Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H:2]1[C@:19](O)([C:20](CO)=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:29])[CH2:6]3)[CH2:3]1.I(O)(=O)(=O)=[O:31]>CO.O>[F:29][C@@H:7]1[C:8]2[C@:14]([CH3:28])([CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C@:15]2([F:27])[C@H:5]([C@H:4]3[C@@:18]([CH2:17][C@@H:16]2[OH:26])([CH3:25])[C@@H:19]([C:20]([OH:21])=[O:31])[CH2:2][CH2:3]3)[CH2:6]1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](C[C@H](F)C4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reaction time: 3 h

Procedure:
6α-Fluoro-dexamethasone (2 g) dissolved in methanol (100 ml) was treated with stirring overnight at room temperature with 1.5 g periodic acid in water (25 ml). The mixture was evaporated to small bulk in a rotary evaporator at 50° C. and refrigerated for 3 hours. The acid was collected by filtration and washed 3 times with small volumes of water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([NH:19][CH2:30][CH3:31])[CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(-c2nc(-c3ccc(F)cn3)no2)cc([N+](=O)[O-])c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNc1cc(C#N)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Temperature: 140 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μL, 1.2 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water. (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3:1:4 afforded 6 mg (38%) of 3-(5-fluoroprid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 7.80 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.12 (br, s, 1H), 3.26 (q, 2H), 1.32 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-2′-acetonaphthone. tlc: Rf=0.8 (50% ethyl acetate in hexanes)
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])[NH:27][C:26](=[O:37])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][C:32](=[O:36])[C@@H:33]([OH:35])[CH3:34])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:37])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC(=O)[C@H](C)O)c(F)cc43)c(C)c2C1=O
Yield: 50.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide, as starting materials to give (S)—N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (37 mg, 50.3%) as an orange solid.
Reaction SMILES: C([NH:4][C:5](=[O:11])[CH2:6][S:7][C:8](=[O:10])[CH3:9])(=O)C.[OH-].[Na+].[O:14]1C=[CH:17][CH:16]=[C:15]1C(Cl)=O>CO>[O:14]1[CH:15]=[CH:16][CH:17]=[C:9]1[C:8]([S:7][CH2:6][C:5]([NH2:4])=[O:11])=[O:10]
Reactant: CC(=O)NC(=O)CSC(C)=O
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)CSC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A slurry was prepared from 8.75 g. (0.05 mole) of N-acetyl-2-(acetylthio)acetamide and 100 ml. of methanol at -5° C., and nitrogen was bubbled through the slurry. There was then added 2.0 g. (0.05 mole) of sodium hydroxide in 20 ml. of methanol. The reaction mixture was aged for 1 hour and then concentrated under high vacuum while the temperature was kept below 30° C. Next, 100 ml. of dimethylformamide was added and the reaction mixture was cooled to 0° C. There was then added 7.2 g. (0.055 mole) of 2-furoyl chloride, and the reaction mixture was aged for 3 hours at 0° C., after which it was concentrated under high vacuum. The residue was charged to a silica gel column and eluted with 50% ethylacetate/hexane. The product was recrystallized from toluene and air dried to yield 2.9 g., m.p. 126°-128° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:20]=1)#[N:2].O1CCCC1.Cl.[OH-].[Na+]>O>[NH2:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[CH:20]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Reaction time: 24 h

Procedure:
