Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[C:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7](C)[CH:6]=[CH:5][C:4]=1O.[OH2:18].[CH3:19][Si](C)(C)[Cl:21]>C(C(C)=O)C>[ClH:21].[CH3:17][N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1([CH3:19])[C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][CH:14]=1
Reactant: O
Reactant: Cc1ccc(O)c(N(C)C)c1C1CCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCC(C)=O
Product: CN(C)C1CCCCC1(C)c1cccc(O)c1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In order to prepare the hydrochloride salt, 42 g of the base 3-[2-(dimethylamino)methyl(cyclohex-1-yl)phenol were added to 210 ml methyl ethyl ketone. Subsequently 2 ml water and 23 ml trimethylchlorosilane, dissolved in 45 ml methyl ethyl ketone, were added. The reaction mixture was cooled down to 0° C. by cooling with ice and was kept cold overnight (in a refrigerator at about 4° C.). The solid substance that precipitated out was filtered out by suction using a suction filter, with application of a vacuum, and then washed with 30 ml of acetone. The yield of 3-[2-(dimethylamino)methyl(cyclohex-1-yl)]phenol hydrochloride was 49 g (corresponding to 100% of the theoretical value). According to NMR and GC analyses, the produce was >95% trans diastereomer. The melting-point was 122-126° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(F)c3)ccn2c1=O
Yield: 80.4 %

Procedure:
Methyl 1-cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-phenyl-boronic acid (71 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (96 mg, 77%). ESI-MS m/z: 352 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: COC(=O)COc1ccc(O)cn1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a mixture of 0.5 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.80 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-y]nitrobenzene and 5 ml of N,N-dimethylformamide was added 0.35 g of potassium carbonate, and the mixture was stirred for 1.5 hours at 50° C. The solution was cooled to room temperature, poured into a mixture of water, hydrochloric acid and saline, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol (1.0 g, 5.6 mmol), 1-(2-bromoethoxy)-4-chlorobenzene (1.19 g, 5.1 mmol), potassium carbonate (1.75 g, 12.6 mmol), and anhydrous N,N-dimethylformamide (6 mL) was added to a 20 mL scintillation vial with a magnetic stirring bar. The vial was capped loosely and the mixture allowed to stir at room temperature for 30 minutes. Progress of the reaction was monitored by analytical HPLC with UV detection (Rt=8.28 min). The mixture contained solids starting at 30 minutes and was stopped stirring at 1 hour. The mixture was transferred into an Erlenmeyer flask with a total of 70 mL of water, and allowed to stir for 10 min. The resulting solid was isolated by filtration, rinsed with 100 mL of water, and allowed to dry under reduced pressure. The off-white powder was >90% pure by analytical HPLC with UV detection at 215 nm. The solid was dissolved in 25 mL of ethanol with gentle warming, diluted with 5 mL of water and allowed to cool. The fine white needles that formed were isolated by filtration, washed with 20 mL of cold ethanol, and dried to afford the title compound (1.43 g, 85% yield). EM (calc.): 334.1; MS (ESI) m/e: 335.1 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (d, 2H), 7.12 (s, 1H), 7.03 (d, 2H), 4.33 (t, 2H), 3.60 (t, 2H), 2.68 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(#N)C>[NH:30]1[C:29]([NH:28][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[N:33][N:32]=[N:31]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccco1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nnn[nH]1)c1ccco1
Yield: 61.5 %

Procedure:
Following the procedure described in Example 120, 2-furancarboxylic acid (5.00 g, 44.46 mmol) is treated with 1,1'-carbonyl diimidazole (8.31 g, 51.25 mmol, 1.15 equiv), triethylamine (10.9 g, 107.6 mmol, 2.4 equiv) and 5-aminotetrazole (4.51 g, 53.02 mmol, 1.19 equiv) in refluxing (17 hours) acetonitrile (250 mL) to give the crude carbamoyl product. Recrystallization from N,N-dimethyl formamide/water afforded 4.90 g (7.96 g theo., 62%) of N-1H-tetrazol-5-yl-2-furancarboxamide as a white solid; mp 280°-283° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2ccnc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(2-methylpyrimidin-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:25][N:24]([CH3:26])[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:4]=2)=[CH:17][CH:18]=1)=[O:27]
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (384 mg) was dissolved in DCM (12 mL) and triethylamine (0.216 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.121 mL) and the reaction was stirred for 15 minutes at RT before being concentrated in vacuo to give the desired material.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][Cl:21])=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OCCCl
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)OCCCl

