Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:15])(=O)[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:5]([Cl:3])(=[O:15])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
The title substance was synthesized as follows: 300 ml of thionyl chloride was dropped into a mixture of 358 g of commercially available terephthalaldehydic acid with 700 ml of toluene and 2 g of pyridine, and the solution was heated under reflux slowly until a homogeneous reaction solution was obtained. After the solution was cooled to room temperature, unreacted thionyl chloride and toluene as a solvent were distilled off in vacuum. Terephthalaldehydic acid chloride (b.p. 133°-135° C./15 Torr) was obtained by the vacuum distillation of the remaining reaction product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[O:23]1[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:23]1[CH:27]=[CH:26][C:25]([CH2:28][N:12]2[C:13](=[O:21])[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:11]2=[O:22])=[CH:24]1
Reactant: OCc1ccoc1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccoc3)C2=O)cc1
Temperature: 130 °C
Yield: 26.7 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 3-furanmethanol (0.19 mmol, 18 mg), diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 17 mg (27%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.61 (bs, 1H), 7.35 (bs, 1H), 7.16 (bs, 1H), 7.15-7.05 (m, 3H), 7.00-6.95 (m, 2H), 6.62-6.51 (m, 4H), 6.48 (bs, 1H), 4.63 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.Br[CH2:16]/[CH:17]=[CH:18]\[CH3:19]>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:16]/[CH:17]=[CH:18]\[CH3:19]
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Reactant: C/C=C\CBr
Product: C/C=C\CC(C#C[Si](C)(C)C)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane (0.157 g, 0.74 mmol) and (Z)-1-bromobut-2-ene (0.12 g, 0.89 mmol) according to General Procedure 11.A provided (Z)-trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)hept-5-en-1-ynyl)silane. The (Z)-1-bromobut-2-ene starting material was synthesized in two steps according to General Procedures 11.F and 11.G.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH3:15])=[CH:10][CH:9]=[CH:8]2)([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>>[Br:16][CH2:15][C:11]1[C:12]2[C:7](=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cc(OC(C)C)ccc12
Product: CC(C)Oc1ccc2c(CBr)cccc2c1

Procedure:
Using general procedure A (Exp. 1.3.), 6-isopropoxy-1-methyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-6-isopropoxy-naphthalene as colorless oil. MS: 279.1 ([M−H]−).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
Sodium azide (0.425 g, 6.54 mmol) was added to a solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (1.16 g, 2.16 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 15 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 73° C. in vacuo for 45 minutes to yield 5-(3-azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as an amber gum (0.770 g, 87.7%); Mass Spectrum (−EI, [M−H]−) m/z 406. 1HNMR (400 MHz, DMSO-d6): δ14.05 (br, 1H), 8.64-8.68 (m, 1H), 8.53 (dd, 1H, J=7.42 Hz and 1.16 Hz), 8.25-8.28 (m, 1H), 8.01-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.26 (d, 1H, J=2.08 Hz), 7.08 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.06 (t, 2H, J=6.14 Hz), 3.49-3.52 (m, 2H), 1.96-1.99 ppm (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH:21]=[CH:22][C:23]=1[CH3:24].[C:33](Cl)(Cl)=[O:34]>C(=S)=S>[CH3:31][C:28]1[C:33](=[O:34])[C:30]2[C:25](=[CH:26][C:27]=1[CH3:32])[C:20]1[C:21](=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=1)[CH:29]=2
Reactant: Cc1ccc(-c2ccc(C)c(C)c2)cc1C
Reactant: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC1=C(C)C(=O)C2=Cc3cc(C)c(C)cc3C2=C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
35.6 g of anhydrous aluminum chloride are added in portions to a solution of 20 g of biphenyl according to (a) and 14 g of phosgene in 130 ml of carbon disulfide at -10° C. to 0° C. in the course of 2 hours. After stirring at room temperature for 15 hours, the mixture is refluxed for 2 hours, poured onto ice-water and extracted with 1.5 l of chloroform. The residue from the organic phase (22.9 g) is separated by column chromatography on silica gel. Elution with methylene chloride/toluene=13:7 gives 9.8 g of 1,2,6,7-tetramethyl-fluorenone (Rf value 0.62) and 10.04 g of 2,3,6,7-tetramethyl-fluorenone (Rf value 0.41).
Reaction SMILES: C1C(C(OO)=[O:8])=CC=CC=1.[CH3:11][C:12]1[CH:17]2[C:18]([CH3:20])([CH3:19])[CH:15]([CH2:16]2)[CH2:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:19][C:18]1([CH3:20])[CH:17]2[C:12]3([CH3:11])[O:8][CH:13]3[CH2:14][CH:15]1[CH2:16]2
Reactant: CC1=CCC2CC1C2(C)C
Reactant: O=C(OO)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C2CC3OC3(C)C1C2
Temperature: -15 °C
Reaction time: 1 h

