Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1.Cl.[NH2:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[S:10]1[C:14]2[CH:15]=[C:16]([C:19]3([C:22]4[N:26]5[N:27]=[C:28]([C:31]6[CH:39]=[CH:38][C:34]([C:35]([NH:41][C@@H:42]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[O:37])=[CH:33][CH:32]=6)[CH:29]=[N:30][C:25]5=[N:24][N:23]=4)[CH2:21][CH2:20]3)[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (42 μL, 0.24 mmol) was added to a mixture of 4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl}benzoic acid (33 mg, 0.080 mmol), tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (23 mg, 0.10 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (42 mg, 0.096 mmol) in DMF (1 mL). The mixture was stirred at RT overnight, and quenched with saturated sodium bicarbonate (5 mL). The reaction mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column with ethyl acetate in hexanes (40%) to afford the desired product. Analytical LCMS: (M+H)+=584.2
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:15]([C:13]1[CH:12]=[CH:11][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH:14]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccn(S(=O)(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
A mixture of 41.4 g of 1-(phenylsulfonyl-1H-pyrrole, prepared as described above, and 17.16 g of acetyl chloride in 200 ml of dichloroethane was added to a suspension of 32 g of aluminum chloride in 200 ml of dichloroethane. The reaction was stirred for one hour, poured onto a mixture of ice and concentrated hydrochloric acid and extracted several times with ether. The extracts were combined and evaporated. The residue was triturated with ether and the solid collected, giving 39 g of 3-acetyl-1-(phenylsulfonyl)-1H-pyrrole.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.S[C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:3][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncn2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Phosphorous oxychloride (4.60 g, 30 mmol) was added to dimethylformamide (32 ml) and stirred 20 min at 0° C. 2-Mercapto-3-methyl-6-pyrimidin-4-yl-pyrimidin-4-one (4.40 g, 20 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 1 hour. The reaction mixture was poured into ice water, neutralized by solid K2CO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (1.20 g, 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:32]([OH:35])(=[S:34])[CH3:33].[Na].C(O)(=S)C.[H-].[Na+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][S:34][C:32](=[O:35])[CH3:33])[CH2:16][CH2:17]2)=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: CC(O)=S
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of N-p-nitrobenzyloxycarbonyl-4-p-toluenesulfonyloxymethylpiperidine (3.72 g) in dry dimethylformamide (10 ml) was added to a solution of sodium thioacetic acid (1 g) prepared from thioacetic acid and sodium hydride in dry dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give a residue which was then purified by silica gel column chromatography to give N-p-nitrobenzyloxycarbonyl-4-acetylthiomethylpiperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:20][C:19]=1[F:27]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (4.00 g, 13.3 mmol; CAN 1211586-75-2) was dissolved in toluene (90 mL) and DMF (2.0 mL) to give a colorless solution. Then B-(4-chloro-3-fluorophenyl)-boronic acid (2.56 g, 14.7 mmol; CAN 137504-86-0), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (544 mg, 667 μmol) and aqueous sodium carbonate solution (53.3 ml, 107 mmol, 2 M) were successively added under stirring in an argon atmosphere. The reaction mixture was stirred 2.5 h at 90° C. Subsequently the reaction mixture was cooled to ambient temperature, poured into ice-water (300 mL), acidified with 2 N HCl (120 mL) and extracted with isopropyl acetate (3×200 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was digested with a mixture of n-heptane and isopropyl acetate (10 mL/2 mL) at ambient temperature, filtered off and washed with isopropyl acetate/n-heptane 1:5 (2×3 ml). The resulting brown solid was digested with dichloromethane (10 mL) at ambient temperature to give the title compound (2.57 g, 55%) after filtration and drying as off-white solid; MS (EI) 347.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:46]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:43])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]4([C:40]([NH2:46])=[O:41])[CH2:37][CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(=O)O)CCC3)CC2)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C(N)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-{[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]methyl}cyclobutanecarboxylic acid (0.4 g), 1-hydroxybenzotriazole ammonium salt (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 93%).
