Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:30]=[C:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[C:42]([CH:43]=O)=[CH:41][CH:40]=[CH:39][N:38]=1>O1CCCC1.CO>[CH3:2][O:3][CH:4]=[CH:43][C:42]1[C:37]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C:31]2=[O:30])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1N1CCCCC1=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC=Cc1cccnc1N1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Methoxymethyl-triphenylphosphonium chloride (3.59 g, 10.48 mmol, 1.3 eq) is dissolved in dry tetrahydrofuran (150 ml) under nitrogen. This solution is cooled at 0° C. and potassium tert-butoxide (1.085 g, 9.67 mmol, 1.2 eq) is added. The reaction mixture is stirred at 0° C. for 30 min. A solution of crude 2-(2-oxopiperidin-1-yl)pyridine-3-carbaldehyde a4-1 (4.2 g, 8.06 mmol, 1 eq) in dry THF (50 ml) is added, then the reaction mixture is warmed up to room temperature and stirred for 1 hour. The solvent is removed under reduced pressure, the residue is taken with ethyl acetate, stirred, filtered and the solid cake washed with ethyl acetate (2 times). The filtrate is evaporated under reduced pressure. The residue is purified by chromatography over silicagel (gradient: CH2Cl2/MeOH/NH4OH 100/0/0 to 97/3/0.3). The product obtained is redissolved in methanol, catched over an acidic column, washed with methanol and then released with ammonia 1M in methanol. The solvent is evaporated under reduced pressure to afford 540 mg of 1-[3-(2-methoxyethenyl)pyridin-2-yl]piperidin-2-one a4-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][CH2:28][OH:29].[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: OCCCBr
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1cc(Cl)cc(OCCCO)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of phenol 25 (8.80 g, 33.0 mmol) and 3-bromno-1-propanol (2.9 mL, 33 mmol) in acetonitrile (300 nL) was added solid cesium carbonate (12 g, 37 mmol). After stirring 16hrs at 50° C., more 3-bromo-1-propanol (3.3 mmol) and cesium carbonate (3.3 mmol) were added and the reaction stirred another 2 hrs. After adding more 3-bromo-1-propanol and cesium carbonate (3.3 mmol each) and sodium iodide (3.3 mmol), the reaction was stirred 30 minutes at 65° C., then cooled and filtered. The filtrate was evaporated in vacuo, the residue dissolved in ethyl acetate, washed with water, and the organic layer dried over Na2SO4 and filtered. The evaporated filtrate then gave product 26 (5.96 g 56%). 1H NMR (300 MHz, CDCl3) δ 7.63 (t, 1H, J=1.5 Hz), 7.48 (dd, 1H, J=2.4 Hz, 1.4 Hz), 7.46-7.31 (m, 5H), 7.09 (t, 1H, J=2.4 Hz), 5.35 (s, 2H), 4.14 (t, 2H, J =6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 2.05 (pentet, 2H, J=6.0 Hz).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].C1C=CC=CC=1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[CH:24]=[CH:2][C:1]([C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1cncnc1C
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncncc1C(=O)C=CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 28.2 g of 5-acetyl-4-methylpyrimidine in 250 ml of a chilled 1:1 mixture of benzene and DMF was added 33.6 g of tert-butoxy-bis(dimethylamino)methane dropwise. The solution was stirred overnight at room temperature. The solvents were evaporated in vacuo to yield 36.2 g of 3-dimethylamino-1-(4-methylpyrimidin-5-yl)-2-propen-1-one as a brick-red solid.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([CH2:12][CH2:13]O)[N:10]=[C:9]3[C:15](=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][S:17][CH2:18][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH3:48]>N1C=CC=CC=1.C(O)C.O>[C:1]1([CH:7]2[N:11]([CH2:12][CH2:13][NH2:48])[N:10]=[C:9]3[C:15](=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][S:17][CH2:18][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: OCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: NCCN1N=C2C(=Cc3ccccc3)CSCC2C1c1ccccc1
Reaction time: 16 h

