Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.CC1(C)C(C)(C)OB([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:39][CH:38]=2)O1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:41][CH:42]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 22.7 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.250 g, 0.56 mmol) was reacted with methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.160 g, 0.56 mmol) to afford the title compound (0.058 g, 22%) as a white solid. MW=456.9. 1H NMR (CDCl3, 500 MHz) δ 8.28 (t, J=1.2 Hz, 1H), 8.30-8.26 (m, 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 4.60 (s, 2H), 3.67 (s, 3H), 3.60 (s, 2H), 3.50-3.45 (m, 2H), 3.18 (t, J=6.5 Hz, 2H), 2.54-2.48 (m, 2H); APCI MS m/z 457 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]1[C:20]2[C@:15]([CH3:22])([CH:16]=[CH:17][C:18](=[O:21])[CH:19]=2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1.S(Cl)([Cl:29])(=O)=O>N1C=CC=CC=1>[Cl:29][C:19]1[C:18](=[O:21])[CH:17]=[CH:16][C@@:15]2([CH3:22])[C:20]=1[C@@H:3]([C:2]([F:24])([F:25])[F:1])[CH2:4][C@@H:5]1[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]1[CH2:7][CH2:8][C:9]2=[O:23]
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](C(F)(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C(Cl)=C1[C@@H](C(F)(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 6α-trifluoromethyl-androsta-1,4-diene-3,17-dione (3.524 g, 10 mmol) in pyridine (35 ml) was added dropwise sulfurylchloride (2.699 g, 20 mmol) at about +5° C. in 20 min. The reaction mixture was stirred further 1 h at +5° C. and then poured onto water. The precipitate was filtered off and the residue purified by trituration in ethylacetate and dichloromethane. Thus almost pure title compound was obtained in about 60% yield (2.32 g).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])O.[Na+]>>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:2]2[C:11]3[N:12]=[C:13]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:14]([CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)[C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCN(c2nc3ccccc3c3c2nc(-c2ccccc2)n3CCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 0.80 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 1 ml of N-methylpiperazine was stirred at 80° C. for 6 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was dried, and the solvent was evaporated. The residue was purified by alumina column chromatography using ethyl acetate—n-heptane (1:3 to 1:1) as eluting solvents, and washed with a mixture of diisopropyl ether and n-heptane to give 0.74 g of colorless crystals. Recrystallization from ethyl acetate gave colorless needles having the melting point of from 140 to 141° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C:15](=[CH2:16])[C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH:18]=2)[C@H:13]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:11]1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:57][Zn]C.ICI.[NH4+].[Cl-]>C1(C)C=CC=CC=1.O>[CH2:50]([O:49][C@H:11]1[C@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH:18]=2)[C:15]2([CH2:57][CH2:16]2)[C@@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C=C1[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1c1ccc(Cl)c(Cc2ccc(CC)cc2)c1
Reactant: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ICI
Product: CCc1ccc(Cc2cc([C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)C34CC4)ccc2Cl)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a vigorously stirred solution of ((1S,2R,3R,4R,6S)-4-(benzyloxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)-5-methylenecyclohexane-1,2,3-triyl)tris(oxy)tris(methylene)-tribenzene (34, 25 mg, 32.7 μmol) in anhydrous toluene (2 mL) under nitrogen at −10° C. was added 2M solution of dimethyl zinc (146 μL, 291 μmol) dropwise and stirred for 15 minutes. Diiodomethane (47 μL, 583 μmol) was added drop-wise and the resulting mixture was stirred over night. 40% product fonnation was observed. More dimethyl zinc (18 more equivalent in two batches over 48 hour period) and diiodomethane (35 equivalent in two batches over 48 hour period) were added and the reaction was 80% complete after 96 hours of reaction. Saturated solution of NH4Cl (1 mL) was added and the mixture was stirred for 30 minutes. The mixture was diluted with water (1 mL) and extracted into ethyl acetate (3×1 mL). The combined organic extracts were washed with 10% sulfuric acid (1.5 mL), saturated NaHCO3 (1.5 mL) and brine (1.5 mL), dried (Na2SO4), filtered and evaporated. Preparative TLC (9:1 hexane:ethyl acetate) afforded 85% compound 36 which was used directly in the next reaction.