Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Br:12])/Br.[CH3:17][S:18][C:19](=[NH:21])[NH2:20].Cl>O>[Br:12][C:11]1[C:9]([C:8]([OH:16])=[O:15])=[N:20][C:19]([S:18][CH3:17])=[N:21][CH:13]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CSC(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ncc(Br)c(C(=O)O)n1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
At 5° C. triethylamine (16.9 ml) was added dropwise to a solution of mucobromic acid (10.31 g) and 2-methyl-isothiourea (11.13 g) in water (200 ml). After stirring at 5° C. for 3 h, the reaction mixture was allowed to warm up (room temperature) and stirring was continued for another 54 h. The reaction mixture was acidified with conc. HCl (33%). The title product was obtained by filtration. Yield: 4.1 g. MS-ESI: [M+H]+=249/251
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cu][C:26]#[N:27].C(N)CN>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cnc(-c2ccc(-c3ccc(Br)cc3)cc2)nc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: NCCN
Product: CCCCCc1cnc(-c2ccc(-c3ccc(C#N)cc3)cc2)nc1

Procedure:
1.5 G. of 5-n-pentyl-2-(4'-bromo-4-biphenylyl)-pyrimidine are heated at reflux for 22 hours with 2.5 g. of copper-(I) cyanide (content 70%) in 50 ml. of dimethylformamide. After cooling, 25 ml. of 10% aqueous ethylenediamine solution are added and, after stirring for a short time, the mixture is extracted with methylene chloride. The organic extract is shaken with a further 25 ml. of ethylenediamine solution and then washed until neutral. The crude concentrate is chromatographed on silica gel with toluene/1% acetone. Recrystallization of the pure fractions from ethyl acetate yields 5-n-pentyl-2-(4'-cyano-4-biphenylyl)-pyrimidine, having a melting point of 123.5°-124° C. and clearing point of 204.5°-205° C.
Reaction SMILES: BrC1N(C(NC2C=CC=CC=2)=O)C(C2C=CN=C3NC(C4C=CC(N(C)C)=CC=4)=NC=23)CNC1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].O=[CH:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75]>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:68]([CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CN(C)c1ccc(-c2nc3c(C4CNCC(Br)N4C(=O)Nc4ccccc4)ccnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Reaction time: 6 h
Yield: 37 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (64 mg, 0.16 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.49 mmol, 0.49 mL) and tert-butyl 3-oxopropylcarbamate (prepared according to the procedure described in Tetrahedron 2003, 59, 1719) (1.1 eq, 0.18 mmol, 31 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 37%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (s, 9H, C(CH3)3), 2.58 (s, br, 4H, piperazine N(CH2)2), 2.89 (t, J=5.5 Hz, 2H, CH2CH2NH), 3.30 (hidden by DMSO peak, 2H, CH2CH2NH), 3.57 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2Ar), 6.92 (s, br, 1H, NH), 7.38 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.76 (dt, J=7.7, 1.5 Hz, 1H, pyridine H-4), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.48 (dd, J=4.8, 1.5 Hz, 1H, pyridine H-6), 8.54 (d, J=1.5 Hz, 1H, pyridine H-2), 12.79 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(N(C(C)C)C(C)C)C.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1.C(OCC)(=O)C>O>[Cl:22][C:23]1[CH:28]=[C:27]([N:10]2[CH2:11][CH2:12][N:7]([CH:3]3[CH2:6][CH2:5][CH2:4]3)[CH2:8][CH2:9]2)[N:26]=[CH:25][N:24]=1
Reactant: C1CC(N2CCNCC2)C1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.8 g (8.4 mmol) of 1-cyclobutylpiperazine dihydrochloride (Zaragoza et al., J. Med. Chem. 2004, 47, 2833) are initially charged in 18 ml of water, and 2.9 ml (2.1 g, 16.9 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are added. The mixture is stirred at RT for 30 min, and 1.3 g (8.4 mmol) of 4,6-dichloropyrimidine are added. The reaction mixture is stirred at 115° C. for 1 h and cooled to RT, 25 ml of ethyl acetate are added and the mixture is extracted with 25 ml of a saturated aqueous sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 100/3). Yield: 1.9 g (89% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:22]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>ClCCl>[CH:22]1([N:26]2[CH2:31][CH2:30][N:29]([C:15]([CH:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:14]3)=[O:17])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CC(C(=O)N2CCN(C3CCC3)CC2)C1
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a stirred solution of 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (250 mg, 1.06 mmol) in dichloromethane (2 mL) at RT was added SOCl2 (115 μL, 1.59 mmol). The mixture was stirred for 18 hours before volatiles were removed at reduced pressure. The residue was then dissolved in dichlormethane (3 mL) and 1-cyclobutylpiperazine (115 mg, 1.28 mmol) followed by DIPEA (940 μL, 5.31 mmol) added. The mixture was stirred at RT for 4 hours and then quenched with saturated aq. NaHCO3 (1 mL). The aqueous phase was extracted with dichloromethane (2×5 mL), the organics combined, washed with brine (2 mL), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (130 mg, 34%), after purification by silica FCC (97.5:2.25:0.25 DCM/MeOH/NH3).