Procedure:
550 ml of a 23.3% (151 g) chloroform solution of 100% perbenzoic acid, are loaded into a glass reactor vessel of 2 l capacity, externally cooled to -15° C. Over a period of around 2 hours 150 g of 95% α-pinene are dripped in, maintaining the temperature between -5° C. and -2° C. The solution is then stirred for 1 hour, lowering the temperature to -10° C. At this temperature the perbenzoic acid which has precipitated out is filtered off. The chloroform solution obtained is washed with a small quantity of a 20% alkaline solution of sodium carbonate (Ha2CO3), in order to eliminate the contained residual benzoic acid. The process is then completed as in example 2a.
Reaction SMILES: CO.[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:4]=1.C=O.[CH:20]([O-])=O.[NH4+]>O>[CH3:20][NH:16][C:15]1[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH3:17])[CH:8]=[CH:7][CH:6]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C[O-]
Reactant: Cc1cccc(Nc2ncccc2N)c1
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNc1cccnc1Nc1cccc(C)c1
Reaction time: 3 h

Procedure:
600 mL of methanol and 24 mL water were added to a 3-neck 2 L round bottom flask. Nitrogen was bubbled directly into the solution. Palladium on carbon was added (10%, 10.35 g, 9.73 mmol) while bubbling continued. Next, N2-(m-tolyl)pyridine-2,3-diamine (19.38 g, 97 mmol) and formaldehyde (37%, 14.48 mL, 195 mmol) were added. The reaction mixture was stirred under nitrogen for 3 h. Next, nitrogen was bubbled into the solution and ammonium formate (123 g, 1945 mmol) was added slowly. The reaction mixture was stirred under nitrogen overnight at room temperature. The reaction mixture was filtered through Celite® and the Celite® was washed with dichloromethane. The filtrate was washed with water twice, and the organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified using column chromatography eluting with 30% ethyl acetate/hexanes to isolate the desired product. The product was combined with material from other reactions and purified by column chromatography eluting with 30% ethyl acetate/hexanes. A dark reddish-brown solid was obtained. The solid was recrystallized from boiling hexanes with a small amount of ethyl acetate to dissolve the solid. The product was filtered off as needles with some reddish color which were washed with hexanes, obtained 15.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([OH:26])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([Cl:35])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 69 h

Procedure:
To a mixture of 10 g of product from Example 64, 0.095 g of dimethylformamide and 150 ml of methylene chloride is added, dropwise, 3.42 ml of oxalyl chloride. The reaction is stirred at room temperature for 69 hours and then concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 10.5 g of the desired product as a yellow oil.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].CN1CCN(S([C:25]2[CH:26]=[CH:27][C:28]([O:45][CH2:46][CH2:47][CH3:48])=[C:29]([C:31]3[NH:39][C:38]4[C:37](=O)[NH:36][C:35](=[O:41])[N:34]([CH2:42][CH2:43][CH3:44])[C:33]=4[N:32]=3)[CH:30]=2)(=O)=O)CC1>N1C=CC=CC=1>[CH2:46]([O:45][C:28]1[CH:27]=[CH:26][CH:25]=[CH:30][C:29]=1[C:31]1[NH:39][C:38]2[C:37]([SH:2])=[N:36][C:35](=[O:41])[N:34]([CH2:42][CH2:43][CH3:44])[C:33]=2[N:32]=1)[CH2:47][CH3:48]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c([nH]1)c(=O)[nH]c(=O)n2CCC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2c([nH]1)c(S)nc(=O)n2CCC
Yield: 129.2 %

