Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[CH:18]=[C:19]([OH:37])[C:20]4[C:26](=[O:27])[CH2:25][C@@H:24]([C:28]5[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([OH:34])[CH:33]=5)[O:23][C:21]=4[CH:22]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43].CC1OC(OCC2OC(OC3C=C4C(C(CC(C5C=CC(OC)=C(O)C=5)O4)=O)=C(O)C=3)C(O)C(O)C2O)C(O)C(O)C1O>>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[CH:18]=[C:19]([OH:37])[C:20]4[C:26](=[O:27])[CH:25]=[C:24]([C:28]5[CH:29]=[CH:30][C:31]([O:35][CH3:36])=[C:32]([OH:34])[CH:33]=5)[O:23][C:21]=4[CH:22]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H:5]([OH:41])[C@H:4]([OH:42])[C@H:3]1[OH:43]
Reactant: COc1ccc([C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2)cc1O
Agent: COc1ccc(C2CC(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2)cc1O
Product: COc1ccc(-c2cc(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3o2)cc1O

Procedure:
hesperidin, (S)-7-[[6-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]oxy]-2,3-dihydro-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one; hesperetin 7-rhamnoglucoside; cirantin; hesperetin-7-rutinoside;
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([CH2:15][C:16]([OH:18])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.[CH3:19]O>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: COc1c(F)cc(CC(=O)O)cc1F
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
Tribromoborane (2.357 mL, 24.93 mmol) was added dropwise to 2-(3,5-difluoro-4-methoxyphenyl)acetic acid (0.84 g, 4.16 mmol) in dichloromethane (5 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. Methanol (8.41 mL, 207.76 mmol) was added dropwise (—care reaction is vigorous and exothermic—mixture maintained a reflux during the addition) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford desired product methyl 2-(3,5-difluoro-4-hydroxyphenyl)acetate (0.660 g, 79%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:24][C:25]([F:29])([F:28])[C:26]#[CH:27]>>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:23])([C:19]([F:21])([F:22])[F:20])[C:27]#[C:26][C:25]([F:29])([F:28])[F:24])=[CH:14][CH:13]=1)[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: C#CC(F)(F)F
Reactant: CN(c1ccc(C(=O)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Product: CN(c1ccc(C(O)(C#CC(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1

Procedure:
The compound was prepared from N-methyl-N-(4-trifluoroacetyl-phenyl)-benzenesulfonamide (Example 22, Step A) and 3,3,3-trifluoroprop-1-yne following the procedure described in Example 29. 1H NMR (CDCl3) δ 3.19 (s, 3 H), 4.30 (br s, 1H), 7.11-7.63 (m, 9 H). Mass Spectrum (CI+) m/e=438 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5]([CH:7]=O)=O>>[NH:3]1[CH:2]2[NH:3][CH2:5][CH2:7][NH:4][CH:1]2[NH:4][CH2:1][CH2:2]1
Reactant: NCCN
Reactant: O=CC=O
Product: C1CNC2NCCNC2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 206 grams of 70% aqueous ethylenediamine (144 grams, 2.4 moles) was added dropwise 115 grams of a 30% aqueous solution of glyoxal (34.8 grams, 0.6 mole). When the addition was completed, the solution was stirred at room temperature for 30 minutes, then concentrated by removing approximately 75 ml of water at 150 mm Hg. The mixture was cooled in an ice bath and the precipitated solid was filtered, stirred in 100 ml of 50% ethanol-isopropanol, and again filtered. The yield of product was 50.6 grams (59%), m.p. 222°-225° C. (dec; literature m.p. 230°-232° C.).
Reaction SMILES: ClC1C=CC([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=3)=C(C=O)C=1.[C:32]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1B(O)O)(=[O:34])[CH3:33]>>[C:32]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:14][CH:13]=[C:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(Cl)cc3C=O)[nH]c2c1
Reactant: COc1ccc(B(O)O)c(C(C)=O)c1
Product: COc1ccc(-c2[nH]c3cc(C(=O)OC(C)(C)C)ccc3c2C2CCCCC2)c(C(C)=O)c1

Procedure:
The title product tert-butyl 2-(2-acetyl-4-methoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 37d was synthesized by following a similar procedure to that used for the synthesis of tert-butyl 2-(4-chloro-2-formylphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 34b, using 2-acetyl-4-methoxyphenylboronic acid 37c instead of 4-chloro-2-formylphenylboronic acid 34a.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH2:69][OH:70]>CN(C=O)C.O>[OH:70][CH2:69][CH2:68][CH2:67][NH:66][C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:32][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:29]
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCO)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (1.00 g, 2.34 mmol) in 20 ml of anhydrous DMF were added HATU (1.07 g, 2.80 mmol) and N,N-diisopropylethylamine (604 mg, 4.68 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-amino-1-propanol (263 mg, 3.51 mmol). The mixture was stirred for another 5 minutes and poured into 200 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 1.10 g, 97%.
Reaction SMILES: [CH:1]#[C:2][CH:3](O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].C(OCC)C>[CH3:1][C:2]1[NH:10][C:11]2[C:16]([C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C#CC(O)CCCCC
Reactant: Nc1ccccc1
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: CCOCC
Product: CCCCCc1c(C)[nH]c2ccccc12
Temperature: 140 °C
Reaction time: 9 h
Yield: 105 %