Reaction SMILES: O[C@@H:2]1[CH2:6][N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](OC)=O)[CH2:3]1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:37]([C:45](OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:37]1[C:3]2[C:4](=[CH:14][CH:18]=[CH:6][CH:2]=2)[N:5]=[CH:7][CH:45]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To the solution of 2-9-2 (0.228 g, 0.745 mmol), (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.219 g, 0.894 mmol) and Triphenylphosphine (0.293 g, 1.117 mmol) in THF (3.72 ml), the Diisopropyl azodicarboxylate (0.217 ml, 1.117 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The crude product was purified by combiflash (25 g silica gel, 0-40% ethyl acetate in Hexanes) to give 1-1-1 (0.320 g, 0.600 mmol, 81% yield). MS-ESI, m/z=534.45 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>O1CCCC1.CN(C)C1C=CC=CC=1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:4]1[C:5](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[C:6]([OH:8])=[O:7])=[O:18]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(F)ccc2C(=O)O)cc(OC)c1OC
Reaction time: 5 h
Yield: 60.3 %

Procedure:
In a mixture of 20 ml of tetrahydrofuran and 1.6 g of dimethylaniline is dissolved 1.6 g of 4-fluoroanthranilic acid. To this solution is added slowly a solution of 2.3 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under room temperature and the mixture is strred at room temperature for 5 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 2.1 g of N-(3,4,5-trimethoxybenzoyl)-4-fluoroanthranilic acid as colorless needles.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].[C:12](#[N:15])[CH:13]=[CH2:14]>>[C:12]([CH2:13][CH2:14][N:11]([CH2:10][CH2:9][O:8][CH3:7])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])#[N:15]
Reactant: C=CC#N
Reactant: COCCN
Reactant: C=CC(=O)OC
Product: COCCN(CCC#N)CCC(=O)OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
At 20 to 30° C., 11.4 g of methyl acrylate was added to 10.0 g of 2-methoxyethylamine, which was allowed to stand for 2 hours. Then 15.0 g of acrylonitrile was added to the reaction solution, which was heated at 70° C. for 20 hours. Vacuum concentration yielded methyl N-(2-cyanoethyl)-N-(2-methoxyethyl)-3-aminopropionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)#[N:25].F[B-](F)(F)F.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C>CN(C)C=O.C(OCC)(=O)C>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)=[O:34])=[CH:28][CH:27]=1)#[N:25]
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2csc(NC(=O)Cc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.41 g 4-(4-Methoxyphenyl)-1,3-thiazol-2-amine was dissolved in 2 ml dimethylformamide. 3.0 ml N,N-Diisopropylethylamine, 1.0 g commercially available (4-Cyano-phenyl)-acetic acid and 2.25 g O-((Ethoxycarbonyl)cyanomethyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate were added. The reaction mixture was stirred at room temperature overnight. Then 200 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml saturated NaHCO3 solution and then dried over MgSO4. The solvents were removed in vacuo and the residue purified by RP-HPLC to obtain 610 mg 2-(4-Cyano-phenyl)-N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-acetamide as yellow solid.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)(O)[O-].[Na+].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:2]#[N:1])[CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: Clc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodium bicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was added dropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) of Example 52 dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 1 hour and poured into water. The resulting solid was collected, dried and weighed 4.0 g. Recrystallization from toluene-hexane afforded 3.1 g (70%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C. To a stirred mixture of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0 g., 0.015 mol) in methanol (30 ml) was added a solution of 25% sodium methoxide in methanol (2.5 ml). The reaction was warmed on a steam bath to effect solution and then stirred at ambient temperature for 16 hours. Most of the methanol was removed in vacuo and the residue was diluted with water. An initial oil solidified and 3.5 g of a solid was collected. This was recrystallized from methanol-water to yield 2.9 g (66%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 173°-175° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:26]=C)[CH:3]=1.CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:26]([C:4]1[CH:3]=[C:2]([CH3:1])[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[N:17][CH:18]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[O:30]