5.6 G. 3-cyano-8-nitrodibenzo[b,f]thiepin is dissolved in 600 cc. tetrahydrofuran and 27 g. stannous chloride dihydrate in 40 cc. water is added, followed by 100 cc. concentrated hydrochloric acid. The mixture is stirred for 24 hours, poured onto ice, and shaken with 300 cc. 20% sodium hydroxide. The organic layer is separated and the aqueous basic layer shaken once more with tetrahydrofuran. The combined organic extracts are dired and the solvent evaporated to dryness and the residue chromatographed on silica gel and eluted with 20% ethyl acetate in benzene to yield 2.45 g. of the pure amine, m.p. 181°-183° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[C:18](=[O:19])[C:9]2=[CH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[CH:17]=[C:8]2[CH2:7]1.[Br:20]Br.O>ClCCl>[Br:20][C:17]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]2[C:18](=[O:19])[CH:6]([CH3:5])[CH2:7][C:8]=12
Reactant: CC1Cc2cc3c(cc2C1=O)CCCC3
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc3c(c2Br)CCCC3)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 43.0 g (322 mmol) of AlCl3 in 50 ml of dichloromethane, a solution of 26.4 g (132 mmol) of 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one in 25 ml of dichloromethane was added dropwise, while vigorously stirring, over 10 min at 0° C. Then, 6.8 ml (21.1 g, 132 mmol) of bromine was added dropwise over 1 h at this temperature. The resulting mixture was stirred overnight at this temperature and then added to 400 ml of cold water. The organic layer was separated, and the aqueous layer was extracted with 3×150 ml of methyl-tert-butyl ether. The combined organic fractions were washed with aqueous Na2CO3, dried over K2CO3, and evaporated to dryness. Fractional distillation gave the title product, b.p. 165-175° C./1 mm Hg. Yield 19.3 g (53%) of yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])[C:13](B4OC(C)(C)C(C)(C)O4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[CH:46]=[CH:45][C:44]2[CH2:43][CH2:42][N:41]3[C:47]4[CH:48]=[CH:49][CH:50]=[C:51]([F:54])[C:52]=4[CH:53]=[C:40]3[C:39]=2[N:38]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:54][C:51]1[C:52]2[CH:53]=[C:40]3[C:39]4[N:38]=[C:37]([C:13]5[C:12]([N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:11][C:10]6[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]7[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=7)[N:9]=6)[CH:14]=5)[CH:46]=[CH:45][C:44]=4[CH2:43][CH2:42][N:41]3[C:47]=2[CH:48]=[CH:49][CH:50]=1
Reactant: CNC(=O)c1c2cc(B3OC(C)(C)C(C)(C)O3)c(N(C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c2cc(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)c(N(C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxamide (70 mg, 0.14 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (46 mg, 0.17 mmol) and K3PO4.3H2O (112 mg, 0.42 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (13 mg, 0.014 mmol) and X-Phos (14 mg, 0.028 mmol) under N2. The reaction mixture was heated to 100° C. and stirred for 3 hours, and then filtered through a celite pad. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC to give the desired product (20 mg, yield: 24%). 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.83 (s, 1H), 7.55˜7.60 (m, 1H), 7.52˜7.54 (m, 2H), 7.45 (s, 1H), 7.09˜7.19 (m, 5H), 6.73 (s, 1H), 6.30 (s, 1H), 6.20 (s, 1H), 4.28 (t, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.25 (t, J=6.0 Hz, 2H), 2.92 (d, J=4.8 Hz, 3H), 2.76 (s, 3H). MS (M+H)+: 613.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:19]=2)[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[NH:22][N:21]=[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[N:19]=2)[CH2:13]1
Reactant: COc1cccc(F)c1C=O
Reactant: c1cc(-c2n[nH]c3ccc(-c4n[nH]c([C@@H]5CCCNC5)n4)cc23)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(F)c1CN1CCC[C@@H](c2nc(-c3ccc4[nH]nc(-c5ccncc5)c4c3)n[nH]2)C1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
Added 2-Fluoro-6-methoxy benzaldehyde (69 mg, 0.44 mmol) to a mixture of (R)-5-(5-(piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole (96 mg, 0.277 mmol) and sodium triacetoxy borohydride (176 mg, 0.833 mmol) in MeOH (8 ml) at room temperature. After stirred for 30 minutes, the solvent was evaporated. Diluted with EtOAc (150 ml), washed with H2O (50 ml), dried (Na2SO4) and concentrated. Crude product was purified on silica gel eluting with 5% v/v MeOH/CH2Cl2 to yield (R)-5-(5-(1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole as a white solid (54 mg).
