][CH:18]=[CH:19][C:20]=2I)[N:6](O)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35]>C(O)(=O)C.Cl.CN(C)C=O>[Cl:42][C:38]1[CH:37]=[C:36]([CH:34]([OH:35])[CH2:33][NH:32][C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:22])[C:15]=2[C:5]2[NH:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
4-Ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.379 g, 0.90 mmol) was dissolved in acetic acid/hydrochloric acid (2 ml/2 mL) and the resulting mixture was stirred at 95° C. for 1 hour. The solvent was evaporated and the crude residue (HPLC 95% (220 nm), LCMS (+ESI, M+H+) m/z 408) was dissolved in methanol (6 mL) and treated with titanium (III) chloride (9.25 wt % in 27.4 wt % hydrochloric acid, ˜1 mL). The reaction was heated at 65° C. for ˜2.5 hours, then water was added and the solvent was evaporated to give a residue (HPLC 83% (220 nm), LCMS (+ESI, M+H+) m/z 392) which was dissolved in N,N-dimethylformamide (6 mL). The resulting solution was treated with triethylamine (0.38 mL, 2.7 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.281 g, 1.35 mmol) and this was heated at 65° C. for 4 hours. The solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.132 g, 34%) as a beige solid. HPLC 97.5% (220 nm), LCMS (+ESI, M+H+) m/z 435; IR ν (cm−1): 3261, 2965, 1642; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.36 (3H, t, J=7.5 Hz), 2.97 (2H, qa, J=7.5 Hz), 3.64 (1H, dd, J=13.5 and 6.9 Hz), 3.70 (1H, dd, J=13.7 and 5.0 Hz), 4.97 (1H, br t), 6.25 (1H, d, J=7.5 Hz), 7.21-7.33 (4H, m), 7.35-7.47 (4H, m), 7.52 (1H, s), 7.69 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[C:6](Cl)=[N:5][S:4][N:3]=1.O.O.O.O.O.O.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[OH-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[ClH:1].[Cl:1][C:2]1[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:5][S:4][N:3]=1
Reactant: Clc1nsnc1Cl
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: Clc1nsnc1N1CCNCC1
Temperature: 70 °C
Yield: 89 %

Procedure:
A mixture of 3,4-dichloro-1,2,5-thiadiazole (4.00 g, 25.8 mmol) and piperazine hexahydrate (25.0 g, 130 mmol) in DMF (25 mL) was heated at 70° C. for 20 minutes. After cooling to ambient temperature, the reaction mixture was basified (11M NaOH) and brine was added. The resulting mixture was extracted with CHCl3 (×3). The combined organic phases were washed twice with brine/water (1:1), dried (MgSO4) and the solvent was evaporated. The resulting oil was purified by column chromatography on silica gel using CHCl3 as eluent to give 2.77 g (52%) of the title compound as a colourless oil which was converted to its hydrochloride salt: mp 231° C. (dec). Anal. (C6H9CIN4S.HCl), calc 29.89, found 30.4. H, N.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:33])[N:6]([CH2:10][C@H:11]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH:7]=[CH:8][CH:9]=1)(=S)[NH2:2].[C:34]([O:38]C)(=O)[NH:35][NH2:36]>>[ClH:24].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:17]2[O:16][CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:10][N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]3[NH:2][C:34](=[O:38])[NH:35][N:36]=3)[C:5]2=[O:33])=[CH:19][C:20]=1[F:25]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C(N)=S)c2=O)C1
Reactant: COC(=O)NN
Product: Cl
Product: O=c1[nH]nc(-c2cccn(C[C@@H]3CNCCO[C@H]3c3ccc(Cl)c(F)c3)c2=O)[nH]1

