Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28].C(Cl)(Cl)Cl>CCCCO.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1ccccn1
Solvent: CO
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(NCc2ccccn2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 1 eq, 2.31 mmol) in n-BuOH (25 mL) under an argon atmosphere, cooled to 0° C., was added DIEA (1.13 mL, 2.80 eq, 6.49 mmol) followed by C-pyridin-2-yl-methylamine (0.48 mL, 2.0 eq, 4.66 mmol). The reaction mixture was stirred at 0° C. for 3 h, and then allowed to return to room temperature over 30 min. and stirred at this temperature for 1 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between citric acid solution (200 mL, 10% aq.) and EtOAc (200 mL), the aqueous phase was separated and extracted with more EtOAc (2×100 mL), and the bulked organic phase containing traces of 6-chloro-2-fluoropurine was discarded. The pH of the aqueous phase was adjusted to 7.0 with NaOH solution (50% w/v, aq.), extracted with EtOAc (4×100 mL), and the bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (95:5→85:15), to afford the title compound as a light yellow solid. Yield: 0.40 g (71%). Mp 217-220° C. 1H-NMR (d6-DMSO, 250 MHz): δ4.58 (d, 2H, J=5.68 Hz, —HNCH2-Pyr), 7.29, 7.71, 8.49 (3×m, 4H, Pyr), 8.10 (s, 1H, —N═CH—NH—), 8.69 (bs, 1H, —HNCH2-Pyr), 13.07 (bs, 1H, —N═CH—NH13 ). FABMS m/z (relative intensity): 245 ([M+H]+, 55), 176 (30), 154 (100), 136 (85). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected: Measured) C11H9N6F .0.4H20: C; 52.55: 52.91, H; 3.93: 3.49, N; 33.42: 33.26.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:18]2[C@:19]3([CH2:36][CH2:35][C@H:34]4[C@@H:24]([CH2:25][CH:26]=[C:27]5[C@:32]4([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]5)[C@@H:21]3[CH2:22][CH:23]=2)[CH3:20])[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Yield: 83.9 %

Procedure:
The method followed that described in Example 1, using in step (b) diethyl(3-pyridyl)borane (0.88 g, 6.0 mmol), androsta-3,5,16-trien-17-yl trifluoromethanesulphonate (2.01 g, 5.0 mmol), prepared in step (a), THF (25 ml), bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol), and aqueous sodium carbonate (2M, 10 ml). Chromatography, on elution with dichloromethane, afforded the title compound (1.39 g, 84%) which crystallised from hexane, m.p. 110°-112° C. 1H-NMR (CDCl3) inter alia δ1.02(3H,s,19-CH3), 1.07(3H,s,18-CH3), 5.44(1H,m,6-H), 5.61(1H,m,3-H), 5.95(1H,dm, J 9.8 Hz, 4-H), 6.01(1H,m,16-H), 7.23(1H,m,Py 5-H), 7.66(1H,m,Py 4-H), 8.46(1H,m,Py 6-H), 8.63(1H,m,Py 2-H); MS m/z 331 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:27]([C:26]2[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=2[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3-c3nccs3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (Example Q) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 524.3 MH+.
Reaction SMILES: [CH:1]([Si:3](OC)([O:6][CH3:7])[O:4][CH3:5])=[CH2:2].[CH:10]([Mg]Br)([CH3:12])[CH3:11].C[O-].[Mg+2].C[O-]>C(OCC)C>[CH:10]([CH:2]=[CH:1][SiH:3]([O:6][CH3:7])[O:4][CH3:5])([CH3:12])[CH3:11]
Reactant: C=C[Si](OC)(OC)OC
Reactant: CC(C)[Mg]Br
Agent: C[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CO[SiH](C=CC(C)C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
206 g (1.39 mol) of vinyl trimethoxysilane and 300 ml of dry diethyl ether were charged in a 2 L four-necked flask equipped with a dropping funnel and a mechanical stirrer in a stream of nitrogen, and cooled to 0° C. 1.67 mol of the above prepared diethyl ether solution of isopropyl magnesium bromide was dropwise added thereto with stirring over a period of 120 minutes, and reaction was carried out at room temperature for 2 hours. After completion of the reaction, magnesium methoxide residue as a by-product was removed by filtration, and the obtained filtrate was distilled under reduced pressure to obtain 141 g (0.882 mol) of isopropylvinyldimethoxysilane as an aimed product. The yield was 63.5%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([O:17]C)=[O:16])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1>Br>[OH:1][CH2:2][C:3]1[NH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([OH:17])=[O:16])=[C:6]([C:8]([F:9])([F:11])[F:10])[N:7]=1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(CO)nc2C(F)(F)F)c1
Agent: Br
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 12 h
Yield: 52.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 3-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 284.1, 2 g, 6.36 mmol), HBr (40% in AcOH) (50 mL). The reaction mixture was stirred for 12 h at 80° C. The crude product (100 mL) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): mobile phase, CH3CN:H2O=1:1; Detector, UV 254 nm to yield 1 g (52%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1Br.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCC1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Br
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C1=CCCC1
Temperature: 80 °C
Yield: 39.7 %

