Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[S:12]([N:15]=C=O)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][S:12](=[O:14])(=[O:13])[NH2:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc([N+](=O)[O-])c1

Procedure:
This compound was prepared according to the procedure used in Example 75. A mixture of 13.9 g (0.1 mole) of 3-nitrophenol and 14.8 g (0.105 mole) of chlorosulfonyl isocyanate in 100 ml of toluene gave 16.9 g (78%) of tan flakes, mp 118°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N+:8]([O-])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:26][C:24](=[O:25])[C:23]([F:34])([F:33])[F:22])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Br)ccc2N1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1OC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A 9.5-g (0.027 mole) portion of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide was added portion-wise to 50 ml of trifluoroacetic anhydride, and the reaction mixture was stirred for 90 minutes. The suspended solid that formed was collected on a filter, washed thoroughly with pentane and dried in a vacuum over KOH. There was obtained 9.72 g (80%) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2one as an off-white crystalline powder: mp 175°-177° (dec.); 19F nmr (DMSO-d6) δ -74.6 ppm (s, 3F) and -112.7 ppm (m, 1F); 1H nmr (DMSO-d6) δ 6.34 ppm (s, 1H), 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6](F)[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].[H-].[Na+]>O1CCOCC1>[CH:18]1([N:17]2[C:6]3[C:7](=[C:2]([CH3:1])[C:3]([F:24])=[C:4]([F:23])[C:5]=3[F:22])[C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16]2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Ethyl 2-(6-methyl-2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate (4.50 g) is dissolved in anhydrous dioxane (26 ml) and thereto 60% sodium hydride (580 mg) is gradully added under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture is poured into ice-water and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated. The residue is added with diethyl ether and crystals are filtered, which are recrystalized from dichloromethane--n -hexane to give ethyl 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.19 g), as white needles, m.p. 180°-183° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9]([NH2:18])([C:15]([OH:17])=[O:16])[CH2:10]2)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](=O)([O:42]N1C(=O)CCC1=O)[O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C(#N)C.O>[C:26]([CH:10]1[C:11]2[C:6](=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1([NH2:18])[C:15]([OH:17])=[O:16])([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:42]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)Oc1cccc2c1CCC(N)(C(=O)O)C2
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
A mixture of racemic 5-isopropoxy-2-aminotetraline-2-carboxylic acid (3.48 g, 5.98 mmole theoretical), triethylamine (1.10 ml, 7.89 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.62 g, 7.77 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for one day. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (500 mg) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-isopropoxy-2-aminotetraline-2-carboxylic acid (0.50 g, 18% yield over 2 steps) as a white solid. HRMS (FAB): C29H30NO5 (M+H) calc. 472.2124; observed: 472.2117.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1C=CC(C#N)=[CH:6][CH:5]=1.[O-]P(OP([O-])([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[CH3:26][O:27][C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=O.Cl>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO.C(#N)C>[CH3:26][O:27][C:28]([C:29]1[CH:6]=[CH:5][C:4]([C:3]([OH:12])=[O:2])=[CH:31][CH:30]=1)=[O:34]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)O)cc1
Reaction time: 25.5 h

