Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:23]([C:19]1[CH:18]=[C:17]([N:13]2[CH2:12][CH2:11][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:15][CH2:14]2)[CH:22]=[CH:21][N:20]=1)#[N:24]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc(C#N)c2)CC1
Temperature: 100 °C
Yield: 44 %

Procedure:
A mixture of tert-butyl methyl(piperidin-4-yl)carbamate (465 mg, 2.173 mmol, 1.0 eq.), 4-chloropyridine-2-carbonitrile (300 mg, 2.173 mmol, 1.0 eq.) and K2CO3 (600 mg, 4.34 mmol, 2.0 eq.) in THF (4 ml) was heated for 48 hours at 100° C. in a pressure vessel. The mixture was filtered and washed with THF (10 ml). The filtrate was concentrated and purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 44% (300 mg, 0.949 mmol)
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O[CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[N:15]([CH2:30][C:31]1[N:32]2[CH:38]=[N:37][CH:36]=[C:33]2[S:34][CH:35]=1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1csc2cncn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1csc2cncn12
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Diphenylphosphoryl azide (0.259 ml) and 0.157 ml of 1,8-diazabicyclo[5,4,0]-7-undecene were added to suspension of 154 mg of 3-hydroxymethylimidazo[5,1-b]thiazole in 2 ml of toluene. The mixture was stirred at room temperature for 30 hr. Brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to give 156 mg of 3-azidomethylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(CO)NC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and 2-amino-2-methyl-1-propanol (25.5 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (91 mg, 76%) as a white solid. MS: m/e=430.1 [M−H]−.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:9]([O:11]N1C(=O)CCC1=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:9]([NH:29][C@H:30]([C:43]([O:45][CH3:46])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(N[C@H](C(=O)ON1C(=O)CCC1=O)c1ccccc1)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Z-Phg-OSu (640 mg) in DMF (10 ml), 463 mg (1.84 mmol) of Tyr(3-tBu)-OMe and 408 mg (3.34 mmol) of DMAP were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give Z-Phg-Tyr(3-tBu)-OMe in the amount of 905 mg (quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[CH2:17]([O:19][C:20](=[O:34])[CH:21](P(OCC)(OCC)=O)[CH2:22][CH2:23][CH2:24][Cl:25])[CH3:18].O.[OH-].[Li+].O>C1COCC1.C(O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:34])/[C:21](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH2:22][CH2:23][CH2:24][Cl:25])[CH3:18]
Reactant: CCOC(=O)C(CCCCl)P(=O)(OCC)OCC
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (5 g) obtained in Example 1 in THF (60 mL) and ethanol (20 mL), 5-chloro-2-(diethoxyphosphoryl)valeric acid ethyl ester (7.6 g) and lithium hydroxide monohydrate (2.9 g) were added one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3.76 g of the title compound was obtained by purifying the residue by silica gel chromatography (heptane: elution solvent: ethyl acetate=1:1), and re-crystallizing the obtained solid from a mixed solvent of ethyl acetate and hexane.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3].[Br:9][CH:10](O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:7][CH2:8][CH2:10][Br:9])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: COC(=O)C(O)CO
Reactant: CC(O)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCCBr)C(O)CO
Yield: 92 %

Procedure:
A mixture of methyl glycerate (2 g, 0.17 moles) and bromoethanol (5.28 g, 0.42 moles was heated at 60° C. under nitrogen in the presence of a catalytic amount of p-toluene sulfonic acid for 10 h. The excess bromoethanol was removed on rotary evaporator under reduced pressure. The crude mixture was diluted with large volume of chloroform (100 mL) and the free acid was neutralized by adding anhydrous sodium carbonate. Filtration and removal of the solvent gave the crude product which was purified by chromatography on a silica gel column eluting with chloroform:methanol (9:1). Removal of the solvent on a rotary evaporator gave bromoethyl glycerate (3.26 g, 92% yield) which showed the following characteristics: 1H NMR (200 MHz, CDCl3), δ 3.52 (m, 2H, CH2Br), 3.90 (m, 2H,CO2CH2), 4.27 (s, 2H, OH), 4.36 (m, 2H, CH2OH), 4.52 (m, 1 H, CH), 13C NMR (50 MHz, CDCl3) δ 28.42, 63.76, 64.50, 71.58, 172.13.
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[Li]CCCC.[O:31]1[C:35]2=[N:36][CH:37]=[C:38]([CH:40]=O)[CH:39]=[C:34]2[CH:33]=[CH:32]1>C1COCC1>[O:31]1[C:35]2=[N:36][CH:37]=[C:38]([CH:40]=[CH:6][C:4]([NH:3][CH3:2])=[O:5])[CH:39]=[C:34]2[CH:33]=[CH:32]1
Reactant: CNC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cnc2occc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)C=Cc1cnc2occc2c1
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a solution of 0.25 g of methylcarbamoylmethyl-triphenyl-phosphonium chloride (J. Med. Chem. 2003, 46, 399) in 1 ml of THF was added 0.88 ml of n-BuLi (1.6M) at −60° C. After stirring for 1 h at −60° C. a solution of 0.1 g of furo[2,3-b]pyridine-5-carbaldehyde in 1 ml of THF was added and the resulting reaction mixture was stirred for 5 h reaching slowly rt. The reaction mixture was poured over ice. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC using EtOAc as eluant yielded 0.13 g of 3-furo[2,3-b]pyridin-5-yl-N-methyl-acrylamide as a mixture of E/Z isomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCCCCC.O>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 16 mg (0.022 mmol) of [(t-Bu)2P(Cl)PdCl2]2, 1.0 (8.8 mmol) of chlorobenzene, 1.3 g (10.66 mmol) of Ph—B(OH)2, 3.7 g (26.77 mmol) of K2CO3 in 5 mL of THF. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 220 mL of hexane and 150 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (100 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 0.72 g (53% yield) of biphenyl.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C@H:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:2]1.[CH3:14][C:15]1[S:24][C:23]2[NH:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N:19]=[C:18](N)[C:17]=2[CH:16]=1.C1(C)C=CC=CC=1.CS(C)=O>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][C@@H:8]2[NH:9][CH2:10][CH2:11][N:12]([C:18]3[C:17]4[CH:16]=[C:15]([CH3:14])[S:24][C:23]=4[NH:22][C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[N:19]=3)[CH2:13]2)=[CH:2]1
Reactant: c1cc(CC[C@H]2CNCCN2)co1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccoc2)C1
Temperature: 100 °C
Reaction time: 48 h
Yield: 23.6 %