Procedure:
Using tert-butyl (6R,7R)-6-[(3-carbamothioyl-2-oxopyridin-1(2H)-yl)methyl]-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and methyl carbazate, and in the same manner as in Example 200, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22])#[N:17]>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:16]#[N:17])=[C:19]([CH2:20][CH2:21][CH3:22])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: O=Cc1ccccc1Cl
Reactant: CCCC(=O)CC#N
Reactant: Nc1cc[nH]n1
Solvent: CC#N
Product: CCCC1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
To a solution of acetonitrile (4.8 g) in THF (150 mL) was added n-BuLi (67 mmol) at −78° C. Further, methyl butanoate (10 g) was added and the mixture was stirred for one hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyanopentan-2-one (5.5 g) as a colorless oil. A solution of 2-chlorobenzaldehyde (1.9 g), 3-aminopyrazole (1.0 g) and 1-cyanopentan-2-one (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (1.3 g) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([C:9](=[O:25])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[OH:11])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-Benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:25])=[CH:9][C:8]=1F.CO>C(Cl)(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N:15]1[CH2:16][CH2:17][N:13]([C:10]2[CH:9]=[C:8]3[C:7]([C:6](=[O:5])[NH:2][NH:3]3)=[CH:12][CH:11]=2)[C:14]1=[O:25]
Reactant: NN
Reactant: COC(=O)c1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccncc1N1CCN(c2ccc3c(=O)[nH][nH]c3c2)C1=O
Temperature: 120 °C
Yield: 41.2 %

Procedure:
Hydrazine hydrate (10 mL) was added to 2-fluoro-4-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (I-135a: 350 mg, 1.06 mmol) and the resulting mixture was heated to 120° C. for 18 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ice water and ethylacetate. The aqueous layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (10% MeOH in CHCl3), followed by preparative HPLC afforded 135 mg of the product (41.2% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH:19]12[O:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][N:17]([C:4]1[N:3]=[C:2]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:7]=[C:6]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:9]=[CH:10][C:5]=13)[CH2:18]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(-c3ccccc3)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)cc1

