Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.O.O.[F-].[K+].[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1B(O)O)#[N:43].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:30][C:4]1[S:3][C:2]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:42]#[N:43])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C#N)sc2N)c1N1CCC[C@@H](N)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
A mixture of (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (122 mg, 0.20 mmol), potassium fluoride dihydrate (62 mg, 0.66 mmol) and 2-cyanophenylboronic acid (88 mg, 0.60 mmol) in THF (3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2) (24 mg, 0.020 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 80° C. for 2 hr. Water was added and the mixture extracted with EtOAc. The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperature for 4 hr. The solvents were removed under reduced pressure and the residue dissolved in MeOH/water (3 mL, 3:1) and K2CO3 (66 mg, 0.48 mmol) added. The mixture was heated at 80° C. for 6 hr. The solvents were removed under reduced pressure and the residue purified by preparative HPLC to yield 355 as an orange solid (36 mg, 51%). 1H NMR (400 MHz, d4-MeOD) δ 7.87 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 3.75 (s, 3H), 3.40-3.26 (m, 4H), 3.18-3.10 (m, 1H), 2.05-1.86 (m, 3H), 1.87-1.67 (m, 3H). LCMS (ES+) m/z 437 (M+1).
Reaction SMILES: O.O.O.[F-].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[C:23]([O:24]COCC[Si](C)(C)C)=[C:22]([Si](C)(C)C)[CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:37]=1)#[N:6]>O1CCCC1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:37]=1)#[N:6]
Reactant: CC1(C)N=C(c2nccc([Si](C)(C)C)c2OCOCC[Si](C)(C)C)c2cc(C#N)ccc2O1
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)N=C(c2ncccc2O)c2cc(C#N)ccc2O1
Yield: 13.1 %

Procedure:
Molecular sieves 5A (5 g) and tertrabutylammonium fluoride trihydrate (3.2 g) were added to a solution of 6-cyano-2,2-dimethyl-4-[4-trimethylsilyl-3-(2-trimethylsilylethoxymethyloxy)pyridin-2-yl]-2H-1,3-benzoxazine (2.5 g) in tetrahydrofuran (20 ml), and the mixture was heated under reflux for 30 minutes. After air-cooling, the mixture was extracted by addition of ethyl acetate. The organic layer was washed with saturated saline solution, the solvent was distilled off under reduced pressure and the residue was crystallized from ethyl acetate to obtain 6-cyano-2,2-dimethyl-4-(3-hydroxypyridin-2-yl)-2H-1,3-benzoxazine (0.19 g) (Compound 12).
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:21][CH2:20]2)[C:9]1=[O:33])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:10]2[C:11](=[O:15])[C:12]([CH3:14])=[CH:13][NH:8][C:9]2=[O:33])[CH2:24][CH2:23]1
Reactant: COc1ccccc1N1CCN(CCCn2c(=O)c(C)cn(Cc3ccccc3)c2=O)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1ccccc1N1CCN(CCCn2c(=O)[nH]cc(C)c2=O)CC1
Yield: 71.1 %

Procedure:
A mixture of 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione (809 mg, 1.8 mmol), prepared as in Example 25, 10% palladium on carbon (800 mg) and of 0.1N ammonium formate (180 mL, 18 mmol in methanol) was heated 10 hours at reflux. The reaction mixture then was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) eluting with ethyl acetate to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione (459 mg, 1.28 mmol), m.p. 168°-170° C. The free base was recrystallized from a solution of hydrochloric acid in methanol to give 3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 245°-248° C. Anal.: Calcd. for C19H26N4O3.(HCl)2 : C, 50.99; H, 6.71; N, 12.52%; Found: C, 51.06; H, 6.47; N, 12.58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH2:61])[CH:56]=[C:55]2[CH3:62]>CN(C=O)C.O.CCOC(C)=O>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[N:57]([NH:61][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:16])[CH:56]=[C:55]2[CH3:62]
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: Cc1cn(N)c2ccc(F)cc12
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (372 mg, 1.7 mmol), HCTU (757 mg, 1.83 mmol), and DIPEA (780 μL, 4.47 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3-methyl-indol-1-ylamine (250 mg, 1.52 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (332 mg, 60%) as a solid. MS: 365 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.08 (s, 1H), 9.43 (s, 2H), 8.36 (d, 1H), 8.20 (dt, 1H), 7.70-7.62 (m, 1H), 7.48 (dt, 1H), 7.40 (dd, 1H), 7.35 (dd, 1H), 7.32 (s, 1H), 7.03 (dt, 1H), 2.27 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1
Reactant: O=C(O)CSc1ccc([N+](=O)[O-])c2ccccc12
Solvent: CO
Product: Nc1ccc(SCC(=O)O)c2ccccc12
Yield: 112 %