Procedure:
3a,4,6,7-Tetrahydro-3-phenyl-7-(phenylmethylene)thiopyrano[4,3-c]pyrazole-2(3H)-ethanol is suspended in pyridine and treated with one equivalent of tosyl chloride. After standing at room temperature for about 16 hours, the mixture is poured into water and the tosylate is dissolved in ethanol, cooled and saturated with ammonia gas. After standing for 3 days, the excess ammonia and solvent are removed by evaporation to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][CH:3]=1.ClC1C(Cl)=C(Cl)C(Cl)=CC=1.[F-].[K+].ClC1C(Cl)=C(Cl)C(Cl)=CC=1[C:26]([F:28])=[O:27]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:26]([F:28])=[O:27]
Reactant: O=C(F)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: Fc1ccc(F)c(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: Clc1ccc(Cl)c(Cl)c1Cl
Product: O=C(F)c1cc(F)c(F)c(F)c1F
Yield: 43 %

Procedure:
DE-A 3 420 796 describes a process for the preparation of 2,3,4,5-tetrafluorobenzene derivatives, in which 2,3,4,5-tetrachlorobenzene derivatives are reacted with potassium fluoride in a solvent at elevated temperature. Using 2,3,4,5-tetrachlorobenzoyl fluoride as starting material and continuously distilling off the mixture of the fluorination products at from 800 to 500 mbar produces, after fractional distillation of the mixture of the fluorination products, the desired 2,3,4,5-tetrafluorobenzoyl fluoride in a yield of only 10% of theory, while significantly more undesired fluorination products are obtained, namely 2,3,4-trifluoro-5-chlorobenzoyl fluoride in a yield of 43% of theory and 2,4-difluoro-3,5-dichlorobenzoyl fluoride in a yield of 14% of theory (see Example 2 in DE-A). If 2,3,4,5-tetrachlorobenzonitrile is used as starting material and the fluorination mixture is subjected to fractional distillation, the ratios are obviously similar, although no information concerning the amounts of the tetrafluoro-, tetrafluorochloro- and difluorodichlorobenzonitriles obtained is given (see Example 5 in DE-A).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCC3Cc4ccccc4N3)cc2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
A mixture of 3.55 g of 5-[4-(1-t-butoxycarbonyl-indolin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 4) and 30 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was poured into water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.41 g of the title compound. This product was dissolved in ethanol and precipitated by adding water, to give a powder melting at 55.8°-58.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.CO>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 50 °C
Yield: 71.1 %

Procedure:
N-(4-Nitro-phenyl)-methanesulfonamide (Example 3a, 25 g, 115.62 mmol) was dissolved in N,N-dimethylformamide (15 mL) with gentle heating to ˜50° C. via heat gun. Ethyl acetate (100 mL) and methanol (100 mL) were added followed by 10% palladium on carbon (4 g). The mixture was degassed while stirring and the flask was charged with hydrogen gas via balloon. The mixture was stirred at 25° C. for 4.5 h. The mixture was filtered through Celite (rinsed with ethyl acetate) and concentrated in vacuo to a yellow green solution with a volume of ˜10 mL. Dichloromethane (˜50 mL) was added and a solid began to precipitate. The mixture was stirred at 25° C. for 30 min. The solid was collected by vacuum filtration and dried in vacuo to afford the desired product, N-(4-amino-phenyl)-methanesulfonamide (15.32 g, 82.26 mmol, 71% yield) as a beige powder. 1H NMR (400 MHz, DMSO-d6) δ 2.79 (3H, s), 5.00 (2H, s), 6.49 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.6 Hz), 8.87 (1H, s).
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[O:9])=[CH:6][CH:5]=1.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1.[OH-].[Na+]>[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:1])[C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: COc1cccc(-c2cc(=O)[nH]c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Methyl iodide (1.58 ml) was added to a solution of interm. (5-f) (7.6 g) and benzyl-triethylammonium chloride (BTEAC) (2.23 g) in THF (80 ml) and sodium hydroxide (40%, 80 ml). The mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: DCM 100%). The desired fractions were collected and the solvent was evaporated, yielding 7.1 g (90%) of 6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-1-methyl-2(1H)-quinolinone (interm. 5-g).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]OC1CCCCO1.[O:22]1C=C[CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:10][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Brc1ccccc1COCCOCCOC1CCCCO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Brc1ccccc1COCCOC1CCCCO1
Reaction time: 4 h