Procedure:
A mixture of 2-nitrobenzaldehyde (4.536 g), 2-chloroethyl acetoacetate (4.94 g) and piperidine (110 mg) in benzene (18 ml) and acetic acid (360 mg) was refluxed for an hour under azeotropic dehydration. The reaction mixture was washed with water and dried. The solvent was distilled off to give an reddish oil of 2-chloroethyl 2-(2-nitrobenzylidene)acetoacetate, and thus obtained oil was treated with ethyl 3-amino-4,4-diethoxycrotonate (7.1 g) to give yellow granules of 2-chloroethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 82° to 84° C. (recrystallized from diisopropyl ether).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(N(CC)CC)C>C(Cl)Cl>[N:17]1([CH2:16][CH2:15][CH2:14][NH:13][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCCCn1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A solution of 4-nitrobenzoyl chloride (18.5 g, 0.1 mol) in DCM (200 ml) was added dropwise to a stirred solution of 1-(3-aminopropyl)imidazole (14.0 g, 0.112 mol) and triethylamine (15 ml, 0.107 mol) in DCM (200 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour, and the solid which had separated out was collected by filtration and washed with water (100 ml) and acetone (100 ml) to give the product (21.6 g, 79%). NMR: 1.9-2.0 (m, 2H), 3.2-3.3 (m, 2H), 4.0 (t, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.65 (s, 1H), 8.05 (d, 2H), 8.3 (d, 2H), 8.8 (br s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH2:7]([NH2:10])[C:8]#[CH:9]>C1COCC1>[CH2:7]([N:10]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[C:8]#[CH:9]
Reactant: C#CCN
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: C#CCN1CCNC1=O
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Chloroethyl isocyanate (12.2 g, 0.11 mol) was added at 0° C. to a stirred solution of propargylamine (6.6 g, 0.12 mol) in THF (200 mL). The solution was allowed to warm to room temperature and sodium hydride (5.5 g of 50% in oil, washed with ether to remove the oil) was added. The reaction was quenched with acetic acid (6.0 mL), the THF was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate was evaporated and the residual solid was crystallized from ethyl acetate; Skellysolve B to give 11.1 g of 1-(2-propynyl)-2-imidazolidinone, m.p. 110°-115° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O.Br[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]([F:56])([F:57])[O:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:48][CH:49]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(OC(F)(F)F)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-4-(trifluoromethoxy)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (50%) as a white solid: mp 99-101° C.; MS (ES+) m/z 456.3 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:15]([OH:22])[C:16]([O:18]C(C)C)=[O:17])[C:9]([O:11]C(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([C@H:8]([C@H:15]([OH:22])[C:16]([OH:18])=[O:17])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)[C@@H](Cc1ccccc1)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 48 h
Yield: 29.3 %

Procedure:
Diisopropyl (2S,3R)-2-benzyl-3-hydroxysuccinate (9.76 g; 31.65 mmol; 1.00 eq.) was taken in THF (150 mL), cooled to 0° C. and was treated with KOH (10.65 g; 189.90 mmol; 6.00 eq.) in water (50 mL). The resulting mixture was stirred at RT for 48 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was chilled to 0° C. and cautiously acidified with an aqueous solution of HCl (1 N) until pH 3.8. The solid that separated was collected by filtration to give the title product (single diastereoisomer) as white solid (2.08 g, 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.[CH3:14][I:15]>O1CCOCC1>[I-:15].[CH3:13][N+:2]([CH3:14])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1
Reactant: COc1ccc(CN(C)C)cc1O
Reactant: CI
Solvent: C1COCCO1
Product: COc1ccc(C[N+](C)(C)C)cc1O
Product: [I-]
Yield: 81 %

