Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]>C1COCC1.O1CCOCC1.O=[Mn]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([C:15](=[O:16])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1C(=O)C#Cc1ccccc1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgCl in THF (1.25 ml) was added drop wise at 0° C. under N2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [1H-NMR (CDCl3) 7.68 (d, 1H, J=2.49 Hz); 7.46-7.43 (m, 2H); 7.36 (dd, 1H, J=8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1H, J=6.77 Hz); 5.79 (d, 1H, J=5.23 Hz); 4.64-4.58 (m, 1H); 3.13 (d, 1H, J=5.91 Hz); 1.37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. 1H-NMR (CDCl3) 8.00 (d, 1H, J=2.61 Hz); 7.61-7.52 (m, 3H); 7.44-7.35 (m, 3H); 6.88 (d, 1H, J=8.91 Hz); 4.68-4.60 (m, 1H); 1.36 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28]([N:30]=[N+]=[N-])[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1.[Pd]>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28]([NH2:30])[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
0.65 mMol of 7-(6-azido-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 5 ml THF are hydrogenated in the presence of 0.1 g Pd/C (10% Engelhard 4505). Filtration and chromatography (Combi Flash; hexane/EtOAc 19:1→11:9→1:3) of the concentrated filtrate gives the title compound: MS: [M+1]+=444; HPLC: AtRet=10.6; Anal.: C,H,N,F.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[S:13](=[O:17])(=[O:16])([OH:15])O>OS(O)(=O)=O.O=S(=O)=O>[N:1]1[CH:6]=[CH:5][C:4]([S:13]([OH:15])(=[O:17])=[O:16])=[C:3]([S:13]([OH:17])(=[O:16])=[O:15])[C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=S(=O)(O)c1ccnc(-c2ccccn2)c1S(=O)(=O)O
Temperature: 20 °C

Procedure:
2 g of 2,2′Bipyridine was charged into a reactor, and 20 cc of concentrated sulfuric acid was added to it. This mixture was stirred until the amine dissolved. 20 cc of oleum 65% was added to this mixture under rapid stirring, and the reactor was cooled to about 20° C. After the solution of oleum, the reactants and contents were heated to 50° C. and maintained at this temperature for 48 hours. The reactor and its contents were cooled, and distilled water (10 cc) was added to the reaction mixture to quench the oleum. 50% NaOH solution was added to this solution, under cooling (10° C.) until the sulfuric acid solution was neutralized. The solution was concentrated and then methanol was added to extract the water-soluble ligand from the sodium sulfate powder. The methanol was evaporated to yield the water-soluble sodium salt of 2,2′bipyridine di sulfonic acid. [1.2 g] The product consists of mixtures of the bis sulfonation products as indicated by elemental analysis and 1h NMR. These can be used as such in synthesis of metal complexes for catalysis.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1)[NH2:19]>>[CH3:24][O:23][C:21]1[CH:20]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([NH:2][CH3:1])[CH:4]=2)[CH:17]=[C:16]([O:15][CH3:14])[CH:22]=1
Reactant: CNc1cc(C(=O)O)ccc1OC
Reactant: COc1cc(N)cc(OC)c1
Product: CNc1cc(C(=O)Nc2cc(OC)cc(OC)c2)ccc1OC
Yield: 50 %

Procedure:
Using 3-methylamino-4-methoxybenzoic acid and 3,5-dimethoxyaniline as materials, compound 40 is synthesized following a similar method as in Example 28. Yield: 50%.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[OH:33]>CC#N>[OH:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[NH:27][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Cn1c(Cl)nc2ncn(Cc3ccccc3)c2c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(Cc3ccccc3)c2c1=O

