Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20][O:21][NH2:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].N1C=CC=CC=1>C(O)C>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21][N:22]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH3:10])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NOCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 3′-fluoro-4′-hydroxyacetophenone (0.063 g, 0.411 mmol), O-(4-nitrobenzyl)hydroxylamine hydrochloride (0.100 g, 0.491 mmol) and pyridine (0.13 ml, 1.61 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 5h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with dichloromethane/water. The resultant mixture was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to an off-white solid. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a 3′-fluoro-4′-hydroxyacetophenone-O-4-nitrobenzyloxime (CP9-132) as light yellow solid (0.081 g, 65%),
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH:26]1([CH2:25][CH2:24][C:23]([NH:22][C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[N:4]4)=[O:13])[CH:16]=2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc2nccnc2c1

Procedure:
Using an analogous procedure to that described in Example 5, quinoxaline-6-carboxylic acid was reacted with N-(3-amino4-methylphenyl)-3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-0.97 (m, 2H), 1.04-1.24 (m, 3H), 1.40-1.78 (m, 8H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.69 (s, 1H), 8.22 (d, 1H), 8.44 (d, 1H), 8.74 (s, 1H), 9.05 (m, 2H), 9.84 (s, 1H), 10.25 (s, 1H); Mass Spectrum: M+H+ 417.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-methoxybenzene. Yield 19%. MS M+H calculated 396.1; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: O.O.O.C([O-])(=O)C.[Na+].[CH3:9][C@H:10]1[C@@:19]2([CH3:20])[C:14]([CH2:15][CH2:16][C@@H:17]([C:21](Cl)([CH3:23])[CH3:22])[CH2:18]2)=[CH:13][C:12](=[O:25])[CH2:11]1.O>C(O)(=O)C>[CH3:9][C@H:10]1[C@:19]2([CH3:20])[CH2:18][C@H:17]([C:21]([CH3:23])=[CH2:22])[CH2:16][CH2:15][C:14]2=[CH:13][C:12](=[O:25])[CH2:11]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H](C(C)(C)Cl)C[C@]21C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CCC2=CC(=O)C[C@@H](C)[C@]2(C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Sodium acetate trihydrate (0.22 g, 1.6 mmol) was added to a single-neck round bottom flask that had been fitted with a reflux condenser. A solution of the chloroenone Compound 8 (0.14 g, 0.54 mmol) in glacial acetic acid (4 mL) was injected into the flask, and the mixture was heated to 100° C. and held at that temperature for 2 hours. The reaction mixture was then cooled to room temperature, poured into cold water, and extracted with chloroform. The organic layer was then washed with successive portions of 2% aqueous KOH, 2 N HCl, NaHCO3, and brine, and then dried over MgSO4. The excess solvent was removed via rotary evaporator to provide nootkatone as a yellow oil (93%). The overall yield from β-pinene to nootkatone was 23% using path b, and 25% using path a, both of which are relatively high overall yields. Because the Oxy-Cope reaction and the methylation both provided the desired enantiomeric product, the enantiomeric purity of the final nootkatone product was little changed from that of the β-pinene starting product. Qualitatively, the fragrance of the synthesized nootkatone was identical to the fragrance of nootkatone derived from other sources. NMR data matched that previously reported for nootkatone: 1H NMR: (250 MHz, CDCl3), δ 5.77 (s, 1H), 4.75–4.72 (m, 2H), 2.62–2.43 (m, 1H), 2.41–2.22 (m, 4H), 2.09–1.87 (M, 3H), 1.46–1.38 (m, 1H), 1.12–1.10 (m, 4H), 0.98 (d, 3H).
Reaction SMILES: C(O[NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[SH:13])(C)(C)C.[CH:14](O)=O>>[S:13]1[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=[CH:14]1
Reactant: O=CO
Reactant: CC(C)(C)ONc1cnccc1S
Product: c1cc2scnc2cn1

Procedure:
In formic acid (60 ml) was dissolved 3-(tert-butoxyamino)-4-mercaptopyridine (9.20 g), followed by heating under reflux for 4 hours. After the reaction mixture was concentrated under reduced pressure and a 5N aqueous solution (100 ml) of potassium hydroxide was added to the residue, the resulting mixture was extracted with ether. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue and the solid so precipitated was collected by filtration, whereby the title compound was obtained as a colorless solid (3.97 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[CH2:8].[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]2[CH2:8][CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][C:4]=3[CH:17]2[C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Reactant: C=Cc1cccn1C
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)(C#N)N1C(=O)C2CCc3c(ccn3C)C2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 589.2 %

Procedure:
A mixture of 1-methyl-2-vinylpyrrole (3.90 g, 36.0 mmol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (7.00 g, 36.0 mmol) and chloroform is stirred overnight at room temperature and concentrated in vacuo. The resultant residue is flash chromatographed (silica gel, 50% ether:hexanes eluent) to afford the title product as a clear yellow glass (63.5 g, 58.8%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5](CN=C=O)[CH:4]=[C:3]([CH2:11][N:12]=[C:13]=[O:14])C=1.C1(CN=C=O)C(C[N:22]=[C:23]=[O:24])=CC=CC=1>>[CH2:1]([N:22]=[C:23]=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:11][N:12]=[C:13]=[O:14]
Reactant: O=C=NCc1cccc(CN=C=O)c1
Reactant: O=C=NCc1ccccc1CN=C=O
Product: O=C=NCCCCCCN=C=O