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>CO>[N+:6]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]([O:18][CH3:1])=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Trimethylsilyl chloride (5.6 mL, 2.0 equiv.) was added to a stirred solution of (3-nitrophenyl)acetic acid (4.0 g) in methanol (60 ml). The resulting solution was stirred at room temperature for 18 hours, then concentrated at reduced pressure and partitioned between DCM and aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound as a colourless liquid (4.2 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[C:9]([CH3:15])[C:8]=2[C:16]=1[O:17][CH3:18])(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:16]([O:17][CH3:18])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]
Reactant: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To 75 mg (0.3 mmol) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 1 mL of oxalyl chloride and the mixture was refluxed for 2.5 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 163 mg (0.46 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 54 mg (31% yield) of (S)-2-{4′-[(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14].Cl.Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH2:37])[CH2:33][N:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH:37][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:2]=1[F:1])=[O:14])[CH2:33][N:34]([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C=NCCCCCCOCc1cccc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)NCCCCCCOCc1cccc(F)c1F
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A solution of [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (224 mg, 0.83 mmol) in dichloromethane (1 mL) was added at 0° C. to a suspension of (R)-3-amino-4-dimethylamino butyric acid benzyl ester dihydrochloride (255 mg, 0.83 mmol) in dichloromethane (4 mL), then a solution of triethylamine (167 mg, 1.65 mmol) in dichloromethane (1 mL) was added dropwise over 25 min. The reaction mixture was kept at <5° C. for 1 h, then allowed to reach room temperature over 1 h. Insoluble material was removed by filtration and the filtrate evaporated. The residue was purified by preparative HPLC to afford (R)-3-{3-[6-(2,3-difluoro-benzyloxy)-hexyl]-ureido}-4-dimethylamino-butyric acid benzyl ester (56 mg, 13%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]([O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:11]=1)([CH3:8])[CH3:7].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C:10]([O:9][CH:6]([CH3:7])[CH3:8])=[N:11][C:12]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:13]2)=[O:22])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Diethylamine (14 ul) and triethylamine (17 ul) in CH2Cl2 (5 ml) was added to 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid (33 mg), HOBt (18 mg), EDCI (25 mg) at 0° C. in order. The mixture was stirred at room temperature for 3 hrs and washed with 8% NaOH, water and brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by preparative LC-MS to give 31 mg of product as yellow solid. (80% yield). LC-MS: m/e 382 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]2[C@H:6]([O:17]2)[C@@H:7]1[OH:8]
Reactant: OC[C@@H]1CC=C[C@@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H]2O[C@@H]2[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
(1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) was dissolved in DCM (143 mL) and the solution was cooled to 0° C. 3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixture was stirred at 23° C. for 4 h. TLC indicated complete conversion. Silica gel (20 g) was added, the mixture was concentrated to dryness and was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to afford the title compound (2.75 g, 76%). 1H NMR (CDCl3, 300 MHz) δ: 4.58 (d, J=8.1 Hz, 1H), 3.69 (s, 1H), 3.68 (s, 1H), 3.60 (s, 1H), 3.52 (s, 1H), 2.47-2.40 (m, 1H), 2.14 (ddd, J=1.5, 10.2, 15.3 Hz, 1H), 2.01 (dd, J=1.5, 15.3 Hz, 1H), 1.62 (bs, 2H) ppm. LC/MS: Rt=0.37 min, ES+ 131 (AA standard).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]1([F:29])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](Cl)=[O:27])[C:19]=2[O:18]1>>[F:29][C:17]1([F:16])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([NH:15][C:13]3[N:14]=[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:3]5[CH:4]=[CH:5][O:1][CH:2]=5)[N:11]4[N:12]=3)=[O:27])[C:19]=2[O:18]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1cccc2c1OC(F)(F)O2
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1cccc2c1OC(F)(F)O2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (Alpha, 66 mg; 0.3 mmol; 1.2 eq.) as a white powder (75.2 mg, 78%). HPLC, Rt: 4.01 min. (purity 97.4%). LC/MS, M+(ESI): 385.3, M−(ESI): 383.3.