Procedure:
A microwave tube was charged with 2-bromo-4-tert-butyl-5-nitrophenyl methyl carbonate (200 mg, 0.60 mmol), 1-cyclopentenylboronic acid (91 mg, 0.81 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), 2 M Na2CO3 (1.5 mL), ethanol (1.5 mL) and toluene (3 mL) under inert atmosphere and was heated under microwave irradiation at 80° C. for 4 h. The reaction was extracted with ethyl acetate then washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided 4-tert-butyl-2-cyclopentenyl-5-nitrophenyl methyl carbonate (76 mg, 40% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.57 (s, 1H), 6.28 (t, J=1.9 Hz, 1H), 3.86 (d, J=12.5 Hz, 3H), 2.69 (td, J=7.5, 3.2 Hz, 2H), 1.93 (dd, J=7.6, 15.0 Hz, 2H), 1.36-1.33 (m, 11H).
Reaction SMILES: N1C=CC=CC=1.O[CH2:8][C:9]1[C:21]2[C:20]3[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=3[N:14]([CH3:23])[C:13]=2[C:12](=[O:24])[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1.CS([Cl:35])(=O)=O.ClCCl>O1CCCC1>[Cl:35][CH2:8][C:9]1[C:21]2[C:20]3[CH:19]=[C:18]([CH3:22])[CH:17]=[CH:16][C:15]=3[N:14]([CH3:23])[C:13]=2[C:12](=[O:24])[N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(CO)nn(-c3ccccc3)c(=O)c1n2C
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(CCl)nn(-c3ccccc3)c(=O)c1n2C
Temperature: 60 °C
Reaction time: 15 h
Yield: 49.8 %

Procedure:
50 ml of pyridine are added to a suspension of 9.5 g (29.7 mmol) of 1-(hydroxymethyl)-5,8-dimethyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one in 600 ml of tetrahydrofuran heated to 60° C. 4.5 ml (59.4 mmol) of methanesulphonyl chloride are added and the mixture is left standing for 15 h at room temperature. 500 ml of dichloromethane are added, the precipitate is removed by filtration, separation is carried out by settling and the organic phase is washed with water. It is dried over sodium sulphate and the solvent is evaporated under reduced pressure. 5 g (14.8 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a brown solid (352 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH2:25])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[CH2:7][C:8](=[O:28])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:27])[CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:40](=[O:42])[CH3:41])=[C:20]([Cl:26])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(N)c(Cl)c1)CC2
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(Cl)c(NC(C)=O)c(Cl)c1)CC2
Temperature: 25 °C

Procedure:
A solution of 3 gm (0.0063 mol) of 1-[7,8-dimethoxy-1,3,4,5,-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{4amino-3,5-dichloro-phenyl}ethyl)-amino]-propane in 50 ml of chloroform and 0.7 gm (0.007 mol) of triethylamine was mixed at the boiling point in portions with altogether about 0.8 ml of acetyl chloride. After boiling it for several hours, the reaction mixture was cooled to room temperature and washed with water. The aqueous phase was made strongly alkaline with 2N sodium hydroxide and extracted with methylene chloride. The separated organic phase was dried over sodium sulfate and evaporated. The crude product thus obtained was purified by chromatography on silica gel (particle size: 0.063 to 0.2 mm, eluant: methylene chloride/methanol=8:1).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[F:25])([CH2:11][CH:12]([CH3:14])[CH3:13])C(OCC)=O)C>CC(O)=O.O.CCO>[F:25][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[C:19]([F:21])=[CH:20][C:15]=1[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 64.7 %

Procedure:
The above 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester (57.0 g, 152.8 mmol) was dissolved in AcOH/H2O/EtOH (400 mL/120 mL/50 mL) and the reaction mixture was heated under reflux for 96 h. After cooling the solvent was evaporated under reduced pressure and water (200 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined extracts were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a yellow oil which crystallized on standing to yield 27 g of 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid. Chromatography of the residual oil (Heptane-EtOAc gradient) gave an additional 3 g of product (72% combined yield). 1H NMR (300 MHz, CDCl3/TMS): δ 9.63 (br s, 1H), 7.82 (dd, J=8.8, 6.0 Hz, 1H), 7.38 (dd, J=11.0, 5.8 Hz, 1H), 4.14-4.08 (m, 1H), 2.05-1.95 (m, 1H), 1.76-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 177.6, 158.2 (d, 1JCF=232.5 Hz), 150.9 (d, 1JCF=262.5 Hz), 136.0, 134.7, 119.0 (d, 2JCF=20.0, Hz), 113.1 (d, 2JCF=29.4 Hz), 41.7, 41.3, 26.0, 22.6, 21.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:14])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)c(Br)c1
Reaction time: 2 h