Procedure:
1-Octyne-3-ol (1.136 g, 9 mmol), aniline (0.559 g, 6 mmol), Ru3(CO)12 (16.0 mg, 0.025 mmol) and aniline hydrochloride (0.130 g, 1.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 140° C. for 9 hours. After cooling, diethyl ether (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby an 11:1 mixture of 3-methyl-2-pentyl indole and 2-methyl-3-pentyl indole (1.262 g; 6.3 mmol; yield, 95%; purity, about 95% or more) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].C([Mg]Br)C.[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23](Cl)=[O:24]>ClCCl.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:23]([CH:19]1[C:20]([CH3:22])([CH3:21])[C:18]1([CH3:26])[CH3:17])=[O:24])=[CH:7][NH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cccc([N+](=O)[O-])c23)C1(C)C
Yield: 8.5 %

Procedure:
A mixture of 4-nitroindole (1.0 g, 6.2 mmol), ethylmagnesium bromide (1.0 M in THF, 6.8 mL, 6.8 mmol), zinc chloride (1.0 M solution in Et2O, 6.8 mL, 6.8 mmol) and the product of Example 1A (6.8 mmol) in 15 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.15 g, 0.53 mmol, 8% yield). MS (DCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:30])[C:15]([C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)=[O:16])=[C:4]([O:31][CH3:32])[CH:3]=1.I[CH:34]1[CH2:37][O:36][CH2:35]1.Cl.N[C@@H]1CCCC[C@H]1O.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH4+].[Cl-]>CC(O)C.[Ni](I)I.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:30])[C:15](=[O:16])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([CH:34]3[CH2:37][O:36][CH2:35]3)[CH:18]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(B(O)O)cc(C(F)(F)F)c1
Reactant: IC1COC1
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C2COC2)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a suspension of 3-((4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylboronic acid (0.1 g, 223 μmol) in 2-propanol (1 mL) were added 3-iodooxetane (41.0 mg, 223 μmol), (1R,2R)-2-aminocyclohexanol hydrochloride (2.03 mg, 13.4 μmol), nickel(II) iodide (4.18 mg, 13.4 μmol) and sodium hexamethyldisilazan (40.9 mg, 223 μmol) and the suspension was heated in a microwave oven at 80° C. for 20 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The mixture was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.004 g; 3%). MS (ESI): m/z=461.15 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[C:18]=1[CH3:19].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:21]([C:23]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:24])[N:22]=2)[C:18]=1[CH3:19]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1nc2ccc(I)c(C)n2c1-c1ccccn1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1c(I)ccc2nc(C(=O)Nc3ccccc3)c(-c3ccccn3)n12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 852 μL of aniline in 104 mL of toluene cooled to 0° C. are added dropwise 6.2 mL of a 2M solution of trimethylaluminium in toluene, followed by addition, at 20° C., of 1.5 g of ethyl 6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate. The reaction mixture is stirred for 2 hours at 20° C. The resulting mixture is cooled to 4° C. and 120 mL of saturated ammonium chloride solution are then added. After concentrating under reduced pressure, the residue is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate, filtered through Celite and evaporated to dryness under reduced pressure. The residue is triturated in methanol, filtered off and dried to give 1.15 g of 6-iodo-5-methyl-N-phenyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:72])[CH2:12][C@@H:13]([NH:25][C:26]([C@H:28]1[NH:46][C:45](=[O:47])[C@H:44]([CH2:48][CH2:49][CH2:50][NH:51]C(OC(C)(C)C)=O)[NH:43][C:42](=[O:59])[C@@H:41]([NH:60]C(OC(C)(C)C)=O)[CH2:40][C:39]2[CH:68]=[C:35]([CH:36]=[CH:37][C:38]=2[OH:69])[C:34]2=[CH:70][C:30](=[C:31]([OH:71])[CH:32]=[CH:33]2)[CH2:29]1)=[O:27])[CH2:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)(C)(C)C.[ClH:74]>O1CCOCC1>[ClH:74].[ClH:74].[ClH:74].[ClH:74].[NH2:60][C@H:41]1[CH2:40][C:39]2[CH:68]=[C:35]([CH:36]=[CH:37][C:38]=2[OH:69])[C:34]2=[CH:70][C:30](=[C:31]([OH:71])[CH:32]=[CH:33]2)[CH2:29][C@@H:28]([C:26]([NH:25][C@H:13]([CH2:12][C:11]([NH:10][CH2:9][CH2:8][NH2:7])=[O:72])[CH2:14][CH2:15][CH2:16][NH2:17])=[O:27])[NH:46][C:45](=[O:47])[C@H:44]([CH2:48][CH2:49][CH2:50][NH2:51])[NH:43][C:42]1=[O:59]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@@H](CC(=O)NCCN)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 30 mg (0.029 mmol) of tert-butyl(2-{[(3S)-6-[(tert-butoxycarbonyl)amino]-3-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)hexanoyl]amino}ethyl)carbamate (Example 193A) in 2 ml of a 4M solution of hydrogen chloride in dioxane is stirred at RT for 20 min. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[NH:3]1.[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:15]1([C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[N:10]3)=[O:14])[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12
Reactant: O=C(O)c1ccc2[nH]c(=O)cnc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)cnc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 45 %