Procedure:
70 mg 20 was dissolved in 50 ml methanol. The solution was pumped at a rate of 1.0 ml/min through H-cube (25° C., 40 barr, full H2 mode) affording a colorless solution which turned in air slightly brown. The solution was concentrated to dryness affording a quantitative yield of the product 69.5 mg as a grey solid. 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.54 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.44 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 3.42 (s, 2H). LRMS (ES−) 188 (M—H—CO2)−; HRMS (ES−) m/z calculated for C12H10NO2S (M−H)− 232.0438, found 232.0435.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][O:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COCCOc1ccc([N+](=O)[O-])cc1Cl
Temperature: 50 °C
Yield: 94.7 %

Procedure:
2-Chloro-1-fluoro-4-nitrobenzene (0.8 g, 4.56 mmol) and 2-(methyloxy)ethanol (0.52 g, 6.84 mmol) were combined and dissolved in Acetonitrile (15 mL). Potassium carbonate (2.4 g, 17 mmol) was then added and the resulting mixture was heated at 50° C. for 16 h. The reaction was not complete so additional potassium carbonate (1.0 g, 7.24 mmol) and 2-(methyloxy)ethanol (0.08 g, 1.05 mmol) were added as well as DMF (3 mL) to aid in solubilizing the reaction which was then heated at 85° C. for 16 h. The reaction was cooled to rt then diluted with EtOAc (250 mL) and water (150 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield 1.0 g of the compound. 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.21 (m, 1H), 7.38 (d, 1H), 4.35 (m, 2H), 3.72 (m, 2H), 3.32 (s, 3H).
Reaction SMILES: C([N:3](CC)[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6]N)C.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][CH2:6][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][NH2:3])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Product: CC(C)(C)NCC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using tert-butylamine LC/MS (M+H)+: 283. HPLC ret. time (Condition B): 2.202 min.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]([C:23]1[CH:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1)[CH2:8][NH:9][C:10]([CH3:22])([CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][C@H:7]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:8][NH:9][C:10]([CH3:21])([CH3:22])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(Cc1ccc(N)cc1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a slurry of [2(R)-(tert-butyl-dimethyl-silanyloxy)-2-(6-chloro-pyridin-3-yl)-ethyl]-[1,1-dimethyl-2-(4-nitro-phenyl)-ethyl]-amine (8.0 g) and 10% palladium-on-carbon (4.0 g) in MeOH (200 mL) was added ammonium formate (22 g) and the resulting mixture was stirred at ambient temperature for 3 h. The reaction mixture was filtered through Celite®, washing with MeOH and the filtrate concentrated in vacuo. The resulting semi-solid was partitioned between ethyl acetate and half-saturated aqueous sodium bicarbonate, the organic phase was separated, dried (Na2SO4) and concentrated in vacuo to afford 6.5 g of the title compound (I-2g) as a dark oil.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CO[C:10]1[CH:16]=CC(O)=C[CH:11]=1.CO>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4].C(O)CCC>[C:1]([O:6][CH2:7][CH2:11][CH2:10][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc(O)cc1
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CO
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
An 74.1 g (1.0 mole) amount of n-butanol, 250.2 g (2.5 moles) of methyl methacrylate, 0.488 g (0.001 mole) of zirconium acetylacetonate and 0.28 g of hydroquinone monomethyl ether were added to a one liter flask fitted with an agitator, thermometer and fractionating tower and were heated and agitated. An azeotropic mixture of methyl methacrylate and methanol from the upper part (top) of the fractionating tower was removed at a reflux ratio of 5 to 10:1 to continuously advance the reaction. The reaction was conducted for 1.5 hours while the temperature at the top was 65° to 70° C. and the flask temperature was 104° to 130° C. The reaction showed a 99.5% conversion of n-butanol and a 99.2% yield of n-butyl methacrylate.
Reaction SMILES: [O:1]=[O+][O-].C=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH2:6]1.CSC>CO>[O:1]=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[CH2:6]1
Reactant: O=[O+][O-]
Reactant: C=C1CC(C(=O)OCCC)C1
Solvent: CO
Solvent: CSC
Product: CCCOC(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 88 %