Procedure:
To a dioxane solution (250 ml) of the dimethyl(3-hydroxy-4-methoxybenzyl)amine thus obtained (16 g, 88.5 mmol) was added methyl iodide (8.26 ml, 132 mmol) and the resulting mixture was refluxed for 4 h. The solid formed was filtered and washed with dioxane to yield 23 g (81%) of the trimethyl(3-hydroxy-4-methoxybenzyl) ammonium iodide salt. This latter was suspended in 100 ml xylene, triethyl phosphite (18 ml, 107 mmol) was added and the resulting mixture was refluxed for 16 h. The solid formed was filtered and the solvent and excess of phosphite were evaporated under vacuum to give after short path distillation diethyl (3-hydroxy-4-methoxybenzyl)phosphonate as a viscous oil (4 g, 10%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([N:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13].C1(NC2CCCCC2)CCCCC1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1>ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:36])(=[O:3])=[O:2].[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N+:14]([CH2:12][CH3:13])([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(C)c1ccccc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC[N+](C)(Cc1ccc(OC)cc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
19.07 g (0.1 mol) of tosyl chloride, 13.5 g (0.1 mol) of N-ethyl-N-methylaniline and 27.20 g (0.15 mol) of dicyclohexylamine were dissolved in 60 g of dichloromethane, and, after cooling to 5° C., there was added 13.81 g (0.1 mol) of 4-methoxybenzylalcohol. While suppressing excessive elevation of the temperature, the reaction was allowed for 6 hours. After the completion of the reaction, the mixture was concentrated, and the precipitated white solid was washed with ether and dried to give N-(4-methoxybenzyl)-N-ethyl-N-methyl-anilinium tosylate. Yield: 50%.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: NO
Reactant: C=CCN(CC(=O)c1cccnc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC(=NO)c1cccnc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 91.8 %

Procedure:
tert-Butyl N-allyl-N-[2-oxo-2-(3-pyridyl)ethyl]carbamate (31.34 g 113.41 mmol) is dissolved in ethanol (110 mL) with stirring under nitrogen. Hydroxylamine hydrochloride (18.31 g, 260.85 mmol) and pyridine (12.84 mL, 158.78 mmol) are added. The resulting solution is heated at 80° C. under nitrogen for 2 hours and then is cooled to room temperature. The solvents are partially evaporated and the resulting residue is then partitioned between 2 M sodium hydroxide (150 ml) and dichloromethane (500 mL). The phases are separated and the aqueous phase is re-extracted with dichloromethane (2×250 mL). The organic extracts are combined and evaporated under reduced pressure. The crude product is purified by silica gel column chromatography using a gradient of 0-10% 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (30.34 g, 91.82%) as a mixture of E/Z isomers. ES/MS (m/e) M+1=292.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:26])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[O:26])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A suspension of [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (3.3 g, 8.77 mmol) in ethanol (40 mL) was treated with aq 2 N NaOH (24 mL, 47.8 mmol). After stirring for 4 h, the solution was concentrated in vacuo until most of the ethanol was removed, and the mixture was acidified to pH of 1 with 2 N HCl. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO4 and concentrated to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid as an off-white solid (3.00 g, 98%): mp 148–151° C.; Rf 0.39 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 9.20 (t, J=6.3 Hz, 1 H) 8.18 (s, 1 H), 8.09 (dd, J1=7.2 Hz, J2=2.7 Hz, 1 H), 7.90 (dd, J1=8.7 Hz, J2=7.0 Hz, 1 H), 7.79 (d, J=7.5 Hz, 1 H), 7.61 (t, J=7.8 Hz, 1 H), 7.08 (dd, J1=10.8 Hz, J2=2.1 Hz, 1 H), 6.91 (dt, J1=8.7 Hz, J2=2.4 Hz, 1 H), 4.89 (s, 2 H), 4.62 (d, J=6 Hz, 2 H). ESI-LC/MS m/z calcd for C16H13FN2O6: 348.3; Found 347.0 (M−1)−. Anal. calcd for C16H13FN2O6: C, 55.18; H, 3.76; N, 8.04. Found C, 55.02; H, 3.79; N, 7.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[CH:5][C:6]([CH2:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:26][NH:25][C:20](=[NH:21])[CH2:19][N:16]1[C:17]([CH3:18])=[C:13]([CH2:12][C:6]2[CH:5]=[C:4]([CH3:23])[C:3]([O:2][CH3:1])=[C:11]3[C:7]=2[CH2:8][CH2:9][CH2:10]3)[C:14]([CH3:22])=[N:15]1
Reactant: NO
Reactant: COc1c(C)cc(Cc2c(C)nn(CC#N)c2C)c2c1CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(C)cc(Cc2c(C)nn(CC(=N)NO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 33 h
Yield: 81.2 %