Procedure:
Phosphorus pentasulphide (0.7 g, 3.1 mmol) was added portionwise to a stirred suspension of 8-[5-(4-methylpiperazine-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropurine-2,6-dione (1.5 g, 23.3 mmol) in pyridine (15 mL) and the resulting mixture stirred under reflux for 3 hours, then evaporated under reduced pressure to give crude 8-(2-propoxyphenyl)-3-propyl-6-mercapto-3,7-dihydropurin-2-one (1.38 g) which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH3:18][Zn]Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH3:18])[N:8]=[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:10]=1)[CH3:2]
Reactant: C[Zn]Cl
Reactant: CCOC(=O)c1cc(Cl)nc(N(CC)CC)c1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(C)nc(N(CC)CC)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-6-diethylamino-isonicotinic acid ethyl ester (10.1 g, 31.6 mmol) in dioxane (120 mL), Pd(dppf) (262 mg, 0.322 mmol) is added. MeZnCl (8.40 g, 72.4 mmol) is added dropwise to the mixture before it is stirred at 75° C. for 18 h. The mixture is carefully diluted with water, then extracted with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-diethylamino-6-methyl-isonicotinic acid ethyl ester (6.39 g, containing some methyl ester) as a pale yellow oil; LC-MS: tR=0.70 min, [M+H]+=237.11.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)c(I)nc1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(C#N)nc1OC
Temperature: 150 °C

Procedure:
To a solution of 3-chloro-2-iodo-5,6-dimethoxypyridine (1-6c, 230 mg, 0.768 mmol) in DMF (7.7 mL) was added copper cyanide (138 mg, 1.54 mmol) and heated to 150° C. for 20 minutes in a microwave reactor. The mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to yield the desired product (1-6d) as a bone-colored crystalline powder. ESI+ MS [M+H]+ C8H8ClN2O2=198.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[BH:15]([OH:17])[OH:16]>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:9](=[CH:10][C:11]([CH3:12])=[CH:2][CH:3]=2)[S:8][CH:7]([B:15]([OH:17])[OH:16])[CH2:6]1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCS2
Reactant: OBO
Product: Cc1ccc2c(c1)SC(B(O)O)CC2(C)C