Procedure:
Combine (S)-2-(2-furan-3-yl-ethyl)-piperazine (550 mg, 3.05 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (700 mg, 3.05 mmol), toluene (6 mL) and DMSO (1.5 mL). Heat at 100° C. After 48 h, cool to ambient temperature and dilute with ethyl acetate. Filter the solids and dilute the filtrate with water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 282 mg (24%) of the title compound: mass spectrum (ion spray): m/z=393 (M+1), 391 (M-1). HR-MS calculated for C22H25N4OS: 393.1749. Found 393.1742. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]([C@@H:8]2[CH2:12][C@H:11]([S:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10][N:9]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])=[O:7])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][S:13][C@@H:11]2[CH2:10][N:9]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[C@H:8]([C:6]([N:4]3[CH2:5][CH:2]([NH:1][C:46]([O:48][CH2:49][C:50]4[CH:51]=[CH:52][C:53]([N+:56]([O-:58])=[O:57])=[CH:54][CH:55]=4)=[O:47])[CH2:3]3)=[O:7])[CH2:12]2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.67 h
Yield: 58.2 %

Procedure:
0.81 g of (2S,4S)-2-(3-aminoazetidin-1-ylcarbonyl)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] was dissolved in 20 ml of methylene chloride, and 0.32 g of diisopropylethylamine and 0.40 g of p-nitrobenzyl chloroformate were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 40 minutes. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 60 9385, manufactured by Merck, 40 g) to give 0.64 g of the title compound, in the form of an amorphous powder, from the fraction obtained by solution with a 99:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: C[N:2]1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][C:3]1=O.P(Br)(Br)(Br)(Br)[Br:18].P(Br)(Br)(Br)=O.N>>[Br:18][C:3]1[CH:4]=[CH:5][C:6]2[C:15](=[C:14]3[C:9](=[CH:8][CH:7]=2)[CH:10]=[CH:11][CH:12]=[N:13]3)[N:2]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: Cn1c(=O)ccc2ccc3cccnc3c21
Agent: N
Agent: O=P(Br)(Br)Br
Product: Brc1ccc2ccc3cccnc3c2n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.9 %

Procedure:
Under a stream of argon, to compound (2) (10 g; 47.6 mmol), phosphorus pentabromide (28 g; 65 mmol) and phosphorus oxybromide (50 g; 174 mmol) were added at room temperature. The reaction temperature was raised to 80° C. and the reaction mixture was stirred for 6 hours. The reaction mixture was cooled in an ice bath, and then poured into ice water. Concentrated aqueous ammonia was added thereto and the resulting mixture was made alkaline. The reaction mixture was extracted with chloroform, and the organic layer thus obtained was washed with water, dried over sodium sulfate, and then evaporated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (SiO2, 250 g) (toluene/ethyl acetate=5/1 to 3/1 to 1/1 to ethyl acetate), to give 6.9 g (yield: 94%) of the title compound (7).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:39])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:38])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:41])[CH3:40])(=O)C.[OH-].[Na+]>O1CCCC1.CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:39])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:38])[CH2:12][CH2:13][C@@:14]3(/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:41])[CH3:40]
Reactant: CCOC(=O)/C=C/[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Temperature: 20 °C
Yield: 71.3 %

