Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 105 %

Procedure:
The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 92 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C16H18FN3, 271.15. found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.47 (m, 2H), 7.31-7.27 (m, 2H), 3.55-3.51 (m, 1H), 3.41-3.39 (m, 2H), 3.23-3.14 (m, 2H), 3.00-2.83 (m, 2H), 0.93-0.084 (m, 4H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([C:29]1[O:33][C:32]([C:34]2[C:38]([CH:39]=O)=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[N:36]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[N:35]=2)=[N:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[O:33][C:32]([C:34]2[C:38]([CH:39]=[C:1]([Br:5])[Br:2])=[C:37]([C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[N:36]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[N:35]=2)=[N:31][N:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C=O)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C=C(Br)Br)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of carbontetrabromide (313 mg, 0.94 mmol) in methylene chloride (15 ml) at 0° C. was added triphenylphosphine (248 mg, 0.95 mmol). The reaction mixture was stirred at 0° C. for 10 minutes and then 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carbaldehyde (300 mg, 0.63 mmol) in methylenechloride (10 ml) was added slowly. The reaction temperature was warmed slowly to room temperature and stirred overnight. The resulting solution was quenched with saturated ammonium chloride and extracted organic layer with ethyl ether (50 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (110 mg, 37%) and produce 2-tert-butyl-5-(5-(4-chlorophenyl)-4-(2,2-dibromovinyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (230 mg, 58% yield) as white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH3:6][O:7][Si:8]([O:15][CH3:16])([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][NH2:12]>Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>[CH3:6][O:7][Si:8]([O:13][CH3:14])([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][NH:12][C:3](=[O:5])[CH2:2][Br:1]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)CBr)(OC)OC
Reaction time: 2 h

Procedure:
Binder DNA oligonucleotide-derivatized porous silicon films were employed to test the selectivity and limits of detection of a contemplated sensor. For attachment of DNA, a trimethoxy-3-bromoacetamido-propylsilane linker was synthesized by reaction of bromoacetic acid with trimethoxy-(3-aminopropyl)silane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride in methylene chloride as solvent The linker product was purified by column chromatography on silica gel. The oxidized porous silicon samples were then contacted with a toluene solution of the linker for 2 hours. The resulting linker-bound substrate was thoroughly rinsed with pure toluene and methylene chloride, and dried for about 18 hours under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[F:7][C:8]([F:22])([F:21])[C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16](O)=[O:17])=[CH:15][C:11]=2[CH:10]=1>C(O)C>[F:21][C:8]([F:7])([F:22])[C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16]([O:5][CH2:1][CH3:2])=[O:17])=[CH:15][C:11]=2[CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
Then, 254 mg of oxalyl chloride was added to a mixture of 400 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid and 20 ml of ethanol while ice-cooling, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added chloroform, and then the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 330 mg of ethyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (the present compound 5).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH2:40][OH:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O>C(Cl)Cl>[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]([CH:40]=[O:41])[CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCCCC(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CC1CCCCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h
Yield: 23.5 %

Procedure:
Dess-Martin periodinane (2.78 g, 6.56 mmol) was slowly added to a stirring 0° C. solution of 3-hydroxymethyl-azepane-1-carboxylic acid benzyl ester (146) (1.2516 g, 5.02 mmol) in CH2Cl2 (18.2 mL). The reaction was stirred for 1 hour until the reaction was judged complete by HPLC. The reaction was concentrated in vacuo, and a minimal amount of CH2Cl2 was added. Et2O was added to precipitate the periodinane by-product, and the reaction was filtered, concentrated, and immediately purified through an automated silica get column with 1:1 Hexanes:EtOAc to obtain pure 3-formyl-azepane-1-carboxylic acid benzyl ester (147) (0.3086 g) in 62% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (10.2 g, 67 mmol) in acetonitrile (250 mL) was added potassium carbonate (27.6 g, 200 mmol) and methyl iodide (4.1 mL, 66 mmol). The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the solid was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was dissolved in dichloromethane (250 mL). The solution was washed with 2N NaOH (aq.) (200 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to yield 1-methoxy-2-methyl-4-nitrobenzene (9.5 g, 57 mmol, 85%).
Reaction SMILES: C(C1OC1)Cl.[OH-].[Na+].Cl.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[NH:19]CC(O)COC1C2SC=C(C)C=2C=CC=1>C(O)C>[NH2:19][CH:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1
Reactant: Cc1csc2c(OCC(O)CNC3CCc4ccccc4C3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCC1CO1
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 33, but starting from 7-hydroxy-3-methylthiophene and epichlorohydrin in the presence of sodium hydroxide and contacting a solution of the obtained raw epoxide in absolute ethanol with a solution of 2-aminotetralin in absolute ethanol, N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(3-methylbenzothien-7-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 28, wherein Z is methyl and the chain bridges position 7 of the Ar radical and position 2 of the tetralin moiety).
Reaction SMILES: [O:1]=[C:2]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]CC2C=CC=CC=2)[NH:9][N:8]=1)=[O:6]>CO.[Pd]>[O:1]=[C:2]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:40])([F:42])[F:41])[CH2:30][CH2:31]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[NH:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2O)[nH]n1
Yield: 42 %