Procedure:
To a stirred solution of [4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-yl]-acetonitrile (2.0 gm 0.00647 mole) in methanol (50 ml), A suspension of Hydroxylamine hydrochloride (2.29 gm, 0.033 mole) and Potassium carbonate (4.37 gm, 0.0317 mole) in water (20 ml) was added. The reaction mixture was stirred for 30-36 hours at 70° C., cooled and then was filtered. The obtained solid was washed with water (10 ml) and finally with Hexane and dried under vacuum to give 1.8 gm of desired product
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[N:23][N:24]([CH3:38])[C:25]=4[NH:26][C:27]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[O:28])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C.O>[CH3:38][N:24]1[C:25]([NH:26][C:27]([O:29][C@@H:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])=[O:28])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)[CH:10]=3)=[CH:16][CH:17]=2)[N:22]=[N:23]1
Reactant: CCOC(=O)C1(c2cccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3cccc(C4(C(=O)O)CC4)c3)cc2)nnn1C)c1ccccc1
Reaction time: 20 h
Yield: 88.3 %

Procedure:
To a solution of (R)-1-(4′-(1-methyl-5-((1-phenylethoxy)carbonylamino)-1H-1,2,3-triazol-4-yl)biphenyl-3-yl)cyclopropanecarboxylic acid ethyl ester (90 mg, 0.176 mmol) in THF (5 mL) and ethanol (5 mL) was added an excess of sodium hydroxide (1.76 mL, 1.76 mmol, 1.0 M) in water at room temperature. The resulting colorless solution was stirred for 20 h at which time LCMS analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and the basic aqueous layer was neutralized with 1.0 N HCl. The resulting white solids were collected by filtration and washed with water and hexanes. After air drying, 75 mg (88% yield) of the (R)-1-(4′-(1-methyl-5-((1-phenylethoxy)carbonylamino)-1H-1,2,3-triazol-4-yl)biphenyl-3-yl)cyclopropanecarboxylic acid was isolated as a white solid. LC/MS calcd. for C28H26N4O4 (m/e) 482.0, obsd. 483.1 (M+H, ES+).
Reaction SMILES: CCN(C(C)C)C(C)C.CO[C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([OH:25])=O)[C:18](=[O:22])[O:19]2)=[CH:14][CH:13]=1.CN([C:29]([O:33]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C=O>[C:51]1([NH:50][C:23]([C:17]2[C:18](=[O:22])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:21]=3[O:33][CH3:29])=[O:25])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COc1ccc2cc(C(=O)O)c(=O)oc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3ccccc3)c(=O)oc12
Temperature: 25 °C
Yield: 82 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 7-methoxy-3-carboxy-coumarin (0.050 g, 0.23 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, aniline (0.021 g, 0.23 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.055 g of 1541H in an 82% yield: LCMS (ESI) m/z 296 (MH+).