Procedure:
The same isocyanuration reaction as in Production Example 1 was carried out except that 3,290 g of hexamethylene diisocyanate and 210 g of "Takenate 500" (xylylene diisocyanate produced by Takeda Chemical Industry Co., Ltd.) were used instead of 3,500 g of hexamethylene diisocyanate, and the amount of the isocyanuration catalyst used in production Example 1 was changed to 4.7 g. There was obtained 4,219 g of the reaction mixture containing the deactivated catalyst.
Reaction SMILES: [Br-].[C:2]1([S+:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.[C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])(=[O:34])[CH3:33].[Na].O>ClCCl>[OH:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][C:26]([CH2:33][C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])=[O:34])([CH2:25]3)[CH2:31]1)[CH2:29]2.[C:2]1([S+:8]2[C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: [Br-]
Agent: [Na]
Agent: c1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Solvent: ClCCl
Solvent: O
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 97 %

Procedure:
5-phenyl-5H-dibenzo[b,d]thiophenium bromide (28.0 g, 82.04 mmol) and 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate-sodium salt (35.68 g, 83.7 mmol) were dissolved in dichloromethane (500 mL) and water (500 mL) and stirred at r.t. for 16 h. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×300 mL). The combined organic layers were washed with water (4×500 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×350 mL) to afford the title compound (54.00 g, 99%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.55 (d, J=8 Hz, 2H), 8.41 (d, J=8 Hz, 2H), 8.02 (dt, J=7.5, 0.5 Hz, 2H), 7.77-7.84 (m, 5H), 7.67 (t, J=7.5 Hz, 2H), 4.31 (t, J=6.5 Hz, 2H), 3.63 (s, 10H), 2.71 (tt, J=14, 6.5 Hz, 2H), 1.52-1.80 (m, 12H).
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12](=[O:18])(=[O:17])[CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21].C(O)(=O)C.Cl>O>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12](=[O:18])(=[O:17])[CH2:13][CH2:14][C:15]1=2
Reactant: CN(C)CCCN
Reactant: O=C(CC1CS(=O)(=O)CCC1=O)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCS(=O)(=O)C2