Reaction SMILES: C1([C@@H](N[C:10](=[O:39])[CH2:11][C@H:12]([OH:38])[CH2:13][C@H:14]([OH:37])/[CH:15]=[CH:16]/[C:17]2[C:18]([CH:34]3[CH2:36][CH2:35]3)=[N:19][C:20]3[C:25]([C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)C)C=CC=CC=1.[OH2:40].[OH-].[Na+].Cl>C(O)C>[CH:34]1([C:18]2[C:17](/[CH:16]=[CH:15]/[C@@H:14]([OH:37])[CH2:13][C@@H:12]([OH:38])[CH2:11][C:10]([OH:39])=[O:40])=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:36][CH2:35]1
Reactant: C[C@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 52.5 °C
Reaction time: 0.25 h

Procedure:
(E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide (4.0 g, 6.53 mmol) is dissolved in ethanol (40 mL). Water (40 mL) and sodium hydroxide powder (2.64 g, 66 mmol) are added and the mixture is heated at 50-55° C. for 26 h, until an in-process control (HPLC) indicated complete conversion. Hydrochloric acid (59 mL of a 1M solution, 59 mmol) is added slowly over a time period of 15 minutes. The solvent is distilled under reduced pressure and the residue is dissolved in water (80 mL). The water solution is extracted with tert-butyl-methyl ether (3×80 mL) and the organic phase is removed. The water phase is evaporated under reduced pressure and the residue is re-dissolved in water (176 mL). Hydrochloric acid (6.53 mL of a 1M solution, 6.53 mmol) is added to precipitate the acid, followed by the addition of ethyl acetate (176 mL). The mixture is stirred for 15 min. and the layers are separated. The organic layer is washed with water (90 mL). Charcoal (0.5 g) is added to the organic layer and the mixture is stirred at 30-35° C. for several hours. Filter-aid (Cellflock, 1.0 g) is added and stirring is continued for additional 30 min. The charcoal is removed by filtration on a filter-aid to obtain a clear solution and the solvent is evaporated at 30-35° C. under reduced pressure, to obtain (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid as a white solid. For the formation of the calcium salt, the acid (2.55 g, 6.05 mmol) is suspended in water (40.5 mL) and sodium hydroxide (0.260 g, 6.5 mmol) is added to obtain a clear solution of the corresponding sodium salt. A solution of calcium chloride (0.399 g, 3.49 mmol) in water (2 mL) is added dropwise to the solution of the sodium salt. A suspension is formed immediately upon addition of calcium chloride. The suspension is stirred for 4 hours at 20-25° C. and for 2 hours at 15-17° C. The product is isolated by filtration, the filter cake is washed with cold water and dried in vacuo at 20-25° C. to obtain
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([OH:17])=O)=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([CH3:14])[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([NH:22][C:15]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:14])=[N:12]2)=[CH:7][CH:6]=1)=[O:17])([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)N
Reactant: Cc1ccc2ccc(C(=O)O)c(C3CC3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(C(=O)NC(C)(C)C)c(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 8-cyclopropyl-2-methylquinoline-7-carboxylic acid (0.050 g, 0.220 mmol) and 2-methylpropan-2-amine (0.116 mL, 1.10 mmol) in DMF (1 mL) was added HATU (0.125 g, 0.33 mmol) at ambient temperature and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified directly by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 25 column volumes) to give N-tert-butyl-8-cyclopropyl-2-methylquinoline-7-carboxamide (0.033 g, 53.1%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
A mixture of 4-(3-chloromethylphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.10 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate as colorless crystals (2.78 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11]([NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:15]([O-])([O-])OCC>>[Cl:1][CH2:2][C:3]1[N:12]2[CH:15]=[N:14][N:13]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: NNc1nc(CCl)nc2ccccc12
Reactant: CCOC([O-])[O-]
Product: ClCc1nc2ccccc2c2nncn12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