Procedure:
Heat at reflux for 2 days a mixture of 2-chloro-1-methyl-7-(phenylmethyl)purin-6-one (3.14 g=11.4 mmol), triethylamine (1.7 g=16.8 mmol), and (±)-trans-2-aminocyclopentanol (4.04 g=39.9 mmol) in CH3CN (150 ml). Collect the precipitate, wash with water, and dry to give the title compound, a solid, FAB MS: M+1=340.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.S(Cl)([Cl:19])=O.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:19])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)cc1OC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: ClCc1ccc(Br)cc1OC1CCCCC1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a solution of (4-bromo-2-cyclohexyloxyphenyl)methanol (5.46 g) in dichloromethane (16 ml) was added thionyl chloride (3.42 g) dropwise at 5° C. under nitrogen, and the mixture was stirred at the same temperature for 1.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated and dried in vacuo to give 4-bromo-1-chloromethyl-2-cyclohexyloxybenzene (5.59 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:21][CH2:22][CH2:23][N:24]2[C:33](=[O:34])[CH2:32][C:31]3[CH:30]=[CH:29][C:28]4[N:35]=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[O:44][CH3:45])[NH:37][C:27]=4[C:26]=3[C:25]2=[O:46])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:48][CH2:49][CH2:50]Br.[OH-].[Na+].[CH3:54][CH2:55]O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:21][CH2:22][CH2:23][N:24]2[C:33](=[O:34])[C:32]3([CH2:55][CH2:54][CH2:50][CH2:49][CH2:48]3)[C:31]3[CH:30]=[CH:29][C:28]4[N:35]=[C:36]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[O:44][CH3:45])[NH:37][C:27]=4[C:26]=3[C:25]2=[O:46])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(CCCN2C(=O)Cc3ccc4nc(-c5ccccc5OC)[nH]c4c3C2=O)C(=O)OC(C)(C)C)cc1OC
Reactant: CCO
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCN(CCCN2C(=O)c3c(ccc4nc(-c5ccccc5OC)[nH]c34)C3(CCCCC3)C2=O)C(=O)OC(C)(C)C)cc1OC
Yield: 43 %

Procedure:
A solution of tert-butyl [2-(3,4-dimethoxyphenyl)ethyl]{3-[2-(2-methoxyphenyl)-7,9-dioxo-1,6,7,9-tetrahydro-8H-imidazo[4,5-h]isoquinolin-8-yl]propyl}carbamate (100.0 mg, 0.159 mmol), 1,3-dibromopropane (43.9 mg, 0.19 mmol) and aqueous 1 N NaOH solution (0.32 mL, 0.32 mmol) in water (1.0 mL) and EtOH (1 mL) was heated at 80° C. for 2 h. The cooled mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel; hexane:EtOAc 1:1) to yield the title compound (47 mg, 43% yield) as a white foam.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[C:12]3[NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]2)=[CH:5][N:4]=1)#[N:2].C(O)(C(F)(F)F)=O>>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=4)[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:22][CH2:23]2)=[O:20])[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cnc(C#N)nc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N)CC4)c3c2)cn1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(2-cyanopyrimidin-5-yl)-3-(cyclopropane carbonyl)quinolin-4-ylamino]cyclohexylcarbamate (52 mg, 0.100 mmol) was reacted with TFA (1 mL) to afford the desired product (13.7 mg, 33%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.33 (s, 2H), 9.19 (s, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.20 (dd, J=8.7, 2.0 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 4.25-4.16 (m, 1H), 3.15-3.07 (m, 1H), 2.90-2.81 (m, 1H), 2.34 (d, J=13.1 Hz, 2H), 2.12 (d, J=11.8 Hz, 2H), 1.69-1.59 (m, 2H), 1.55-1.45 (m, 2H), 1.24-1.19 (m, 2H), 1.15-1.10 (m, 2H); ESI MS m/z 413 [C24H24N6O+H]+; HPLC 94.9% (AUC), tR=9.67 min.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(=O)C(O)=O.[CH2:25]1[C:28]2([CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:27][O:26]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:29]3[CH2:30][CH2:31][CH2:32][C:28]43[CH2:25][O:26][CH2:27]4)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: C1CNC2(C1)COC2
Agent: O=C(O)C(=O)O
Product: O=C(c1cc(OCC(F)(F)F)c(C2CC2)cn1)N1CCCC12COC2