Procedure:
10% Pd/c (20 mg) was added to a stirred solution of 5-(2-Benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (103 mg, 0.17 mmol))(prepared by the method as described above) in MeOH (50 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 6 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure to afford 35.8 mg (41.3% yield) of 5-(2-Hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.92%. 1H NMR (DMSO): δ 13.1 (s, 1H), 10.3 (s, 1H), 8.2 (s, 1H), 7.74 (m, 2H), 7.62 (m, 2H), 7.52 (m, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.96 (m, 1H), 6.86 (m, 1H), 4.1 (m, 2H), 3.55 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:24][C:25]([C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1)=[O:26].CCN(C(C)C)C(C)C.[CH2:45]([S:47](Cl)(=[O:49])=[O:48])[CH3:46]>C(O)(C(F)(F)F)=O>[CH2:45]([S:47]([N:15]1[CH2:14][CH:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:24][C:25]([C:27]4[N:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]5=[N:29][CH:28]=4)=[O:26])[CH:4]=3)[N:12]=2)[CH2:16]1)(=[O:49])=[O:48])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC(c2nc(-c3ccc(F)c(NC(=O)c4cnc5ccccn45)c3)no2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl 3-(3-(4-fluoro-3-(imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F27) (14.4 mg, 0.03 mmol) was dissolved in TFA (0.5 mL) and stirred at room temperature for 10 minutes. Then TFA was removed under vacuum. The residue was dissolved in anhydrous dichloromethane (1 mL) and DIEA (13.0 mg, 0.10 mmol) and ethanesulfonyl chloride (5.8 mg, 0.045 mmol) were added. The reaction was stirred at room temperature for 10 minutes. The solvent was removed and the crude was purified by preparative HPLC to afford N-(5-(5-(1-(ethylsulfonyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (F28). 1H NMR (400 MHz, CDCl3) δ 9.50 (d, J=2 Hz, 1H), 9.09 (dd, J=2, 7.2 Hz, 1H), 8.21 (s, 1H), 7.87 (m, 1H), 7.79 (m, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.41 (m, 1H), 7.22 (dd, J=8.8, 10.4 Hz, 1H), 7.02 (dt, J=0.8, 6.8 Hz, 1H), 4.34 (m, 4H), 4.07 (m, 1H), 3.00 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H). MS m/z 471.1 (M+1)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[N:26]=[CH:25]2)=[O:20])[C:12]1C=CC=CC=1.[C:50](OC[C@@H]1OC1)(=[O:54])CCC.[NH4+].[Cl-]>O1CCCC1>[OH:54][CH2:50][C@@H:11]1[O:18][C:19](=[O:20])[N:21]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=[CH:25]3)[CH2:12]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc2c(cnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc2c(cnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C