Procedure:
In a similar manner to Example 3(a), starting with 5.8 g (21.4 mmol) of 6-bromo-4,4,7-trimethylthiochroman, 3.88 g (76%) of the expected boronic acid are obtained, with a melting point of 252-3° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+]>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Temperature: 78 °C
Yield: 74 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.172 g, 0.4594 mmol) and ethyl formate (0.111 mL, 1.37 mmol) were dissolved in anhydrous ethanol (5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.86 mL, 2.3 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCH(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.136 g, 0.34 mmol, 74%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:17]=[C:13]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:20]#[N:21])[CH:16]=[CH:15][C:14]1=2
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CCCC2=O
Temperature: 135 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (11.5 g, 39.0 mmol), prepared in the previous step, and zinc cyanide (2.7 g, 23.5 mmol) in dry dimethylformamide (100 mL) was degassed and put under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (1.7 g, 1.5 mmol) was added and the mixture again degassed and put under a nitrogen atmosphere. The mixture was stirred at 135° C. overnight. An additional 171 mg of tetrakis(triphenylphosphine)palladium(0) was added and the reaction stirred for another 4 h. The reaction mixture was filtered through the Celite™ reagent and rinsed with ethyl acetate. The filtrate was washed with water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated in vacuo to give 8.1 g of crude product. Purification of the crude product on silica gel using a step-wise gradient of 5% to 15% ethyl acetate: hexane as the eluent gave 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (2.8 g, 41%), MS(ES) m/z 172 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:21][C:22]([O:24][CH:25]1[CH2:29][C:28](=[O:30])[N:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[C:26]1=O)=[O:23].C(N(CC)CC)C>C(#N)C>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][N:27]2[C:28](=[O:30])[CH2:29][CH:25]3[O:24][C:22](=[O:23])[CH:21]=[C:26]23)=[CH:37][CH:36]=1
Reactant: O=C(CBr)OC1CC(=O)N(Cc2ccc(Cl)nc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1C=C2C(CC(=O)N2Cc2ccc(Cl)nc2)O1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
569 mg (2.17) of triphenylphosphine are added to 712 mg (1.97 mmol) of 1-[(6-chloropyridin-3-yl)methyl]-2,5-dioxopyrrolidin-3-yl bromoacetate (XI-1) in 40 ml of acetonitrile, and the mixture is stirred at 50° C. for 3 hours. 0.29 ml (2.08 mmol) of triethylamine is added, and the mixture is stirred at 50° C. for about 16 hours. The entire reaction mixture is concentrated under reduced pressure and the residue that remains is then taken up in a little ethyl acetate, the insoluble solid is filtered off and the filtrate is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 305 mg (59% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-6,6a-dihydro-2H-furo[3,2-b]pyrrol-2,5(4H)-dione.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[N:33]=1.O>C(#N)C>[Br:30][CH2:31][C:32]1[N:33]=[C:34]([CH2:38][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:12]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[O:13])=[O:7])=[CH:22][CH:23]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccc(CBr)n2)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To 3-{[4-(hydroxy)benzoyl]amino}-N-cyclopropyl-4-methylbenzamide (1.50 g, 4.84 mmol) and potassium carbonate (3.34 g, 24.2 mmol) in refluxing acetonitrile (20 mL) was added a solution of 2,6-bis(bromomethyl)pyridine (5.13 g, 19.4 mmol) in acetonitrile (10 mL) over 25 mins. The reaction was cooled to room temperature and water (20 mL) was added. The mixture was extracted with DCM (3×30 mL) and the organic layers were combine and evaporated to leave a solid which was triturated with hot ethyl acetate to give 3-[(4-{[6-(bromomethyl)pyridin-2-yl]methoxy}benzoyl)amino]-N-cyclopropyl-4-methylbenzamide as a white solid (1.449 g, 61%); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 2.27 (s, 3H), 2.85 (m, 1H), 4.73 (s, 2H), 5.30 (s, 2H), 7.19 (d, 2H), 7.32 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.81 (s, 1H), 7.90 (t, 1H) 7.98 (d, 2H), 8.38 (d, 1H), 9.85 (s, 1H); Mass Spectrum: M+H+ 494, 496 Br pattern.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[C:15](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:23]=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A solution of 6.0 g (16.3 mmol) of 4-(2,2-Dibromo-vinyl)-piperidine-1-carboxylic acid tert-butyl ester in 150 ml THF was treated at −78° C. with 21.4 ml (34.2 mmol) of n-BuLi (ca 1.6 M in hexane). After 2 h at this temperature 4.9 g (16.3 mmol) of paraformaldehyde were added. The reaction was warmed up to RT for 3 h and after 1 h at this temperature partitioned between water/ether (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 4:1) gave 3.34 g (86%) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 239 (M).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([O:29]CC#N)=[O:28])[N:25]=1)([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)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCON=C(C(=O)OCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
A mixture of 8.69 g of the product of Step A in 52 ml of dioxane was cooled on an ice bath and 17.1 ml of N sodium hydroxide solution were added thereto dropwise over 20 minutes. Spontaneous heating occured and then 10.5 ml of 2N hydrochloric acid were added thereto. The dioxane was distilled and only water remained as solvent. 20 ml of water and 30 ml of ether were added thereto and the mixture was stirred for 15 minutes and was vacuum filtered. The crystal were rinsed with water and ether and dried to obtain 4.32 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-cyanomethoxyimino-acetic acid melting at about 180° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Yield: 21 %

Procedure:
154.7 g of 2,2,6,6-tetramethyl-4-piperidone, 160 g of piperidine and 10.0 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of benzene. The solution was refluxed by heating for 8.5 hours, whilst the water formed in situ was removed with a Dean-Stark separator. The reaction mixture was then poured into a mixture comprising 700 ml of water, 200 ml of concentrated aqueous ammonia and 100 g of ice. The organic layer was separated, washed three times with water and then dried over anhydrous magnesium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 46.6 g of 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine (bp 80° - 82° C/1 mmHg).