Procedure:
Into a 20-mL glass vial equipped with stirring bar was added 0.0252 g (0.155 mmol, 0.052 M) of 4-cyanobenzoic acid methyl ester, 2.67 mL of potassium pyrophosphate buffer (20 mM, pH 7.0), and 0.30 mL of a 50 wt % cell suspension (0.155 g wet cell weight, 37.3 mg dry cell weight) of Acidovorax facilis 72W (ATCC 55746) cells in 0.35 M potassium phosphate buffer (pH 7.0, previously heat-treated at 50° C. for 20 min ), and the resulting 3 mL suspension stirred at 25° C. After 25.5 h, the pH of the reaction mixture was adjusted to between 1.5 and 2.0 with 6.0 N HCl, then 9.0 mL of a mixture of acetonitrile (44% v/v) and methanol (56% v/v) was added and the resulting mixture filtered and analyzed by gas chromatography. The conversion of 4-cyanobenzoic acid methyl ester was complete, and the yield (determined by GC) of 1,4-benzenedicarboxylic acid monomethyl ester was 94%, with no production of 4-cyanobenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:13](=O)[CH2:14]Br)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[S:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:13]1[N:44]=[C:42]([NH:41][C:31]2[CH:32]=[CH:33][C:34]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:29]([O:28][CH3:27])[CH:30]=2)[S:43][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CBr
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)OC(C)(C)C)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 102 mg (0.33 mmol) (S)-[1-(2-bromo-acetyl)-3-methyl-butyl]-carbamic acid tert-butyl ester, 42 mg (0.33 mmol) N,N-diisopropyl ethyl amine and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under vacuo. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 97 mg (69%) ((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a light yellow solid. MS ISP (m/e): 472.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.35 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.23 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 6.99 (d, 1H), 6.55 (s, 1H), 4.59 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.70-1.55 (m, 3H), 1.39 (s, 9H), 0.90 (s, 6H). α589=−43.2; T=20° C.; c=1 g/m100 ml, solvent=MeOH.
Reaction SMILES: Cl.C(NCC(C(C1C=CC(O)=C(O)C=1)=O)C)(C)(C)C.C([Cl:26])(=O)C(C)(C)C.FC(F)(F)C(O)=O.Cl.Cl.[C:36]([NH:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[C:46]([O:57][C:58](=[O:63])[C:59]([CH3:62])([CH3:61])[CH3:60])[CH:45]=1)=[O:43])([CH3:39])([CH3:38])[CH3:37]>[Pd]>[ClH:26].[C:58]([O:57][C:46]1[CH:45]=[C:44]([CH:49]=[CH:48][C:47]=1[O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[CH:42]([OH:43])[CH2:41][NH:40][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:63])[C:59]([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: [Pd]
Agent: CC(CNC(C)(C)C)C(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
3,4-Dihydroxyphenyl 1-(tert-butylaminomethyl)ethyl ketone hydrochloride (8 g.) was reacted with 18 ml. of pivalyl chloride in 35 ml. of trifluoroacetic acid, the resulting ester-amine salt was converted to the ester-amine, and the ester-amine was treated with hydrochloric acid to yield 10.5 g. of 3,4-bis-(pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride, m.p. 200°-202° C. (uncorr.). This ketone was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst to yield 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 205°-207° C. (uncorr.).