Procedure:
A solution of 2.0 g (0.0075 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one-1,1-dioxide, 0.85 g of dimethylaminopropylamine and 30 ml. of acetic acid is heated under reflux for 5 hours. The reaction solution is cooled, diluted with water, adjusted to a pH of 1 with hydrochloric acid, and then washed with ether. The solution is made basic with sodium bicarbonate and extracted with ether. The ether extract is dried and concentrated to a solid. The solid is recrystallized from 2-propanol to give off-white needles of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole-5,5-dioxide, m.p. 123° to 125°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: N[C@H](CO)c1ccccc1
Product: O=C(N[C@H](CO)c1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-2-amino-2-phenylethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield (S)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxy-1-phenylethyl)terephthalamide. MS (Q1) 506 (M)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]=[C:18]([CH3:30])[N:17]=1)=O>O1CCOCC1.CCCCCC>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[N:19]=[C:18]([CH3:30])[N:17]=2)=[O:13])[S:3][CH:4]=1
Reactant: COC(=O)c1cc(-c2cc(F)cc(F)c2)nc(C)n1
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)nc(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of 156 mg (1.37 mmol, 1.8 equiv.) of 2-Amino-4-methylthiazole in 4 ml of dry dioxane were added 0.68 μl (1.37 mmol, 1.8 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 1 h at room temperature. Then 200.0 mg (0.76 mmol) of 6-(3,5-Difluoro-phenyl)-2-methyl-pyrimidine-4-carboxylic acid methyl ester were added and the reaction was heated to 90° C. for 4 h. The reaction was quenched by cautious addition of 0.2 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) and recristallised from diisopropyl ether to yield the title compound (152.0 mg, 58%) as a white solid, MS (ISP): m/e=347.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH:35]([NH2:38])([CH3:37])[CH3:36].[CH:39]([OH:41])=[O:40].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:39]([OH:41])=[O:40].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:38][CH:35]([CH3:37])[CH3:36])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CC(C)N
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)NCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and isopropylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 29 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.[I:25]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[I:25])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Solvent: CC#N
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(I)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
A mixture of 2-[4-(2-methoxyethoxy)phenyl]-6-propoxyimidazo[1,2-b]pyridazine (327 mg, 1.00 mmol), N-iodosuccinimide (225 mg, 1.00 mmol) and acetonitrile (4 mL) was stirred at room temperature for 1.5 hours. The mixture was filtered and the collected solid washed with cold, fresh acetonitrile to afforded Compound 96 (344 mg, 76%) as an off-white solid. 1H n.m.r. (CDCl3) δ 1.08, t, J=7.3 Hz, 3H; 1.8-2.0, m, 2H; 3.47, s, 3H; 3.75-3.83, m, 2H; 4.15-4.23, m, 2H; 4.41, t, J=6.6 Hz, 2H; 6.76, d, J=9.5 Hz, 1H; 7.04, d, J=9.3 Hz, 2H; 7.80, d, J=9.9 Hz, 1H; 8.04, d, J=8.7 Hz, 2H. Mass spectrum (APCI+) m/z 454 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH3:19][CH:20]([CH3:25])[CH2:21]B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COC(OC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH:20]([CH3:25])[CH3:21])=[O:5])[CH3:2]
Reactant: CC(C)CB(O)O
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: COC(C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(CC(C)C)c2c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
The mixture of 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c, 1.3 g, 5 mmol), (2-methylpropyl)boronic acid (1.0 g, 10 mmol), sodium carbonate (3.18 g, 30 mmol) and POPd (bis[bis(1,1-dimethylethyl)phosphinous acid-κP]dichloropalladium, CAS: 391683-95-7) (75 mg, 0.15 mmol) in dimethyloxyethane (DME) (20 mL) was stirred at 100° C. for 2 days. After cooling to room temperature, the product was extracted with ethylacetate. The combined organic layers were successively washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 3-cyano-4-isobutyl-quinoline-6-carboxylic acid ethyl ester (1.1 g, 79%) as a clear oil. LC-MS m/e 283 (MH+).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl.CC(O)C>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:4][CH:2]([CH3:3])[CH3:1]
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ncnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Potassium t-butoxide (4.1 ml, 4.1 mmol; 1M in THF) was added to a suspension mixture of 6-bromo-4-chloro-quinazoline (1.0 g, 4.0 mmol) and 2-propanol (0.313 ml, 4.1 mmol) in THF (20 ml). After stirring at 50° C. for 30 minutes, the mixture was cooled to room temperature and the THF was removed in vacuo. The residue was taken up in ethyl acetate (50 ml) and the organic layer was washed with water followed by brine. The organic layer was dried over Na2SO4 and the residue purified by silica gel chromatography with gradient of 11 to 32% ethylacetate-hexane. Product containing fractions were pooled and concentrated to afford the title compound as beige solid (0.93 g, yield: 85%). The resulting compound was characterized as follows: MS (m/z) 266.75 [M+H]+; HPLC Rt=1.68 minutes (Method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([N:21]=[C:22]=[S:23])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[CH3:11][O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=[S:23])[NH:10][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: NS(=O)(=O)c1cccnc1
Reactant: COc1nc(N=C=S)nc(OC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1nc(NC(=S)NS(=O)(=O)c2cccnc2)nc(OC)n1
Yield: 75.8 %

Procedure:
A mixture of 1.58 g of 3-pyridinesulfonamide, 2.04 g of 4,6-dimethoxy-2-isothiocyanato-1,3-5-triazine and 1.5 g of anhydrous potassium carbonate was stirred in 75 ml of acetone for 60 hours at ambient temperature. The reaction mixture was then poured into 500 ml of cold water, acidified with hydrochloric acid and the precipitated product was removed by filtration to yield 2.7 g of the desired compound, m.p. 158°-160°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5][N:4]=1.C(OO)(C)=[O:23]>C(C#N)(C)=O>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5][N:4]=1)=[O:23]
Reactant: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Reactant: CC(=O)OO
Agent: CC(=O)C#N
Product: CS(=O)c1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (636 mg) in AcCN (3 mL) was added AcOOH (39% in AcOH, 0.7 mL). The mixture was stirred at room temperature for 20 h, and the solids were collected by filtration and dried in vacuo to give 2-(methylsulfinyl)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (530 mg). MS 317.2 (M+H).
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:41])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.1 g (2.27 mMol) of 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide was stirred in 100 ml of ethanol saturated with hydrogen chloride for 5 hours first at 0° C. and then at room temperature until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off at a maximum bath temperature of 30° C. and the oily residue was taken up in 100 ml of absolute ethanol and mixed with 1.6 g (22 mMol) of ammonium carbonate. After 18 hours stirring at room temperature the solvent was distilled off in vacuo and the crude product was purified by flash chromatography (silica gel; gradient: water/methanol=19:1 to 4:1). When the eluates are evaporated down the desired compound is obtained as a white foam. Yield: 0.77 g (63% of theory), Rf value: 0.19 (silica gel; dichloromethane/ethanol=3:7) C27H27N5O3S (501.60) Mass spectrum: (M+H)+ =502
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].C1(C)C=CC=CC=1>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: CCSSCC
Reactant: Oc1ccccc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCSc1ccccc1O
Yield: 46.7 %

Procedure:
A similar run using phenol (142 g, 1.51 moles), toluene (150 ml), zirconium tetrachloride (6.0 g, 0.026 moles), and ethyl disulfide (62.0 g, 0.50 moles) gave ortho-(ethylthio)phenol (36.0 g, 46% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)co1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)co1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1584 mg, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in 1,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80° C. After 1 hr, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol, 26% yield) as a white powder: LCMS (ES) m/e 206 (M+H)+.