Procedure:
An ozone gas was blown into a solution (200 mL) of propyl 3-methylidenecyclobutanecarboxylate (15 g) in methanol at −78° C. for 2 hr. Dimethyl sulfide (21 g) was added to the reaction mixture at the same temperature, and the mixture was warmed to room temperature over 1 hr. The obtained mixture was concentrated and purified by silica gel column chromatography to give the title compound as a colorless oil (13 g, 88%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([CH:23]=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:23][C:22]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:14][C:15]2[C:20]([C:21]=1[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1c(C=O)c(-c2ccc(F)cc2)nc2ccccc12
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH2 Cl2 (10 ml) was added over a 15 minute period to a cold (-10° C.) solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (1.744 gm, 5.95 mmol) (the preparation of which is described in Example 2) and triphenylphosphine (4.680 gm, 17.84 mmol) in CH2Cl2 (34 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow-orange oil. The oil was chromatographed (flash, Merck SiO2, 30% CH2 Cl2 in hexane followed by 1:1 CH2Cl2 in hexane followed by straight CH2Cl2) to give 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as a colorless foam (2.572 gm,
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH:46][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=3)[S:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccc(C)nc3)nc12

Procedure:
From 6-methylnicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine in dioxane and DMF. ES-MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1(C)C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].IC>O1CCCC1.CO>[CH3:11][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:29]=2)[CH2:25][CH2:26]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium bis(trimethylsilyl)amide (67 ml of a 0.5M toluene solution) was added slowly to a stirred solution of 6-nitroindoline (5.0 g) in anhydrous tetrahydrofuran (200 ml) at -78° C. under a nitrogen atmosphere. Iodomethane (2.09 ml) was added then the reaction mixture was allowed to warm to room temperature then stirred overnight. Methanol (5 ml) was added then the solution was evaporated to dryness. The residue was dissolved in diethyl ether (300 ml), washed with water, saturated brine then dried (magnesium sulphate) and evaporated to dryness. The crude product was purified by column chromatography on silica using 10% ethyl acetate/petroleum ether (60-80)→30% ethyl acetate/petroleum ether (60-80) and the product crystallised from diethyl ether/petroleum ether (60-80) to afford 0.9 g.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1)#[N:2].C(OCC)(=O)C.Cl.P([O-])(OCC)(SCC)=[S:22].C(=O)([O-])O.[Na+].[OH-].[Na+]>>[NH2:2][C:1](=[S:22])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: CCOP([O-])(=S)SCC
Reactant: CCOC(=O)c1cnn(CC#N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(CC(N)=S)c1
Reaction time: 23 h
Yield: 72.5 %