Reaction SMILES: [F:1][C:2]1(B(O)O)[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:19]O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([OH:19])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CCCCCCOC1C=C(F)C=CC1(F)B(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1c(F)ccc(F)c1O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
White crystals of 1,4-difluoro-2-hexyloxybenzene-1-boronic acid (48 g) were dissolved in warm toluene (150 ml) and hydrogen peroxide (43 ml, 30%) was added drop-wise. Heating was continued for 45 min at 100° C. Once the solution had cooled to room temperature water was added (50 ml) and the layers were separated. The toluene layer was washed with ferrous ammonium sulphate (10%, 2×50 ml) and water (2×50 ml). The combined organic extracts were dried with magnesium sulphate, filtered and the solvent was removed to yield crude 3,6-difluoro,2-hexyloxyphenol as a pale yellow oil (31.67 g, 100%). The crude product was dissolved in toluene (150 ml), extracted with sodium hydroxide solution (10%w/v in methanol, 3×50 ml). The purple, aqueous extract, containing the phenoxide anion of the product, was then re-acidified with concentrated HCl until all of the colour had been displaced (pH˜4). The phenol was then extracted with dichloromethane (3×100 ml), washed with water (3×50 ml), dried with magnesium sulphate and filtered. Removal of the solvent in vacuo yielded the required product as an orange/brown oil (27.2 g, 87%). Kugelrohr distillation was performed under reduced pressure (2 mbar), the colourless distillate collected when the oven temp was 100° C. was found to contain only 4 (26.5 g, 82%), (Found: C, 62.65; H, 6.9. C12H16O2F2 requires C, 62.6; H, 6.9; O, 13.91; F, 16.52%); vmax(film)/cm−1 3524 and 2932 (C—H aliph), 2300 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.32 (4H, m, 2×—CH2—), 1.34 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.17 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 5.70 (1H, s, —OH, removed with D2O), 6.58 (1H, ddd, 3J(H,F)=13.3, 3J(H,H)=7.4, 4J(H,F)=4.5 Hz, C3H), 6.74 (1H, ddd, 3J(H,F)=18.3, 3J(H,H) 7.4, 4J(H,F)=4.6 Hz, C4H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.31 (CH3), 22.91 (CH2), 25.78 (CH2), 30.34 (CH2), 31.87 (CH2), 74.90 (CH2), 106.65 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C4), 110.75 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C5), 135.67 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C1), 138.42 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C2), 147.65 (C, dd, 1J(C,F)=239, 4J(C,F)=2.6 Hz, C6), 151.7 (C, dd, 1J(C,F)=248, 4J(C,F)=2.6 Hz, C3); m/z 230 (M+, 10%), 146 (M+-alkoxy chain, 100%), 43 (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3CCCCC3)=NN=2)N=1>>[CH2:17]([C:16]1[N:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:10][C:11]2=[N:14][N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cc1ccccc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(-c2cc3nnc(Cc4ccccc4)n3nc2-c2ccccc2Cl)cc1
Yield: 54.6 %