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Oxa-5-aza-spiro[3.4]octane oxalate (CAN 1380571-82-3) as starting materials and isolated (37.6 mg, 46%) as colorless oil; MS (ESI, m/z): 357.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1.I[CH:22]([CH3:24])[CH3:23].[H-].[Na+].O>O1CCOCC1>[CH:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:20]=[C:10]3[NH:11][C:12](=[O:19])[C:13]4[C:18]([N:9]3[N:8]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:2]1)([CH3:24])[CH3:23]
Reactant: O=c1[nH]c2cc(C3CCCNC3)nn2c2ccccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCCC(c2cc3[nH]c(=O)c4ccccc4n3n2)C1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and 2-iodopropane (0.09 mL, 0.9 mmol) in dioxane (2 mL) and was treated with sodium hydride (0.01 g, 0.4 mmol). The mixture was stirred overnight at 65° C., cooled to ambient temperature, treated with water and concentrated. The residue was purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H), 7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H), 2.99-3.10 (m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0 Hz, 1H), 2.38 (td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7 Hz, 1H), 1.83-1.92 (m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3, 4.0 Hz, 1H), 1.14-1.19 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)COC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of ethyl 7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.36 g), tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1M aqueous sodium hydroxide solution (7.9 mL). The mixture was stirred at 50° C. for 2 h and at room temperature over night. To the mixture was added 1M aqueous sodium hydroxide solution (10.5 mL). The whole was stirred at 50° C. for further 1 h. The reaction mixture was concentrated in vacuo. The residue was acidified with 1M hydrochloric acid. Ethyl acetate and water were added to the mixture and the organic layer was separated. The organic layer was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was triturated and washed with hexane to give the title compound (1.288 g, 58%) as a pink solid. The solid was recrystallized from ethyl acetate-hexane to give white crystals. mp 135.9-137.4° C.
Reaction SMILES: [CH:1]([S:3]([CH2:6][CH3:7])(=[O:5])=[O:4])=[CH2:2].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C=CS(=O)(=O)CC
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 66.1 %

Procedure:
A mixture of ethyl vinyl sulphone (600 mg), 5-bromo-3-(1-methyl-4-piperidinyl)-1H-indole (1.00 g), palladium acetate (50 mg), tri-o-tolylphosphine (244 mg) and triethylamine (700 mg) in dry dimethylformamide (10 ml) was stirred and heated at 100°-110° for 4 h. The dimethylformamide and triethylamine were removed in vacuo. The residual gum was chromatographed on silica (140 g; Merck 9385), using a mixture of dichloromethane, ethanol and ammonia (80:8:1) as the eluant, to give a gum (750 mg). The material was rechromatographed on silica (Merck 9385; 100 g), using a mixture of dichloromethane, ethanol and ammonia (90:8:1) as the eluant. Fractions containing mainly the product were combined and evaporated to give a gum. A few fractions contained small amounts of the pure product. These were kept separate, combined and evaporated. The residual gum was crystallised from a small amount of a mixture of ethyl acetate and cyclohexane. Some of the crystals were then used to seed the crystallisation of the main batch of the product, also from a mixture of ethyl acetate and cyclohexane. The two batches of solid product were combined and dried in vacuo to give the title compound (310 mg) as a powder, with m.p. 98°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:9])=[O:18])[N:3]=1
Reactant: CSc1cccc(Br)n1
Reactant: CS(=O)c1ccc(Br)cn1
Product: CS(=O)c1cccc(Br)n1

Procedure:
The title compound was prepared from 2-bromo-6-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[H][H]>O.[Ru]>[C:6]([CH:5]1[CH2:4][NH:3][C:2](=[O:1])[CH2:10][CH2:9]1)([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(O)nc1
Agent: [Ru]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(C(=O)O)CN1
Yield: 72.9 %