Reactant: CC(C)=O
Reactant: C=Cc1cc(C)c(Cc2ccc(-c3ccnc(C)c3)nc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-c3ccnc(C)c3)nc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-methyl-5-((2′-methyl-[2,4′-bipyridine]-5-yl)methyl)-2-vinylbenzoate (0.11 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.33 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.11 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[H][H].[Cl:11][C:12]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C)C=O>[ClH:11].[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:12]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Fc1ccc(-c2cc3ccccc3nc2Cl)cc1
Reactant: [H][H]
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1nc2ccccc2cc1-c1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Dimethylaminoethanol (1.07 g.) was added dropwise to a suspension of sodium hydride (0.56 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml.) at 0°-5°. When all the hydrogen had evolved, 2-chloro-3-(4-fluorophenyl)quinoline (2.69 g.) was added and the mixture was stirred at ambient temperature for 16 hr. The mixture was then poured into ice-water (500 ml.) and extracted with ethyl acetate (5×100 ml.). The ethyl acetate extract was washed successively with water (50 ml.) and saturated brine (50 ml.), and then dried (MgSO4). The solvent was evaporated under reduced pressure and the residual oil was chromatographed on basic alumina (100 g.; Brockmann Grade III), eluted with increasing concentrations of ethyl acetate in petroleum ether. The eluate obtained with 10% v/v ethyl acetate in petroleum ether was evaporated. The residual oil was dissolved in diethyl ether (100 ml.), and ethereal hydrogen chloride was added until precipitation was complete. The mixture was filtered and the solid residue was crystallised from methanol-ethyl acetate to give 2-(2-dimethylaminoethoxy)-3-(4-fluorophenyl)quinoline hydrochloride, m.p. 168°-171°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:25]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:24]([O:26][C:27](=[O:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and the following starting materials: 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[O:4][CH2:3]1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:16](O)C>>[CH:9]1([NH:15][CH2:3][C:2]([OH:4])([CH3:1])[C:5]([O:7][CH2:8][CH3:16])=[O:6])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1(C)CO1
Reactant: NC1CCCCC1
Reactant: CCO
Product: CCOC(=O)C(C)(O)CNC1CCCCC1
Temperature: 80 °C

Procedure:
A mixture of methyl 2-methylglycidate (3.2 mL, 30 mmol) and cyclohexylamine (5.2 mL, 45 mmol) in ethanol (50 mL) was heated at 80° C. for 24 h. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (6.7 g, 97%). [M+H] calc'd for C12H23NO3, 230; found 230.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].S1(CCCC1)(=O)=O.Br[CH2:13][CH3:14].[C:15]([CH2:17][CH2:18][N:19]([CH2:26][CH2:27][OH:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:16]>O>[C:15]([CH2:17][CH2:18][N:19]([CH2:26][CH2:27][O:28][C:2](=[O:1])[NH:3][CH2:13][CH3:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:16]
Reactant: N#CCCN(CCO)c1ccccc1
Reactant: CCBr