Procedure:
1 M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.1 mL, 1.1 mmol) was added dropwise with stirring at −78° C. to 5-benzyloxycarbonylamino-1-tritylindazole (0.510 g, 1 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture was stirred at −78° C. for 1.5 h. (R)-Glycidyl butyrate (0.160 mL, 1.2 mmol) was added dropwise with stirring. The mixture was allowed to warm to r.t. overnight. Saturated aq. NH4Cl (10 mL) was added, and the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried (MgSO4). Solvent was evaporated to 3 mL, and the residue was triturated with hexanes (50 mL). White crystalline product was filtered off, washed with hexanes, and dried in vacuo. Yield 0.440 g (93%). MS (m/z): 232.1 [M−Trt]−. 1H NMR.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19][NH2:20])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19]([NH2:20])=[O:27])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: NSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: NS(=O)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 31.7 %

Procedure:
To an ice cooled stirred solution of 10 (1.5 g, 5 mmol) in ethanol:H2O (525 mL, 20:1, v/v), m-chloroperoxybenzoic acid (1 g, 1 eq.) in ethanol (50 mL) was added dropwise during 20 min. After 4 h the separated crystals were filtered off, the filtrate was evaporated to dryness, triturated with methanol, filtered, washed with methanol and dried at room temperature to yield 11, (0.5 g, 31% yield), m.p. >120° C. The filtrate was evaporated and purified by chromatography as described for 6 to yield another crop of 11, (0.25 g, 15%: overall yield 46%). IR (KBr): 1060 (vs, br, S=O), 1330 (s, S=O), 3000-3600 (NH2, OH) cm-1 : UV: λmax (pH 1) 272 nm (ε 3,000): λmax (pH 7) 275 nm (ε7,100): λ max (pH 11) 272 nm (ε 1,700): 1H NMR (DMSO-d6): δ 6.46 (d, 1, J =5.16 Hz, C1'H), 6.71 (s, 2, SONH2, exchanged with D2O), 8.83 (s, 1, C2H), 9.06 (s, 1, C8H), and other sugar protons. Anal. Calcd for C10H13N5O5S·0.3H2O (321.32): C, 37.38: H, 4.24: N, 21,80: S, 9.97. Found: C, 37.03: H, 4.19: N, 21.42: S, 10.37.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH3:31])[CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:32]C)C1C=CC=CC=1.[BrH:34]>C(O)(=O)C>[BrH:34].[OH:32][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[CH:16]([C:19]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:20][CH2:21][CH2:22]1)[N:15]([CH3:31])[CH2:14][CH2:13]2
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)N(C)CC2
Agent: Br
Solvent: CC(=O)O
Product: CSc1ccccc1C1(C2c3cc(O)c(O)cc3CCN2C)CCC1

Procedure:
7-Benzyloxy-6-methoxy-2-methyl-1-[1-(2-methylthiophenyl) cyclobutyl]-1,2,3,4-tetrahydroisoquinoline (1.7 g) was heated under reflux for 2 hours with 48% aqueous hydrobromic acid (15 ml) and glacial acetic acid (15 ml). The solvents were removed by evaporation in vacuo and the residue dried by azeotropic distillation with propan-2-ol. The residue was then dissolved in propan-2-ol, decolourised with charcoal and the solvent evaporated to yield 6,7-dihydroxy-2-methyl-1-[1-(2-methylthiophenyl )cyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrobromide (1.1 g).
Reaction SMILES: C(O)(=O)C.[CH:5](N)=[NH:6].[Cl:8][C:9]1[C:14]([NH:15][C:16](=[NH:26])[C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:13]2[O:27][CH2:28][O:29][C:12]2=[CH:11][CH:10]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:14]([NH:15][C:16]2[C:17]3[C:22](=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[F:25])[N:6]=[CH:5][N:26]=2)=[C:13]2[O:27][CH2:28][O:29][C:12]2=[CH:11][CH:10]=1
Reactant: N=C(Nc1c(Cl)ccc2c1OCO2)c1c(F)cc(F)cc1F
Reactant: N=CN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 25 °C