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 mmol) are dissolved in a microwave vial in DME (18 mL). Na2CO3 (2.5 mL, 2M in water) is added along with a catalytic amount of tetrakis triphenylphosphine palladium. The mixture is heated in a sealed tube under microwave irradiation at 185 C for 40 min. The mixture is diluted with 50 mL EtOAc and washed with a saturated solution of NaHCO3 (2×50 mL). The aqueous layers are extracted with EtOAc (50 mL) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. Purification gives the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[S:31])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[BrH:1].[C:16]1([CH2:15][O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]3[S:31][CH:2]=[C:3]([C:5]4[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=4[CH3:10])[N:32]=3)=[CH:25][CH:24]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=S)Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(OCc4ccccc4)cc3)n2)c(C)s1
Yield: 78.1 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (336.3 mg, 1.08 mmol) was allowed to react with 4-benzyloxyphenyl thiourea (279 mg) as described in Example 154, step (a) to give 450 mg (76% yield) of methyl 4-(2-{[4-phenylmethoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C23H20N2O3S3, 468.61 (M+H), found 469.2.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17](=[O:31])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[CH3:32])(C)(C)C.[OH-].[Li+]>O.CO.O1CCCC1>[C:25]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([O:16][CH2:15][C:11]2[C:10]([CH3:32])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:33])=[O:5])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(COC(=O)N(c2ccccc2)c2ccccc2)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[(Diphenylcarbamoyloxy)methyl]-2-methylphenoxy}acetic acid tert-butyl ester (104.1 g, 233 mmol) and lithium hydroxide (10.3 g, 245 mmol) were dissolved in a mixture of water (100 mL), methanol (300 mL), and tetrahydrofuran (300 mL). The mixture became solid, but reliquefied upon heating at reflux temperature. The clear solution was stirred at room temperature for about 16 hours, and evaporated in vacuo. The residue was poured into dilute hydrochloric acid and extracted with dichloromethane. Evaporation of the solvent and recrystallization of the residue from hexane/acetone gave {3-[(diphenylcarbamoyloxy)methyl]-2-methylphenoxy}acetic acid as off-white granules (87.0 g, 95%); m.p. 180.1-180.7° C. Analysis for C23H21NO5: Calcd.: C, 70.58; H, 5.41; N, 3.58. Found: C, 70.51; H, 5.37; N, 3.76.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:3]1=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46](O)=[O:47])[CH:41]=[C:42]([Cl:44])[CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[O:9]=[C:8]1[N:7]([CH:10]([CH3:11])[CH3:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]([CH2:17][C:18]([F:19])([F:21])[F:20])[C:3](=[O:22])[CH:2]1[NH:1][C:46](=[O:47])[CH2:45][C:40]1[CH:39]=[C:38]([Cl:37])[CH:43]=[C:42]([Cl:44])[CH:41]=1
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)N1C(=O)C(N)C(=O)N(CC(F)(F)F)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)N1C(=O)C(NC(=O)Cc2cc(Cl)cc(Cl)c2)C(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a stirring solution of 3-amino-1-(2-propyl)-5-(2,2,2-trifluoroethyl)-1,5-benzodiazepine-2,4-dione (180 mg, 0.57 mmol) in N,N-dimethylformamide (2 mL) was added EDC (131 mg, 0.69 mmol), HOBT (46 mg, 0.34 mmol) and 3,5-dichlorophenylacetic acid (140 mg, 0.69 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate (50 mL), then washed with 10% aqueous potassium hydrogen sulfate (25 mL) then saturated aqueous sodium hydrogen carbonate (25 mL) and finally, brine (25 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 25-40% ethyl acetate:hexane to give 100 mg of product which was crystallized from ethyl acetate/hexane to give colorless crystals (70 mg). m.p.=185°-186° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.N>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:5][CH:4]=2)[CH:17]=[CH:18]1
Reactant: Nc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc(-c3ccc(=O)[nH]n3)cc2)cc1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-3(2H) -pyridazinone hydrochloride (1.5 g), 4H-pyran-4-one (0.71 g), and water (20 ml), was heated under reflux for 2 hours. The pH of the hot solution was adjusted to 8 with aqueous ammonia and the mixture was cooled to give the crude product, 1.84 g, m.p. 338-340° C. Recrystallisation from aqueous ethanol gave the title compound, 1,4 g, m.p. 339-341° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C1C(=O)N([Br:47])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:47])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 1-(4-benzyloxy-3-methyl-phenyl)-ethanone (12.89 g; 53.1 mmol) in CH2Cl2 was added, dropwise, at 0° C., DIPEA (10.9 mL; 63.7 mmol) and trimethylsilyl trifluoromethanesulfonate (11.1 mL; 61.1 mmol). The resulting mixture was stirred at 0° C. for 1 hour, and subsequently, NBS (10.87 g; 61.1 mmol) was added in one portion. The mixture was allowed to warm to RT stirred overnight. Then the mixture was concentrated in vacuo, the residue dissolved in EtOAc, washed with water twice, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 1-(4-benzyloxy-3-methyl-phenyl)-2-bromo-ethanone (11.90 g).
Reaction SMILES: CS(O[CH2:6][C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)([CH2:10]3)[CH2:8]2)(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C=O)C.O>[CH3:21][C:16]1([C:9]23[CH2:10][CH:11]4[CH2:15][C:7]([CH2:6][N:28]5[CH:32]=[N:31][CH:30]=[N:29]5)([CH2:14][CH:13]2[CH2:12]4)[CH2:8]3)[O:17][CH2:18][CH2:19][O:20]1
Reactant: CC1(C23CC4CC2CC(COS(C)(=O)=O)(C4)C3)OCCO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C23CC4CC2CC(Cn2cncn2)(C4)C3)OCCO1
Temperature: 110 °C
Yield: 83.9 %

Procedure:
A stirred mixture of [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl methanesulfonate (2.4 g, 7.5 mmol) [as obtained from preparation 2], K2CO3 (4.5 g, 34.2 mmol), and 1,2,4-triazole (1.5 g, 22.5 mmol) in DMF (30 mL) was heated to 110° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethylacetate. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl}-1H-1,2,4-triazole (1.82 g) as a viscous liquid in 85% yield. m/z (M+1) 290; IR cm−1 2932, 1668, 1506, 1441, 1373, 1311, 1211, 1140, 1047, 876, 753. 1H NMR (CDCl3) 300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 4.03-3.92 (m, 4H), 2.42-2.32 (m, 2H), 1.86-1.79 (m, 1H), 1.74-1.65 (m, 2H), 1.52-1.37 (m, 8H), 1.26 (s, 3H).