Procedure:
The reaction and work up was conducted as described in the preparation of compound 420. Starting materials were compound 417 (8.0 g, 34.9 mmol) in 20 mL dry THF, 3,4-dihydro-2H-pyran (3.2 mL, 34.9 mmol) and p-toluenesulfonic acid (0.14 g, 0.76 mmol) and the reaction time was 4 h. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:2 as the eluent to afford the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH3:21])[CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]#[C:14][CH2:13][N:12]([CH3:11])[CH3:21])=[N:6][S:5](=[O:10])[N:4]=1
Reactant: CN(C)CC#CCCCCN
Reactant: COC1=NS(=O)N=C1OC
Product: COC1=NS(=O)N=C1NCCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (1.57 g) and 7-(dimethylamino)hept-5-ynylamine (1.5 g) were reacted to give a solution of 3-methoxy-4-[7-dimethylaminohept-5-ynylamino]-1,2,5-thiadiazole-1-oxide. Reaction with ammonia gas and purification as in Example 1 gave the title compound (1.8 g), m.p. 154°-5° C. (recrystallisation from isopropanolethyl acetate).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)O1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.CCCCCC.C(OCC)(=O)C>[OH:36][C:32]1[CH:31]=[C:30]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Temperature: 25 °C
Yield: 208 %

Procedure:
The tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (6.42 g, 9.23 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4.69 g, 21.3 mmol, and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) were mixed in dioxane (20 mL), ethanol (10 mL) and 2 M aqueous sodium carbonate (5.0 mL). The solution was refluxed for 4 hours, cooled to room temperature, and poured into ethyl acetate (150 mL). The solution was extracted with 1N aqueous hydrochloric acid (2×100 mL), filtered through celite, extracted with saturated aqueous sodium bicarbonate (2×100 mL), and extracted with saturated with saturated aqueous ammonium chloride (2×100 mL). The solution was dried over sodium sulfate, vacuum filtered through a bed of silica gel and solvent removed at reduced pressure to afford a red oil. The tert-butyl 4-(3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.3 g, 19.2 mmol) was obtained as a combination of two crystallization crops from dichloromethane/hexane crystallization solvents. HRMS m/z 276.1614 (calcd for M+H 276.1594.)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:31])=[CH:8][C:7]=2[O:32][CH3:33])[CH2:2]1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:34]1([N:1]2[CH2:4][CH:3]([O:5][C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]5[N:18]=[C:19]([C:21]6[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=6)[S:20][C:14]=5[C:13]4=[O:31])=[CH:8][C:7]=3[O:32][CH3:33])[CH2:2]2)[CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCC1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CN(C2CCC2)C1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-trifluoromethyl-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.909 g, 1.92 mmol) in dichloroethane (25 mL) and add cyclobutanone (0.502 mL, 6.72 mmol), sodium triacetoxyborohydride (0.814 g, 3.84 mmol), and acetic acid (0.22 mL, 3.84 mmol). Stir the mixture overnight, add saturated sodium bicarbonate, and extract with dichloromethane (3×). Dry the mixture using sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-4.5% gradient of 2N ammonia in methanol/dichloromethane to give 0.400 g (39%) of the desired product. MS/ES m/z 528.0 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1>C(O)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]2)[CH:9]=1
Reactant: O=Cc1cccnc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Product: O=C(O)C1CSC(c2cccnc2)N1
Temperature: 100 °C
Yield: 80855 %