Reaction SMILES: [F:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([F:6])[C:3](O)=[O:4].FC1C=CC(Br)=CC=1.S(Cl)(Cl)=O.CN(C)C=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>O.C(Cl)Cl.N1C=CC=CC=1>[CH3:35][O:34][N:33]([CH3:32])[C:3](=[O:4])[C:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([F:6])[F:1]
Reactant: O=C(O)C(F)(F)c1ccc(F)cc1
Reactant: CNOC
Agent: Cl
Agent: Fc1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C(F)(F)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
alpha,alpha-Difluoro-4-fluorophenylacetic acid [1.0 g, prepared from 4-fluorobromobenzene according to the method of Middleton and Bingham, J. Org. Chem., 45, 2883 (1980)] was stirred under nitrogen with thionyl chloride (0.69 g) and dry N,N-dimethylformamide (0.036 g) at room temperature for 15 minutes and then at 70°-75° C. for one hour. The solution was cooled in ice and N,O-dimethylhydroxylamine hydrochloride (0.62 g), dry pyridine (1.5 g) and methylene chloride (15 ml) were added and the mixture stirred at 0° C. for 20 minutes and at room temperature for a further 30 minutes. Water (10 ml) was added and the methylene chloride layer separated. The aqueous phase was extracted with methylene chloride (2×20 ml) and the combined organic extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica, eluting with methylene chloride to give N-methoxy-N-methyl-alpha,alpha-difluoro-4-fluorophenyl acetamide (1.13 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pt](=O)=O>[N:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCOCC2)nc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: C1CCC(CN2CCOCC2)NC1
Yield: 52.2 %

Procedure:
First, 2-[(4-morpholinyl)methyl]pyridine (94.0 g, 0.53 mol) is dissolved in glacial acetic acid (600 ml) and hydrogenated in the presence of platinum(IV) oxide (10.0 g) as catalyst for 2 hours at a hydrogen pressure of 3 bar and a temperature of 50° C. After cooling, the catalyst is filtered off, the filtrate is freed from solvent and the residue is distilled in vacuo. The desired compound (51.0 g) is obtained in the form of a colorless liquid, boiling point 4 mm Hg 91°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: Fc1ccc(-c2noc(C(F)(F)F)c2-c2cn(-c3ccc(C(F)(F)F)cc3)cn2)cc1
Yield: 34 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone, was converted to the title compound (50 mg, 34%) which was obtained as a white solid. MS: m/e=442.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1.Br/[C:13](=[CH:19]\[C:20]([F:23])([F:22])[F:21])/[C:14]([O:16]CC)=[O:15].IF.[Cl-].[In+3].[Cl-].[Cl-].C(=O)([O-])O.[K+].[Li+].[OH-].Cl>C(OCC)(=O)C.CCO>[CH3:10][C:6]1[N:5]=[C:4]([C:3]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:13]([C:14]([OH:16])=[O:15])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(C(Cl)=NO)n1
Reactant: CCOC(=O)/C(Br)=C/C(F)(F)F
Agent: Cl
Agent: FI
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(-c2noc(C(=O)O)c2C(F)(F)F)n1
Reaction time: 1 h

Procedure:
To a mixture of N-hydroxy-6-methylpicolinimidoyl chloride (2.5 g, 14.65 mmol) and (Z)-ethyl 2-bromo-4,4,4-trifluorobut-2-enoate, Int-I-F (3 g, 12.15 mmol) in ethyl acetate (40 mL) was added indium(III) chloride (0.559 g, 2.53 mmol). After 1 hour, potassium hydrogen carbonate (2.022 g, 20.20 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting material was purified on a silica gel cartridge using an EtOAc/hexanes gradient. The fraction with desired mass was isolated and checked by NMR. The product was found to be contaminated with dimerization product of the starting bromoolefin. This material was hydrolyzed using 1N LiOH (2eq) in EtOH for 1 hour. The pH was adjusted to 6-7 with concentrated HCl. The resulting material was extract with EtOAc 4 times and then extracts were combined, dried, and concentrated to yield 360 mg of 3-(6-methylpyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid. MS (m+1)=273. HPLC Peak RT=1.66 minutes (Analytical Method B).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[N:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[OH:12][N:11]=[C:10]([Cl:13])[C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=C[C@@H]1C[C@H]1c1ccccc1