Procedure:
The title compound is prepared from 2-oxo-1,2-dihydro-quinoxaline-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 45% of theory; LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=346 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: ICCCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1Cc1sc(SCCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OCC)C3)cc1

Procedure:
Method as example 34 using 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and ethyl chloroformate as starting materials.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[C:16]([CH3:28])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[C:16]([CH3:28])[N:15]([CH:36]([CH3:38])[CH3:37])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CC(C)I
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccc(C3CC3)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reaction time: 0.58 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (56 mg) and cesium carbonate (23 mg) in N,N-dimethylformamide (1.5 mL) was added 2-iodopropane (0.043 mL) at 80° C., and the mixture was stirred for 35 minutes. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The obtained crude product was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=7/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-1-isopropyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole )45 mg).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:14][CH:15]=3)[C@@:10]3([CH2:33][O:32][C:31]([NH2:34])=[N:30]3)[C:9]=2[CH:8]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:36]1[NH:37][CH:38]=[CH:39][N:40]=1.CC([O-])=O.[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>C(O)CCC.O.CO>[NH:37]1[CH:38]=[CH:39][N:40]=[C:36]1[C:13]1[CH:14]=[CH:15][C:16]2[O:17][C:18]3[C:9](=[CH:8][C:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:20][CH:19]=3)[C@:10]3([CH2:33][O:32][C:31]([NH2:34])=[N:30]3)[C:11]=2[CH:12]=1
Reactant: Brc1ncc[nH]1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCCCO
Solvent: CO
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3ncc[nH]3)ccc1O2
Temperature: 120 °C

Procedure:
A solution of (S)-2′-(neopentyloxy)-7′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (50 mg, 0.108 mmol) in BuOH (861 μL), 2-bromo-1H-imidazole (0.129 mmol), and KOAc (31.7 mg, 0.323 mmol) in Water (215 μL) was purged with Ar in a sealed tube. AmPhos (1.525 mg, 2.153 μmol) was added and the reaction was heated to 120° C. for 30 min in the microwave. The reaction was cooled to rt, diluted with MeOH (3 ml), loaded onto an AccuBOND II SCX cartridge, washed with MeOH (3 ml) and eluted with 2N NH3 in MeOH (6 ml) to give the crude product which was purified by reverse-phase preparative HPLC using a Gemini NX c!8 column (150*30 mm, 5 um), 0.1% TFA in CH3CN/H2O, gradient 0% to 70% over 10 min to provide (S)-2′-(1H-imidazol-2-yl)-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH3:13])[C:7]=1[Cl:14])=[O:5])[CH3:2].[C:15]([C:19]1[CH:26]=[CH:25]C(CN)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:26]=[CH:25][C:2]([CH2:1][NH:3][C:4]([C:6]2[N:10]([CH3:11])[N:9]=[C:8]([CH2:12][CH3:13])[C:7]=2[Cl:14])=[O:5])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCNC(=O)c1c(Cl)c(CC)nn1C
Product: CCc1nn(C)c(C(=O)NCc2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 200 °C

Procedure:
A mixture of ethyl 4-chloro-3-ethyl-1-methylpyrazole-5-carboxamide and 4-tert-butylbenzylamine is heated to 200° C. for four hours with continuous stirring. Thereafter the reaction mixture is cooled to room temperature and the reaction mixture purified by silica gel chromatography to obtain the desired product 115°-117° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:13].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CS(C)=O.O>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])[CH2:19][CH2:20]1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
10% sodium hydroxide aqueous solution (7.21 g) was added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (2.60 g) obtained in Example 5(1) in dimethylsulfoxide (36 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.97 g) was added thereto. After being stirred for 2.5 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=60:1 to 30:1), thereby yielding the entitled compound (1.99 g) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[OH-:25].[Na+]>O1CCCC1>[Cl:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([CH3:24])[C:11]=2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[CH3:23])[C:6](=[O:25])[CH:7]=1
Reactant: [OH-]
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn2c(=O)cc(Cl)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of 5,7-dichloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (1.30 g, 3.47 mmol) in tetrahydrofuran (25 ml) was added sodium hydroxide solution (3 mL, 17.37 mmol). The reaction mixture was stirred at 50° C. for 3 hours. Solvent was removed. The residue was dissolved with ethyl acetate (50 mL) and 5% HCl solution (20 mL). Organic layer was separated and dried. The crude material was purified on silica gel column (methanol/DCM, 0-10% gradient solvent system) to give the product. It was used for next step. (0.88 g, 68%); LC/MS: MS (ES+) m/e 356 (MH+).