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH2:9][C:4]2=[N:3][N:2]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C=O)C.C(OCC)(=O)C>[C:35]1([NH:34][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][N:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1=CC=C2N=NN=C2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzotriazole-5-carboxylic acid (856 mg), HOAt (715 mg) and EDAC (1.00 g) were dissolved in DMF (17.5 mL) and the mixture was stirred at room temperature 1 hour. A 0.5 mL aliquot of this mixture was added to aniline (13.7 μL, 0.15 mmol) and the resulting mixture was vigorously shaken at room temperature for 16 hours. 1N hydrochloric acid (2 mL) and ethyl acetate (1 mL) were added and the mixture was vigorously shaken at room temperature for 2 hours. The organic phase was isolated and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(S(=O)(=O)c2cnc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of 4-[2-methyl-4-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-sulfonyl]-phenol (46 mg, 0.12 mmol), prepared as described in Example 2, acetic anhydride (0.023 mL, 0.24 mmol), triethylamine (0.05 mL, 0.36 mmol) and CH2Cl2 (4 mL) was stirred at room temperature under N2 for 4 h. The reaction mixture was treated with saturated sodium bicarbonate, and extracted (3×) with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (50:50 hexanes/EtOAc) to provide the target compound (47 mg, 92%) as a white solid: mp 142–144° C.; 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (br s, 1H), 7.99 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 6.92 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.01 (s, 6H); APCI MS m/z 426 [(M+H)+, calcd for C22H24N3O4S, 426.1].
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([O:10][CH3:11])=[C:8]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:34]4[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=4[C:29]([Br:37])=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]4)=[CH:18][C:17]=2[CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:14])=[O:13])[S:7][CH:6]=1)=[O:4].[OH-].[K+]>C1COCC1.CO>[Br:37][C:29]1[C:30]2[S:31][C:32]([CH3:36])=[C:33]([CH3:35])[C:34]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][S:12]([C:8]3[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]=3[O:10][CH3:11])(=[O:14])=[O:13])=[C:17]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:18]=2)=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2
Reactant: COC(=O)c1csc(S(=O)(=O)Oc2ccc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C2CCCC2)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)O)csc1S(=O)(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
At ambient temperature, to a stirred solution of 5-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid methyl ester (0.722 g, 1.05 mmol) in THF:MeOH (3:2, 10 mL) was added 1N KOH (5.26 mL). After 1.5 h, the reaction was quenched with 1N HCl (40 mL) and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 25% EtOAc/hexane gave 0.596 g (85%) of the title compound as a white solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.34-1.39 (m, 2 H), 1.49-1.54 (m, 5 H), 1.62-1.73 (m, 3 H), 1.79-1.83 (m, 1 H), 2.43 (s, 3 H), 3.23 (quintet, 1 H), 3.97 (s, 3 H), 7.24 (dd, 1 H), 7.30 (d, 1 H), 7.34-7.36 (m, 2 H), 7.49 (t, 1 H), 7.64 (t, 1 H), 8.19 (d, 1 H), 8.72 (s, 1 H), 13.34 (br. s, 1 H). IR (KBr) 3400, 2950, 1690, 1375 and 860 cm-1. mass spectrum (-ESI), m/z 669/671 (M-H). Anal. Calcd. for C31H27BrO6S3 : C, 55.44; H, 4.05 N, 0.00. Found: C, 55.25; H, 4.11 N, 0.01.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[CH2:28][CH2:27][O:26][CH2:25][CH:24]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2s1
Temperature: 100 °C
Yield: 37.8 %

Procedure:
To a stirred solution of 600 mg (1.65 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 10 ml dioxane were added 1.23 g (3.30 mmol) tri-n-butyl-(3,6-dihydro-2H-pyran-4-yl)-stannane, 28 mg (0.05 mmol) bis(dibenzylideneacetone)palladium and 61 mg (0.26 mmol) trifurylphosphine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9-1/3 ethyl acetate/hexane) afforded 200 mg [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester as a light brown solid. ES-MS m/e (%): 319 ([M−H], 100).
Reaction SMILES: N#N.C1(/[CH:9]=[C:10](/[C:12]2[O:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=2)\C)C=CC=CC=1.[OH2:22]>CC(C)=O>[C:10]([C:12]1[O:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)(=[O:22])[CH3:9]
Reactant: O
Reactant: CCOC(=O)c1coc(/C(C)=C/c2ccccc2)n1
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NalO4 (23 g, 108 mmol) in water (150) mL was slowly added to a vigorously stirred suspension of silica gel (110 g) in acetone (500 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (500 mL) was added and the reaction mixture was treated at rt with (E)-ethyl 2-(1-phenylprop-1-en-2-yl)oxazole-4-carboxylate (8.3 g, 32.5 mmol) and RuC1-3 hydrate (550 mg, 1.0 mmol). The reaction mixture was stirred at rt in the dark for 60 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:0→1:5 petroleum ether: Et2O) gave the title compound as a yellow solid. TLC:rf (1:1 EA-Hept)=0.52.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>O>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(c2cc(Sc3ccccc3)nc(-c3ccccc3)n2)CC1

Procedure:
A mixture of 3.0 g. of the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 10 ml. of thiophenol is heated under reflux for three hours and then poured into 300 ml. of water. The reaction mixture is basified with 40°/o sodium hydroxide solution. The product which is deposited crystallizes on cooling to afford 3.5 g. of product. Recrystallization from n-heptane affords 4-(4-methyl-1-piperazinyl)-2-phenyl-6-phenylthiopyrimidine, m.p. 125°-128°C.