Procedure:
To a solution of (E)-ethyl 3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-acetoxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylate (1.6 g, 2.82 mmol) in tetrahydrofuran (THF) (15 mL), methanol (10 mL) and water (5 mL) was added sodium hydroxide (4.52 g, 113 mmol). The reaction mixture was stirred at 20° C. for 4 hs. The reaction mixture was evaporated to dryness and adjusted pH to 5 by saturated NH4Cl. The solid is solved into DCM (50 mL), washed with water, dried over Na2SO4 and concentrated to yield the (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylic acid (1.2 g, 2.012 mmol, 71.3%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:18]([C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(Oc2ccccc2)n1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyrimidine (3.0 g, 0.016 mol) in DMF (30 ml) were successively added phenol (1.9 g, 20 mmol), potassium carbonate (3.3 g, 24 mmol) and Cu(I) (100 mg). The reaction mixture was stirred for 7 h at 90° C. The resulting reaction mixture was partitioned between MTBE and water. The aqueous layer was extracted with MTBE. The solvent was removed from the organic layers in vacuo. 2-Phenoxy-4-trifluoromethylpyrimidine was obtained as a yellowish solid (3.0 g). 1H-NMR (CDCl3): δ=7.2-7.5 (m, 6H); 8.7 ppm (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[CH:12]2>CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:13]([CH3:20])=[C:12]2[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: COc1cc2cc(C)[nH]c2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: COc1cc2[nH]c(C)c(C(=O)C(=O)Cl)c2cc1OC
Reaction time: 0.17 h

Procedure:
8.7 g of oxalyl chloride are added dropwise to a stirring solution, cooled to about -10° C., of 12.0 g of 5,6-dimethoxy-2-methylindole in 250 ml of ether. After addition is completed, the mixture is stirred for 10 minutes, producing a bright orange precipitate of 5,6-dimethoxy-2-methyl-3-indole glyoxylyl chloride which is immediately used for the next step.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[CH:21][C:20](N)=[C:19]([CH3:24])[N:18]=2)[C:15]=1[CH3:16])=[O:10])[CH3:7].N([O-])=O.[Na+].[I-:29].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([I:29])=[C:19]([CH3:24])[N:18]=2)[C:15]=1[CH3:16])=[O:10])[CH3:7]
Reactant: [I-]
Reactant: CCOC(=O)c1cnn(-c2ccc(N)c(C)n2)c1C
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(I)c(C)n2)c1C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
After concentrated sulfuric acid (20 ml) were added to 1-(5-amino-6-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (7.8 g) and water (80 ml) at 0° C., sodium nitrite (3.0 g) was added therein in several portions. After stirring for 0.5 hour, potassium iodide (9.96 g) was added in several portions and the mixture was stirred for 2.5 hours at room temperature. A saturated aqueous solution of sodium bicarbonate was added in several portions at 0° C. and then an aqueous solution of sodium sulfite was added and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was washed with ethyl acetate and n-hexane to give the titled compound (7.76 g) as a yellow solid.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C(O)C.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COCCN
Reactant: CSC(=N)Nc1ccccc1N1CCCCC1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: COCCNC(N)=Nc1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 480 h

Procedure:
A mixture of 2-methyl-1-(2-piperidino)phenyl]-2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G), 2-methoxyethylamine (2 ml) and ethanol (40 ml was stirred at ambient temperature for 20 days. Removal of the solvent gave a residue which was dissolved in methanol and treated with fumaric acid to give 1-(2-methoxyethyl)-2-(2-piperidinophenyl)guanidine hemifumarate (m.p. 218°-220° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:22]4[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 60 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
The product of Example 7C (30.0 mg, 0.11 mmole), 4-cyanophenylboronic acid (18.8 mg, 0.13 mmole), palladium(II) acetate (1.2 mg, 0.005 mmole), 2-(dicyclohexylphosphino)biphenyl (3.8 mg, 0.01 mmole) and potassium phosphate (K3PO4) (75 mg, 0.35 mmole) were dissolved in 1 ml of toluene, 0.5 ml of isopropanol and 0.5 ml of water. The mixture was stirred at 60° C. under N2 for 5 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered and concentrated and purified by chromatography (eluting with a mixture of 5% methanol in dichloromethane) to provide the title compound (23.1 mg, 71.3%). 1H NMR (300 MHz, CDCl3) δ ppm 7.60-7.68 (m, 4H) 7.47-7.53 (m, 2H) 6.61-6.68 (m, 2H) 4.14-4.22 (m, 1H) 3.51-3.60 (m, 1H) 3.28-3.35 (m, 1H) 2.93-3.01 (m, 1H) 2.71-2.75 (m, 1H) 2.48-2.61 (m, 3H) 2.32 (s, 3H) 2.14-2.25 (m, 1H) 1.96 (d, J=7.12 Hz, 1H). MS; (M+H)+=281/283.