Solvent: CN(C)C=O
Product: ON=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the crude trans-2-phenylcyclopropanecarbaldehyde oxime rac-I-6C (04 g, 2.51 mmol) in DMF (5 mL) and cooled at 0°C. N-chlorosuccinimide (0.37 g, 2.7 mmol) was added portionwise. The reaction mixture was slowly warmed to rt and stirred fo(14 h. The reaction was quenched with saturated NaCl (aq.) and extracted with Et2O. The organics were collected, washed with water, brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude was purified by column chromatography on silica gel with hexane-EtOAc (5 to 20% gradient as eluant) to yield trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride.
Reaction SMILES: NC(CCCCCCCCC(N)C(C)C)C(C)C.[CH3:19][CH2:20][CH:21]([CH:26]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([CH:38]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40])[NH:28][NH:27]1)[CH2:22][CH2:23][CH2:24][CH3:25]>>[NH2:27][CH:26]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([NH2:28])[CH:38]([CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])[CH:21]([CH2:20][CH3:19])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(CC)C1CCCCCCCCC(C(CC)CCCC)NN1
Agent: CC(C)C(N)CCCCCCCCC(N)C(C)C
Product: CCCCC(CC)C(N)CCCCCCCCC(N)C(CC)CCCC

Procedure:
The procedure described in (a) is repeated, starting from 74.8 g (0.2 mole) of 3,12-di-(3-heptyl)-1,2-diazacyclododecane (diastereoisomer mixture) and using correspondingly reduced amounts of catalyst and solvent, affording after purification by chromatography and distillation 29.9 g (40% of theory) of 6,15-diamino-5,16-diethyleicosane as a colourless oil [b.p. 170° C./0.01 torr; nD20 =1.4662; IR spectrum (liquid) includes bands at 3278, 1613 cm-1 ]. The 1,2-diaza-1,5,9-cyclododecatrienes and 1,2-diazacyclododecanes used as starting materials can be prepared by the methods described in German Offenlegungsschrift Nos. 2,330,087 and 2,549,403.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([NH:15][S:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)(=[O:13])=[O:12])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cccc4cccnc34)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 101.3 %

Procedure:
8-Quinoline sulfonyl chloride (0.172 g, 0.76 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.76 mmol). Using other reagents and reaction conditions as mentioned in Example 1(c) afforded 0.4 g of the required product. 1H NMR (DMSO-d6): δ 6.92 (1H, d), 7.11 (1H, d), 7.18 (2H, d), 7.25 (1H, d), 7.51 (2H, d), 7.56 (1H, dd), 7.66 (1H, t), 7.74 (2H, d), 7.80 (2H, m), 7.98 (1H, d), 8.20 (2H, m), 8.38 (1H, d).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][N:10]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
Sodium hydride (0.108 g, 4.50 mmol) was added to a stirred solution of 6-bromo-1H-indazole-4-carbonitrile (0.5 g, 2.252 mmol) in N,N-dimethylformamide (10 ml) at room temperature. The mixture was stirred at room temperature for 10 mins when p-toluenesulphonyl chloride (0.558 g, 2.93 mmol) was then added. The pale yellow suspension was stirred for 20 mins at room temperature. The mixture was poured into stirring water (100 ml) and the precipitated product collected by filtration. The cream coloured solid was dried in vacuo at 65° C. to give the title compound (0.794 g).