3.1. 88 g of 2-(chloromethyl)-4-hydrazinoquinazoline are suspended in 1.2 l of ethyl orthoformate. The suspension is heated (bath temp. 125° C.) while stirring and the resulting ethanol is distilled off. After 1 h., the mixture is cooled to 15° C., the precipitate is filtered off and washed with 100 ml of diethyl ether. The product is dried in a vacuum. 80 g of crude 5-(chloromethyl)-1,2,4-triazolo [4,3-c]quinazoline are obtained. The filtrate is concentrated in a vacuum and the residue is boiled in 20 ml of ethanol. The mixture is cooled to 0° C., filtered, the filter cake is washed with diethyl ether and the crystals are dried in a vacuum. A second portion of 5.3 g of crude 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline is obtained. The two crude crystallizates (together 85.3 g) are stirred in 8.5 ml of dioxan at 85° C. for 1 h. The insoluble constituent is filtered off and the filtrate is concentrated to about 300 ml in a vacuum. The suspension is cooled, filtered and the filter cake is washed with 100 ml of diethyl ether. 66 g of 5-(chloromethyl)-1,2,4-triazolo [4,3-c]quinazoline of m.p. 189° C. (dec.) are obtained. A second portion of 2.5 g of 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline is obtained after concentration of the filtrate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]1([C:12]2[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:15]1[CH:16]=[CH:17][C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)(=[O:4])[C:2]#[CH:3]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 0.1 %

Procedure:
To an ice cooled and stirred solution of propargylic acid (285 mg, 4.01 mmol) and 4-phenylphenol (693 mg, 4.07 mmol) in dry diethyl ether was added dropwise a solution of N,N′-dicyclohexylcarbodiimide (DCC, 840 mg, 4.07 mmol) and 4-dimethylaminopyridine (DMAP, 3.2 mg, 0.03 mmol) in dry diethyl ether (10 mL) during 2 h under nitrogen atmosphere. Reaction mixture was then stirred at room temperature for 10 h, filtered and the solid was washed with diethyl ether. Then, the combined filtrate was washed with 1 N HCl solution followed by washing with brine and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product that was then purified by column chromatography using ethyl acetate:hexane (1:9) as an eluant to give compound 1 (0.81 mg, 90%). 1H NMR (400 MHz, CDCl3): δ 3.12 (s, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.38 (s, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.57 (s, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 7.64 (s, 1H). HRMS ESI (m/z): Calculated for C15H10O2 ([M+H]+): 223.0681. found: 223.0734.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1.[Cl:15]C1C=C(Cl)C=CC=1C=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:15])[CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: Cc1cccc(-c2ccccc2Cl)n1
Product: Cc1cccc(-c2ccc(Cl)cc2Cl)n1

Procedure:
6-(2,4-dichlorophenyl)-2-methylpyridine was prepared substantially according to the procedures of Example 1 for preparing 6-(2-chlorophenyl)-2-methylpyridine except 2,4-dichlorobenzaldehyde was used to afford 6-(2,4-dichlorophenyl)-2-methylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[Cl:24]CCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)O)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a suspension of 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylic acid (15c) (0.36 g, 1.04 mmol) in dichloromethane (4 ml) oxalyl chloride (0.27 ml, 3.12 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.37 g, 97%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][N:15]([CH3:21])[C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(OCC)(=O)C>C1COCC1>[CH3:14][N:15]([CH3:21])[CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Yield: 47.5 %

Procedure:
Suspend 2-chloro-6-nitrobenzthiazole (8.49 g, 39.6 mmol) in THF (100 mL). Slowly add (3R)-(+)-3-(dimethylamino)pyrrolidine (5.24 g, 45.9 mmol). Stir the reaction overnight at room temperature. Dilute the reaction with ethyl acetate and then wash with water and brine. Concentrate the organic portion in vacuo, and triturate the resulting residue with MeOH to afford the title compound (4.94 g, 43%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, 1H, J=2.2 Hz), 8.14 (dd, 1H, J=9.0, 2.4 Hz), 7.52 (d, 1H, J=8.8 Hz), 4.00-3.43 (m, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.20-2.15 (m, 7H), 1.93 (m, 1H).