Procedure:
Cysteine (24.2 g, 0.2 mole) and 3-pyridine carboxaldehyde (21.4 g, 0.2 mmole) were suspended in 60% aqueous ethanol (400 mL) and the mixture was heated at 100° C. for 5 hours. The reaction mixture was then cooled and most of the solvent was removed in vacuo. The resulting slurry was washed with ethanol and filtered. This material was dried overnight in vacuo at 50° C. to afford the thiazolidine acid (34 g, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](I)[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[N:31][CH:32]=1)#[CH:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:11][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[C:26]#[C:25][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[N:31][CH:32]=1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1I
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Into a reaction flask were added tert-butyl (4-cyano-2-iodophenyl)carbamate (1.4 g, 4.1 mmol), copper(I) iodide (31 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL, 4.5 mmol). The mixture was stirred under N2 bubbling for 5 minutes and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) (prepared according to Example 17, Step B) was then added. The reaction mixture was stirred at 65° C. for 2 hours. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product (0.94 g, 52%). LCMS for C24H27N4O4 (M+H)+: m/z=435.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[N:11]([O-])=O.[Na+]>O.C(O)(=O)C.O>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[N:11]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2[nH]nnc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 mmol of 3,4-Diamino-benzonitrile were suspended in water/acetic acid (4:1) and cooled to 0° C. 1.05 eq of NaNO2 were dissolved in water and added inert 30 min. The reaction was stirred at room temperature overnight. The precipitate was filtered off, washed with ether and dried under vacuum. The intermediate was not further characterized.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1.O>[CH3:4][C:3]1([CH3:5])[C:23]2[C:22](=[C:21]([CH3:27])[CH:20]=[C:25]([OH:26])[CH:24]=2)[CH2:1][CH2:2]1
Reactant: C=CC(=C)C
Reactant: Cc1cccc(O)c1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(O)cc2c1CCC2(C)C
Reaction time: 8 h

Procedure:
449 of isoprene, stabilized with 1.35 g of phenothiazine, were added dropwise over the course of 7 hours to a solution of 648 g of m-cresol, 77 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of xylene at 110° C. To complete the reaction, stirring was continued overnight at 110° C. After cooling, the acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gave 252 g of 3,3,7-trimethyl-5-hydroxy-indane; boiling point 151°-155° C/18 mm Hg; melting point 80° - 81° C. ##STR37##
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:30](B1C2CCCC1CCC2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:30]([C:12]1[N:11]=[N:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2cc(Cc3ccccc3)nnc2OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 64 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1: 0.22 g, 0.67 mmol) in tetrahydrofuran (6 ml) and water (0.6 ml) was added cesium carbonate (0.66 g, 2.01 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.049 g, 0.067 mmol). The reaction was then purged and evacuated with nitrogen several times before 9-benzyl-9-borabicyclo[3.3.1]nonane (9-BBN; 4.02 ml, 2.01 mmol) was added. The reaction vessel was then sealed and heated to 60° C. for 1 hour. Upon cooling, the resulting mixture was diluted with ethyl acetate and washed 5 times with a 1:1 mixture of water and saturated aqueous brine. The organics portion was dried (MgSO4), filtered and concentrated to give an orange oil. The crude oil was purified by silica chromatography (eluting with 0-80% ethyl acetate in petrol) to yield 6-benzyl-3,4-bis(benzyloxy)pyridazine as a colourless oil (yield=64%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:7]2=[N:8][C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][CH:11]=[C:6]2[S:5][CH:4]=1.[K].[O-]CCCC.[CH:38]([C:40]1[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]2([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:63][CH2:62]2)[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[Cl:2][C:3]1[C:7]2=[N:8][C:9]([CH:12]=[CH:38][C:40]3[CH:41]=[C:42]([C@H:46]([S:59][CH2:60][C:61]4([CH2:64][C:65]([O:67][CH3:68])=[O:66])[CH2:62][CH2:63]4)[CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([OH:58])([CH3:57])[CH3:56])[CH:43]=[CH:44][CH:45]=3)=[CH:10][CH:11]=[C:6]2[S:5][CH:4]=1
Reactant: Clc1csc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=O)c2)CC1
Agent: CCCC[O-]
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Cl)c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a suspension of the phosphonium salt from Step 5 (409 mg, 0.85 mmol) in dry THF (5 mL) at -78° C. was added a solution of potassium ten-butoxide (0.716 mL, 1M solution in THF). The mixture was warmed to room temperature for 30 min, and then cooled to -78° C. before adding the aldehyde from Step 17 (300 mg, 0.7 mmol). The mixture was stirred at -78° C. for 30 min, warmed to 0° C. for 15 min. Aqueous NH4OAc was added and the mixture was extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated to an oil. Chromatography of the crude oil on silica gel (eluted with 20% EtOAc in hexane) gave 420 mg (98%) of the title compound.