Procedure:
The title compound (20 mg, 54%) as a white powder was prepared from N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-phenylacetohydrazide (38 mg, 0.085 mmol) and triphenylphosphine dichloride (85 mg, 0.26 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 7B). HPLC/MS (method A): retention time=3.92 min, (M+H)+=431.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc([C@@H](C)O)nc3N21

Procedure:
A solution of 3.09 g (9.27 mmol) (4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 33 mL dichloromethane was cooled to 0 deg C. and treated with 8.8 mL (12.7 g, 0.11 mol) trifluoroacetic acid. The cooling bath was removed and the volatile components were removed at a rotary evaporator. The remaining residue was purified by column chromatography on silica gel (0.032–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1). The remaining oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and extracted with dichloromethane until all product was removed from the aqueous phase. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining light brown oil was purified by column chromatography on a Chiralpak-AD column with 7% ethanol/n-heptane yielding the desired compound as a light brown solid (36.5%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([Cl:11])[CH:20]=[C:19]([Cl:21])[CH:18]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 83.9 %

Procedure:
Reaction of 4-aminoacetophenone (76 mg, 0.56 mmol) in THF (6 mL) with 3,5-dichlorobenzoyl chloride (145 mg, 0.69 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-acetyl-phenyl)-3,5-dichloro-benzamide (145 mg, 0.47 mmol, 84% yield) as a white powder after washing by dichloromethane.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]([N:7]1[N:12]=[CH:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C@@H:33]5[CH2:37][O:36][C@:35]([C:44]6[CH:45]=[CH:46][C:47]([F:51])=[CH:48][C:49]=6[F:50])([CH2:38][N:39]6[N:43]=[CH:42][N:41]=[CH:40]6)[CH2:34]5)=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[C:8]1=[O:9])[C@@H:4]([OH:6])[CH3:5].[CH2:52](O[C@H]([C@H](N1C(=O)N(C2C=CC(N3CCN(C4C=CC(O)=CC=4)CC3)=CC=2)C=N1)CC)C)[C:53]1C=CC=C[CH:54]=1>>[CH2:35]([O:36][CH2:37][C:33]1[CH:32]=[CH:54][CH:53]=[CH:52][CH:34]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH3:1][CH2:2][C@H:3]([N:7]1[N:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][C:28]([O:31][CH2:32][C@@H:33]5[CH2:37][O:36][C@:35]([C:44]6[CH:45]=[CH:46][C:47]([F:51])=[CH:48][C:49]=6[F:50])([CH2:38][N:39]6[N:43]=[CH:42][N:41]=[CH:40]6)[CH2:34]5)=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[C:8]1=[O:9])[C@@H:4]([OH:6])[CH3:5]
Reactant: CC[C@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: CC[C@@H]([C@H](C)O)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
U.S. Pat. No. 5,625,064 discloses a process for the preparation of posaconazole which involves the condensation of 1-((2S,3R)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one with (−)-(5R-cis)-5-(2,4-difluorophenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-3-furanmethylester derivative in the presence of a base to give benzyl ether of posaconazole which is then deprotected either with palladium on carbon in the presence of formic acid or aqueous hydrobromic acid to form posaconazole.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([CH2:12][CH3:13])[CH:4]=[C:5](OCC)[O:6]CC.C([O-])(=O)C.[NH4+:20].C(O)C.C(O)(=O)C>C(OC(=O)C)C>[OH:6][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:12]=[CH:13][N:20]=1
Reactant: [NH4+]
Reactant: CCOC(=CC(CC)C(F)(F)F)OCC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(C(F)(F)F)ccn1

Procedure:
103.5 g (0.35 mol) 3-trifluoromethyl-diethoxypentene acid ethyl ester (mixture of isomers, amount based on GC area-%) and 51.3 g (0.665 mol) ammonium acetate were heated to 150-155° C. over 8 h. A mixture of ethanol, acetic acid and acetic acid ethyl ester (ca. 60 g) was distilled off through a small column (20 cm, filled with 3 mm rings) during this heating period. The sump (79.8 g) can directly be transferred to the next step (yield has been determined only after final methoxylation step).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][NH2:25])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][NH:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(CN)cc12
Solvent: c1ccncc1
Product: CC(CN1C(=O)c2ccccc2C1=O)c1c[nH]c2ccc(CNS(C)(=O)=O)cc12

Procedure:
A stirred solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-methylethyl]-1H-indole-5-methanamine (3.29 g) in dry pyridine (50 ml) cooled in an ice bath was treated with methanesulphonyl chloride (1.64 ml). After 18 h at room temperature the solvent was removed under reduced pressure and the resulting viscous orange oil poured into a mixture of ice and concentrated hydrochloric acid (200 ml) to give a pink solid which was purified by chromatography on kieselgel 60 (200 g) eluted with ethyl acetate/cyclohexanane (1:1) to give the title compound as a yellow foam (0.28 g). This material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-nitro-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (3 g, 9.84 mmol) in CH3OH: DCM (40 mL, v/v=3:1) was added Pd/C (600 mg) and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. TLC showed a complete reaction. The solution was filtered and the resulting filtrate was evaporated to dryness to give the crude product, which used directly in the next step (2.6 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.4, 2.4 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 4.36 (bs, 2H), 4.23-4.19 (m, 2H), 2.81-2.73 (m, 2H), 2.58-2.47 (m, 1H), 1.78-1.73 (m, 2H), 1.61-1.51 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.[Cu]I.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>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)n1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
tert-Butyl (6-iodopyridin-2-yl)carbamate (1.50 g, 4.68 mmol), copper(I) iodide (68.0 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) chloride (100 mg, 0.2 mmol) were stirred in tetrahydrofuran (14 mL) with triethylamine (0.70 mL, 5.0 mmol) under N2 at rt. 3-Ethynylaniline (0.47 mL, 4.5 mmol) was added and the mixture was heated at 60° C. overnight. The mixture was filtered, washed with EtOAc and concentrated under vacuum to give the desired product as a brown solid (1.23 g, 89%). LCMS for C14H12N3O2 ([M-(tBu)+H]+H)+: m/z=254.1.