Procedure:
To the compound (1.14 g, 6.34 mmol) obtained in Example 1a were added 4M hydrogen chloride-ethyl acetate solution (12 mL) and diethyl dithiophosphate (1.59 mL, 9.51 mmol), and the mixture was stirred for 23 hr. The reaction mixture was alkalified with saturated aqueous sodium hydrogen carbonate solution and 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.98 g, 72%) as a colorless solid.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][N:7]=1.Cl.[Cl:9][C:10]1[C:11]([NH:17][NH2:18])=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>C(O)(C)C>[Cl:9][C:10]1[C:11]([NH:17][NH:18][C:3]2[S:4][CH2:5][CH2:6][N:7]=2)=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: CSC1=NCCS1
Reactant: Cc1cccc(Cl)c1NN
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(Cl)c1NNC1=NCCS1

Procedure:
A solution of 11.2 g (5% excess) of 2-methylthio-2-thiazoline in 20 ml of isopropanol was added slowly in the course of 30 minutes to a suspension, which was stirred under reflux, of 15.5 g (0.08 mol) of 3-chloro-2-tolyl-hydrazine hydrochloride in 100 ml of isopropanol.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Cl:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1>>[C:1]([O:7][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:8])[CH:14]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: Oc1cccc(Cl)c1
Product: C#CCCC(=O)Oc1cccc(Cl)c1
Yield: 95.1 %

Procedure:
According to the protocol described in Example 235(B), the reaction between pent-4-ynoic acid (590 mg, 6.0 mmol) and 3-chlorophenol (771 mg, 6.0 mmol) afforded 1.19 g of 3-chlorophenyl pent-4-ynoate (Yield: 95%) as colorless-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent)
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
(3-Phenoxyphenyl)acetic acid (11.5 g) and 36N aqueous sulphuric acid solution (3 cc) in ethanol (200 cc) are brought to boiling for 72 hours. After being cooled to approximately 20° C., the reaction mixture is concentrated to dryness at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil is dissolved in dichloromethane (300 cc); the organic phase is washed with water (150 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is dissolved in a mixture (20 cc) of cyclohexane and ethyl acetate (50:50 by volume), and the solution is poured onto silica (400 g) contained in a column 5 cm in diameter. Elution is performed with a mixture of cyclohexane and ethyl acetate (50:50 by volume), and the corresponding eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl (3-phenoxyphenyl)acetate (7.4 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:10][C:4]1[CH:3]=[C:2]([OH:12])[CH:7]=[N:6][C:5]=1[S:8][CH3:9]
Reactant: CSc1ncc(N)cc1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc(O)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
A slurry of 5-amino-3-methyl-2-methylsulfanylpyridine (20.3 g, 132 mmol) in 20 wt percent aqueous sulfuric acid (170 mL) was cooled to −2° C. via an ice/salt water bath. A solution of sodium nitrite (9.1 g, 132 mmol) in water (30 mL) was added dropwise, maintaining the internal temperature at or below 1° C. After stirring for an additional 20 minutes, the reaction mixture was cautiously poured in portions into a rapidly stirred, hot (100° C.) solution of 20 wt. percent aqueous sulfuric acid (330 mL). Stirring was continued for 10 minutes, then the mixture was allowed to cool to room temperature. The reaction was washed with methylene chloride (3×200 mL), then the pH of aqueous layer was raised to 4-5 (in the cold) with 50 wt percent aq. sodium hydroxide (ca. 160 mL). A precipitate consisting of both a white solid and a reddish brown oil had formed. Additional 20 wt percent aq. sodium hydroxide was added, raising the pH to 6 and resulting in more precipitate/oil formation. The mixture was cooled and filtered, collecting the white solid, while the majority of colored oil remained in the mother liquor. The collected solid was taken up in 5 percent aq. sodium hydroxide (300 mL) and washed with ether (2×100 mL) to remove impurities and unreacted starting material. The aqueous portion was then treated with activated charcoal, filtered through celite, and the pH adjusted to 5-6 with glacial acetic acid. The precipitate was collected by filtration and dried in vacuo affording an off-white powder, 14 g, 90 mmol, 68 percent yield.