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCNC(=O)OCCN(CCC#N)c1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Into a 500 ml. three-necked round-bottomed flask equipped with thermometer, stirrer, reflux condenser, and dropping funnel are placed 40 g. (0.493 mole) of potassium cyanate and 250 ml. of sulfolane (tetrahydrothiophene-1,1-dioxide). This mixture is heated with stirring to 90° C. by means of an oil bath. Bromoethane (95 g., 0.8 mole) is then added dropwise to the mixture over a 1.5 hour period. The temperature of the reaction mixture drops to 75° C. during the addition of bromoethane. A solution of 50 g. (0.228 mole, 86.5%) N-(2-cyanoethyl)-N-(2-hydroxyethyl) aniline in 50 ml. of sulfolane is added, and heating of the resulting mixture is continued at 90° C. for three hours. The reaction mixture is cooled to room temperature and then poured into 2 liters of cold water. The mixture is agitated for 0.5 hour, and the two resulting layers separated. TLC of the organic layer in 4:1 benzene:acetone shows only a trace of starting material. The infrared spectrum of the product of the above formula shows absorptions at 3370, 2250, 1915, 1680, and 596 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([B:20]([OH:25])[OH:21])[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: CCOc1cc(I)ccc1OC(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
To a solution of 2-ethoxy-4-iodo-1-isopropoxybenzene (2.39 g, 7.8 mmol) in THF (25 mL) at −78° C., n-BuLi (1.6 M in hexanes, 6.83 mL, 1.4 eq) was slowly added. The reaction mixture was stirred at −78° C. for 20 min, followed by addition of triisopropyl borate (4.95 mL, 21.5 mmol). The mixture was stirred at −78° C. for 3.0 h and then warmed up to rt over 1.0 h. It was quenched by addition of 5% citric acid (20 mL), followed by a solution of Na2S2O3. After extraction with EtOAc and drying over Na2SO4, the crude product was purified by chromatography to give 1A (1.2 g, 67% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.15 Hz, 6H) 1.49 (t, J=7.03 Hz, 3H) 4.21 (q, J=7.03 Hz, 2H) 4.64 (m, 1H) 7.02 (d, J=8.35 Hz, 1H) 7.70 (s, 1H) 7.79 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13](Cl)[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.C(O)C.C(N(CC)CC)C>CCOCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:26][NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:27])[CH:20]=2)[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cnc(OCc2ccccc2)nc1Cl
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: Fc1cnc(OCc2ccccc2)nc1NNc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 76.9 %

Procedure:
A 25 mL vial was charged with 2-(benzyloxy)-4-chloro-5-fluoropyrimidine (153 mg, 0.639 mmol), (3-(trifluoromethyl)phenyl)hydrazine (338 mg, 1.92 mmol), ethanol (8 mL), and triethylamine (140 μL, 1.00 mmol). The resulting yellow solution was heated at 50° C. on an orbital shaker for 16 h. The crude material was then diluted with Et2O (100 mL) and washed with 1.0 M aqueous NaH2PO4 (50 mL) and then water (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (EtOAc/hexane gradient) to afford 2-(benzyloxy)-5-fluoro-4-(2-(3-(trifluoromethyl)phenyl)hydrazinyl)pyrimidine (186 mg, 77%) as a brown oil: 1H NMR (300 MHz, DMSO-d6) δ 9.74 (bs, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.36 (m, 1H), 7.26 (bs, 5H), 7.01 (m, 3H), 5.14 (s, 2H); MS (ESI) m/z 379 (M+H)+, 377 (M−H)−.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N+:13](=[CH2:15])=[N-].[H-].[Na+].I[CH3:19]>O1CCCC1.C(OCC)C.O>[CH3:19][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][N:13]2[CH3:15])=[CH:5][CH:6]=1)=[O:11]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CI
Reactant: C=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 1H-indole-6-carboxylic acid (2.60 g, 16.1 mmol) in tetrahydrofuran (100 mL) and diethyl ether (100 mL) was treated with ethereal diazomethane until tlc indicated complete consumption of the starting material. After the solution was allowed to stand overnight, the solvent was evaporated under reduced pressure and the resulting residue was dissolved in tetrahydrofuran (100 mL). The solution was cooled to ˜0° C. and sodium hydride (60% suspension in mineral oil; 2.00 g, 50.0 mmol) and then iodomethane (10.00 g, 70.5 mmol) were added. and the reaction mixture was stirred at room temperature overnight. Water (200 mL) was added, carefully at first and the mixture was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed over silica gel (30-50% ethyl acetate/hexanes) to furnish 1-methyl-1H-indole-6-carboxylic acid methyl ester (2.52 g, 83% yield) as a yellow oil that solidified on standing.