Procedure:
2.17 g (9.41 mmol) 3-bromo-4-fluorobenzoic acid were mixed with 20 mL thionyl chloride and then boiled for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:10][N:9]([C:11](=[O:30])[C@H:12]([NH:22]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8]1)[CH2:3][CH2:4][CH3:5]>C(OCC)(=O)C>[ClH:1].[NH2:22][C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:11]([N:9]1[CH2:8][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH2:10]1)=[O:30]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6 ml of a 4N solution of hydrochloric acid in ethyl acetate are added to 615 mg (1.24 mmol) of tert-butyl [(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate (procedure identical to 4-3). The reaction mixture is stirred at ambient temperature for 2 hours. The precipitate obtained is filtered off, washed with diethyl ether and then dissolved in methanol, followed by evaporation of the solvents. 441 mg of (R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one hydrochloride are obtained in the form of a white powder with a yield of 82%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C[O:17][C:18]([C:20]#[C:21][C:22]([O:24]C)=[O:23])=[O:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15]/[C:20](=[CH:21]\[C:22]([OH:24])=[O:23])/[C:18]([OH:19])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(O/C(=C\C(=O)O)C(=O)O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 2060 parts of 2,4-di-t-butylphenol, 1040 parts by volume of acetylene dicarboxylic acid dimethyl ester and 10 parts of benzyltrimethylammonium hydroxide was heated on a steam bath until a rapid exothermic reaction had occurred. The mixture was cooled to room temperature and ether was added. The ether extract was washed with N sodium hydroxide solution, sodium chloride solution and water, then the ether was removed by evaporation. The residue obtained was refluxed for three hours with 5000 parts of 5N sodium hydroxide solution. After cooling the mixture to room temperature, the solid which precipitated was removed by filtration.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:30])[S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl.C[N:49](C)CCCN=C=NCC>O.CN(C)C=O.C(O)C.O1CCCC1>[CH3:30][N:20]([S:21]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([NH2:49])=[O:3])[CH2:7][N:8]=1)=[CH:19]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccnc4)c3[nH]2)S1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccnc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A mixture of ethyl(2-{7-[methyl(pyridin-3-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (330 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at 50° C. for 30 min. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give pale-yellow crystals. A mixture of the obtained crystals, 1H-1,2,3-benzotriazol-1-ol-ammonia complex (1.10 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2.5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-85:15, volume ratio) to give the title compound (130 mg, yield 42%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 185-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:33]=[CH:32][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:16][CH:15]=1)=O>C(O)(=O)C>[NH:22]1[CH2:21][CH2:20][CH:19]([CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:12]3[NH:11][C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]=4[N:1]=3)=[CH:33][CH:32]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(=O)Nc3cccc(C(N)=O)c3N)cc2)CC1
Solvent: CC(=O)O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(CC4CCNCC4)cc3)nc12
Reaction time: 2 h

Procedure:
A suspension of EXAMPLE 20A in acetic acid at reflux was stirred for 2 hours, cooled and concentrated. The concentrate was dissolved in ethyl acetate, washed with sodium bicarbonate and water and concentrated. The concentrate was flash chromatographed on silica gel with 20% Methanol/ethyl acetate. 1H NMR (DMSO-d6) δ 1.27-1.44 (m, 2H), 1.75 (d, J=13.20 Hz, 2H), 1.82-1.97 (m, 1H), 2.65 (d, J=7.06 Hz, 2H), 2.76-2.92 (m, 2H), 3.26 (d, J=12.89 Hz, 2H), 7.35 (t, J=7.83 Hz, 1H), 7.42 (d, J=8.29 Hz, 2H), 7.74 (d, J=0.92 Hz, 1H), 7.76 (d, J=0.92 Hz, 1H), 7.87 (d, J=6.75 Hz, 1H), 8.18 (d, J=8.29 Hz, 2H), 8.25 (d, J=7.98 Hz, 1H), 8.55 (d, J=11.97 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(Cl)nc(Cl)n2)c(C)c1
Reaction time: 3 h

Procedure:
Cyanuric chloride (1.84 g) was allowed to react with 1.9 eq of m-xylene and 2.5 eq (3.35 g) of AlCl3 in 25 mL of chlorobenzene at 5° C. for 0.5 h and then at room temperature for 3 h. Analysis by HPLC, after 2.5 h, showed that less than 8% of cyanuric chloride had reacted to form only 2,4-dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine, no 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine or 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine were present. The reaction was allowed to continue at room temperature. After 24 hours, HPLC analysis showed about 51% cyanuric chloride conversion and formation of 2,4-dichloro-6-(2,4-dimethylphenyl)-1,3,5-triazine and 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine in the ratio of 95:5, respectively. No 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine was detected.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:28])[N:8]2[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([NH:13][C:14]([C:16]3[C:20]([CH3:21])=[C:19]([CH2:22][CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[O:18][N:17]=3)=[O:15])=[C:9]([CH3:28])[N:8]2[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C#CC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1CCC(C)(C)C

Procedure:
N-(2-Cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-5-(3,3-dimethylbut-1-yn-1-yl)-4-methylisoxazole-3-carboxamide (30 mg, 0.075 mmol) in ethanol (5 mL) was degassed thoroughly refilling with nitrogen and Pd—C (16.02 mg, 7.53 μmol) was added. The mixture was stirred under an atmosphere of hydrogen. Upon completion the reaction mixture was filtered through Celite® and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;