Procedure:
To a suspension of 10.0 g of 6-hydroxynicotinic acid in 200 ml water were added 6.5 g of sodium bicarbonate. The resulting solution was subjected to 500 psig hydrogen at 100° C. for 12 hours in the presence of 2.5 g ruthenium on alumina. The catalyst was removed by filtration. The filtrate was acidified to pH 4 with 6N HCl and evaporated to a colorless solid (~15 g ). The solid was treated with 40 ml methanol and filtered to remove most of the sodium chloride. The filtrate was evaporated to give 7.5 g of the title compound: MS m/z 143 (M+); 300-MHz 1H NMR (DMSO-d6) δ1.62-1.77 (m, 1 H), 1.83-1.97 (m, 1 H), 2.00-2.21 (m, 2 H), 2.23-2.35 (m, 1 H), 3.21 (d, J=8 Hz, 2 H), 7, 28 (s, 1 H).
Reaction SMILES: [CH:1]([CH:4]([CH:10]([CH3:13])[C:11]#[CH:12])[C:5]([O:7]CC)=[O:6])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C>O>[CH:1]([CH:4]([CH:10]([CH3:13])[C:11]#[CH:12])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: C#CC(C)C(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CC(C)C(C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
A 250 milliliter flask was equipped with a magnetic stirrer, reflux condenser and nitrogen inlet. Into the flask was added 8.44 grams (0.05 mol) of ethyl 2-isopropyl-3-methyl-4-pentynoate prepared in Part B, 5.56 grams (0.14 mol) of sodium hydroxide, 20 milliliters of ethanol and 20 milliliters of water. Following three days of continuous refluxing and stirring under nitrogen, the reaction mixture was cooled to room temperature, diluted with three times its volume of water and extracted twice with ether. Ice was added to the aqueous phase and it was acidified with 3 N HCl, then extracted three times with ether. The ether was washed twice with water, dried (MgSO4) and removed under vacuum to give 5.87 grams (0.04 mol) of 2-isopropyl-3-methyl-4-pentynoic acid having the appearance of a light yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH2:14]>C1(C)C=CC=CC=1>[C:1]([CH2:3][C:4]([NH:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[CH3:9])=[O:6])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)CC#N
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Ethyl cyanoacetate (51.106 g, 0.4518 mole) was added to 3-(dimethylamino) propylamine (46.162 g, 0.4518 mole) in a 250 ml round bottom flask equipped with a magnetic stir bar. After stirring for approximately 0.5 hr, 50 ml of toluene was added. The clear orange liquid was stirred at room temperature for approximately 15 hours, after which the ethanol and toluene were removed via vacuum distillation. 2-Cyano-N-[3-(dimethylamino)propyl]acetamide was obtained in 96% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C1(C=CC=C(O)C=1)O.C(O[C:41]1[CH:57]=[CH:56][C:44]([C:45]([O:47]C2C=CC(C=O)=CC=2)=[O:46])=[CH:43][CH:42]=1)CCCCCCCCC.[O-]Cl=O.[Na+]>>[CH2:11]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][C:41]2[CH:57]=[CH:56][C:44]([C:45]([OH:47])=[O:46])=[CH:43][CH:42]=2)=[O:18])=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (3.18 g, 28.9 mmol), 10 (8.5 g, 22 mmol), NaH2PO4·H2O (10.39 g, 66.6 mmol), NaClO2 (11.65 g, 0.13 mol). Yield 8.8 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 0.91 (3 H, t, 3J=6.8 Hz, CH3), 1.23-1.59 (14 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 4.07 (2 H, t, 3J=6.5 Hz, O—-CH2), 7.00 (2 H, d, 3J=8.9 Hz, Ar—H), 7.36 (2 H, d, 3J=8.6 Hz, Ar—H), 8.17 (2 H, d, 3J=8.9 Hz, Ar—H), 8.22 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.7, 29.8, 30.0, 32.3, 68.8, 114.8, 121.4, 122.4, 127.0, 132.3, 132.8, 156.0, 164.2, 164.7, 171.7.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:10][CH2:11][CH:12]=[CH2:13])=[C:6]([OH:9])[CH2:7][CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1.CCOC(C)=O>[CH2:11]([O:10][CH:5]([CH:6]([OH:9])[CH:7]=[CH2:8])[CH2:4][OH:3])[CH:12]=[CH2:13]
Reactant: C=CCOC(C(=O)OCC)=C(O)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(CO)C(O)C=C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-allyloxy-3-hydroxy-pentenoic acid ethyl ester (200 mg, 1.00 mmol) in THF (5 mL) was added LiAlH4 (151 mg, 4.00 mmol). The resulting solution was stirred at ambient temperature for 15 min. H2O (10 mL) was added and the mixture was diluted with EtOAc (50 mL×2), washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 50% EtOAc-hexane
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]([Cl:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COC(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)COC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
4.1 g (0.023 m) Benzoyloxy acetic acid (as synthesized in Example XIII) was combined with 2.96 ml (4.3 g, 0.032 m) oxalyl chloride in 50 ml petroleum ether. This was stirred under a CaSO4 drying tube for 5 hrs., at which time 2.0 ml more oxalyl chloride and 50 ml chloroform were added. The reaction was stirred overnight.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccc(Cl)cc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 4-chloro-phenylhydrazine according to the method described for example 43. MS: M=427.1 (M+H)+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]=1[Cl:21]>>[Cl:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[C:14]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:13][C:12]=1[Cl:21]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (-5° C) mixture of 325 parts of nitric acid and 975 parts of a concentrated sulfuric acid solution are added dropwise 220 parts of 1,2-dichloro-4-(1,1-dimethylethyl)benzene. Upon completion, stirring is continued for 30 minutes at 5° C. The reaction mixture is poured onto water: the product precipitates as an oil. The supernatant aqueous water: is decanted and the residual oil is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and recrystallized from 2-propanol, yielding 34.5 parts of 1,2-dichloro-4-(1,1-dimethylethyl)-5-nitrobenzene; mp. 80° C.