Procedure:
Formamidine acetic acid salt (0.185 g) was added to a stirred solution of N1-(6-chloro-2,3-methylenedioxyphenyl)-2,4,6-trifluorobenzamidine (0.204 g) in toluene (5 ml) and the reaction mixture was heated to reflux for 16 hours. A second portion (0.185 g) of formamidine acetic acid salt was added and the reaction mixture was heated to reflux for a further 16 hours. Triethylamine (0.25 ml) was added and the reaction mixture was heated to reflux for a further 3 days. The resultant reaction mixture was cooled to ambient temperature and partitioned between methylene chloride (25 ml) and a saturated aqueous sodium bicarbonate solution (25 ml). The organic solution was washed with 10% aqueous citric acid (25 ml), dried over magnesium sulphate and evaporated. The resultant oil was purified by column chromatography on silica gel using increasingly polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline (0.068 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:33])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O>[C:13]([O:12][C:11]([N:10]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(O)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl (2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4′-hydroxy-1,1′-biphenyl-4-yl)ethyl]carbamate (240 mg) and potassium carbonate (78 mg) in N,N-dimethylformamide (4 ml) was added tert-butyl bromoacetate (110 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-yl]oxy]acetate (245 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(Cl)cccc1OCc1ccccc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of 143 g (1.0 mol) of 3-chloro-2-methylphenol, 139 g (1.1 mol) of benzyl chloride, 276 g (2.0 mol) of potassium carbonate and 680 g of methyl ethyl ketone (MEK) is heated under reflux with stirring. After 8 hours, a further 25 g (0.18 mol) of potassium carbonate are added and the mixture is then heated under reflux for a further 8 hours. The batch is filtered and the filter cake is washed with MEK. After working up by distillation, 206 g of 2-benzyloxy-6-chlorotoluene (b.p. 161 ° C., 3 mbar) are obtained as a pale yellow liquid in 99.6% purity (surface area % according to GC). This corresponds to a yield of 88.3% of theory.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:28])[CH2:9][CH2:10][N:11]([CH2:25][CH2:26]O)[C:12](=[O:24])[CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]1[C:41]2[S:40][C:39](=[O:42])[NH:38][C:37]=2[C:36]([OH:43])=[CH:35][CH:34]=1.C([BH3-])#N.[Na+].N>ClCCl.CO.O.C(O)(=O)C.C(N(CC)CC)C.CS(C)=O>[CH3:7][N:8]([CH3:28])[CH2:9][CH2:10][N:11]([CH2:25][CH2:26][NH:30][CH2:31][CH2:32][C:33]1[C:41]2[S:40][C:39](=[O:42])[NH:38][C:37]=2[C:36]([OH:43])=[CH:35][CH:34]=1)[C:12](=[O:24])[CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: CN(C)CCN(CCO)C(=O)CCOCCc1ccccc1
Agent: Cl
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethyl sulfoxide (0.037 g) in dichloromethane (1 mL) was added to a solution of oxalyl chloride (0.030 g) in dichloromethane (10 mL) at −78° C. The reaction was stirred for 15 minutes and then a solution of N-(2-dimethylaminoethyl)-N-(2-hydroxyethyl)-3-phenethyloxy-propanamide (Example 14a), 0.067 g) in dichloromethane (1 mL+1 mL wash) was added and the reaction stirred for a further 15 minutes. Triethylamine (0.11 g) was added and the reaction mixture was allowed to warm to room temperature over a period of 1 hour. The mixture was subsequently diluted (dichloromethane, 30 mL), the organics washed with saturated sodium hydrogencarbonate solution (20 mL) and then brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a crude aldehyde product which was used immediately. The crude product was dissolved in methanol (10 mL) and 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.054 g) added along with acetic acid (0.1 mL) and water (0.1 mL). After stirring at room temperature for 30 minutes, sodium cyanoborohydride (0.014 g) was added and the reaction mixture was stirred overnight. Ammonia (7N in methanol, 1 mL) was added and the mixture was concentrated. The crude residue was purified by flash silica column chromatography eluting with 1% ammonia; 5%-7% methanol in dichloromethane to afford the titled compound as a white solid (0.012 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 4-chloro-2-methylbenzonitrile (10 g, 66 mmol) in conc. H2SO4 was added KNO3 (7.0 g, 69.3 mmol) at 0° C. in small portions, and then the reaction mixture was stirred overnight at ambient temperature. It was then poured into ice and extracted with AcOEt. The combined extracts were washed by sat. NaHCO3 aq., dried over MgSO4 and concentrated. The resulting precipitates were collected by filtration, washed with ether, and dried under reduced pressure to give 5.5 g (42%) of the title compound.