Reaction SMILES: [CH3:1][CH:2]([CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3](NC(OCC)=O)[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]([CH2:3][NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:16][NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)NCC(C)C(NC(=O)OCC)NC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)NCC(C)CNC(=O)OCC

Procedure:
10 g of the 2-methyl-1,1,3-tri(ethoxycarbonylamino)propane obtained in stage a) are dissolved in 90 ml of ethanol, 3 g of palladium on active carbon (10% Pd) are added, and hydrogenation is carried out in a stirred autoclave at 165° C. and 100 bar of hydrogen for 15 hours. Complete conversion gives 2-methyl-1,3-di(ethoxycarbonylamino)propane with a selectivity of 96%.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=2)[O:4]1.CCN(C(C)C)C(C)C.Cl[C:32]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:36]([CH3:46])[N:35]=[CH:34][N:33]=1>CN1C(=O)CCC1>[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C:37]2[C:32]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([B:5]5[O:4][C:3]([CH3:21])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)=[N:33][CH:34]=[N:35][C:36]=2[CH3:46])=[CH:44][CH:43]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CNCCO3)OC1(C)C
Reactant: Cc1ncnc(Cl)c1Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ncnc(N2CCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.4 g, 4.5 mmol) and DIPEA (6.4 mL, 37 mmol) in NMP (24 mL) was added and 4-chloro-5-(4-fluorobenzyl)-6-methylpyrimidine (reagent preparation 5) (1.7 g, 7.3 mmol). The resulting mixture was heated (120° C.) for 12 h and then partitioned between ethyl acetate (100 mL) and 1N aqueous hydrochloric acid (50 mL). The organic layer was washed with additional 1N aqueous hydrochloric acid (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography on silica (0-30% ethyl acetate/hexanes) provided 4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.7 g, 47% yield) as a white foam. MS (EI) for C27H31BFN3O3: 476 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH:13](B1OB(C=C)OB(C=C)O1)=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>COCCOC.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:13]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[CH2:14]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=C1NCCc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 7-bromo-3,4-dihydro-1(2H)-isoquinolinone (0.679 g, 3.004 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) in 1,2-dimethoxyethane (30 ml) was stirred at room temperature for 0.5 h before addition of 2,4,6-trivinylcyclotriboroxane.pyridine complex (for a synthesis see Kerins, Fergal; O'Shea, Donal F. J. Org. Chem. (2002), 67(14), 4968) (295 mg, 1.218 mmol), K2CO3 (415 mg, 3.004 mmol) and water (10 ml). The reaction was heated at reflux for 1.5 h before cooling to room temperature and addition of water (50 ml). The mixture was extracted with 10% methanol/dichloromethane (3×100 ml), the organic layers were dried with magnesium sulphate and evaporated. Chromatography on silica, eluting with 0-100% ethyl acetate/hexane, gave the product (456 mg, 88%).
Reaction SMILES: [CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.[CH3:33]/[C:34](=[CH:40]\[C@@H:41]([N:45]([CH3:54])[C:46](=[O:53])[C@H:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[NH2:48])[CH:42]([CH3:44])[CH3:43])/[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH3:1][C@@H:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([NH:48][C@@H:47]([C:49]([CH3:52])([CH3:50])[CH3:51])[C:46]([N:45]([CH3:54])[C@@H:41]([CH:42]([CH3:43])[CH3:44])/[CH:40]=[C:34](\[CH3:33])/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:53])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Reactant: C[C@H](C(=O)O)C(C)(C)c1ccccc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
To a cooled (0° C., ice bath) solution of (2S)-2,3-dimethyl-3-phenylbutanoic acid (0.11 g, 0.57 mmol, from Reference Example 25), hydroxybenzotriazole (93 mg, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (0.15 g, 0.80 mmol) in anhydous dimethylformamide (2 ml) is added N-methylmorpholine (95 uL, 0.86 mmol) via syringe under an inert atmosphere. After stirring for 15 minutes at 0° C., the cooling bath is removed, and the resulting mixture is stirred for 1 hour. The solution is cooled at 0° C. (ice water bath), and to this mixture is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate hydrochloride (0.56 mmol) in anhydrous dimethylformamide (2 ml). The cooling bath is removed, and the resulting mixture is stirred for 22 hours at room temperature under an inert atmosphere. The mixture is diluted with water, and the aqueous layer is extracted with ethyl acetate (3 times). The combined extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed (silica gel, flash column), to provide a white foam (0.20 g, 71%). MS (ES+): (M+H)=487.0