Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH3:24]>CO>[CH3:23][C:4]1[CH:3]=[C:2]([NH2:24])[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]-pyrimidin-7-ylamine as colorless crystals, m.p. >230°.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCOCC1>[CH:17]1([C:3]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1ccc(-c2nnc3cc(C4CCC4)c(N4CCOCC4)nn23)cc1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol), morpholine (154 mg, 1.8 mmol) and triethylamine (178 mg, 1.8 mmol) were heated in 1,4 dioxane (6 ml) in a sealed tube at 90° C. for 24 h. The reaction mixture was partitioned (ethyl acetate/water). The organic layer was washed (water, brine), dried (MgSO4) and was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate to give the title compound. 1H NMR (250 MHz, CDCl3) δ 1.96-2.88 (1H, m), 2.48 (2H, m), 3.25-3.28 (4H, m), 3.70-3.76 (1H, m), 3.90-3.94 (4H, m), 7.52-7.55 (3H, m), 7.98 (1H, s), 8.49 (2H, s); MS (ES+) m/e 336 [MH]+.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=1
Reactant: CC1CCCCC1N
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NC2CCCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a mixture of 3 ml of THF and 0.3 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.19 g of 2-methylcyclohexylamine and 0.16 g of triethylamine in order under ice cooling. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.36 g of N-(2-methylcyclohexyl)-3-methoxy 4-(2-propynyloxy)benzamide (hereinafter, described as the compound 2 of the present invention) represented by the formula:
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[S:10][C:11]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 983.4 %

Procedure:
Compound 93 (1.15 g, 0.32 mmol) was dissolved in trifluoroacetic acid (12 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and aqueous 1 mol/L sodium hydroxide solution and a mixed solvent (4:1) of chloroform and 2-propanol were added to the resulting residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 2-amino-4-(2-furyl)-5-(morpholinomethyl)thiazole (835 mg, 100%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH2:12][CH3:13])[CH2:9][C@H:8]2[C@H:14]3[C:23](=[CH:24][CH2:25][C@:6]12[CH3:7])[C:22]1[CH2:21][CH2:20][C:19](=[O:26])[CH2:18][C:17]=1[CH2:16][CH2:15]3)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([CH2:11][CH2:12][CH3:13])[CH2:9][C@H:8]2[C@H:14]3[C:23]([CH:24]=[CH:25][C@:6]12[CH3:7])=[C:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)(=[O:3])[CH3:2]
Reactant: CCC[C@@H]1C[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)C3=CC[C@]2(C)[C@H]1OC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1OC(C)=O
Yield: 93.9 %

Procedure:
A solution of 1.5 g of 17β-acetoxy-16α-propyl-5(10),9(11)-estradien-3-one in 100 ml of methylene chloride is dehydrogenated with 1.8 g of dichlorodicyano-p-benzoquinone under the conditions of Example 1. After crystallization from diisopropyl ether, 1.4 g of 17β-acetoxy-16α-propyl-4,9,11-estratrien-3-one is obtained, m.p. 108°-109° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:33]2[S:32][CH:36]=[CH:35][CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: BrCc1cccs1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccs3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.100 g, 0.23 mmol), prepared as described in EXAMPLE 43, part A, and thiophene-2-ylmethyl bromide (0.10 g, 0.56 mmol). The crude product is triturated with hexane/ether and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]#[CH:11])[CH:6]=[CH:7][C:8]=1[OH:9].[Cl:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH2:15][SH:16].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:9])/[CH:10]=[CH:11]\[CH:15]([S:16][CH:15](/[CH:11]=[CH:10]\[C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=1[Cl:12])[C:14]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:13]=1[Cl:12]
Reactant: Fc1ccc(CS)c(Cl)c1
Reactant: C#Cc1ccc(O)c(OC)c1
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(O)c(OC)c2)c2ccc(F)cc2Cl)c2ccc(F)cc2Cl)ccc1O

Procedure:
A solution of 3-methoxy-4-hydroxyphenylacetylene (0.02 mol), 2-chloro-4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-hydroxystyryl-2-chloro-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: C(OC([NH:8][C@@:9]([CH3:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O.O.O=[Pt]=O>[NH2:8][C@@:9]([CH3:20])([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccccc1)C(=O)O
Agent: O=[Pt]=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@](N)(CC1CCCCC1)C(=O)O

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-2-methyl-3-phenylpropanoic acid (1.95 g, 6.98 mmol) was hydrogenated under H2 (50 psi), catalyzed by PtO2 (200 mg), in TFA/H2O (30/30 mL) overnight. The catalyst was filtered off and concentrated to give (S)-2-amino-3-cyclohexyl-2-methylpropanoic acid in quantitative yield. MS ESI +ve m/z 186 (M+H).
Reaction SMILES: IC1C=CC=CC=1S(O)(=O)=O.OOS([O-])=O.[K+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26]>C(OCC)(=O)C>[CH3:18][CH2:19][CH2:20][CH2:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(O)CCCC
Agent: O=S(=O)(O)c1ccccc1I
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(=O)CCCC
Temperature: 70 °C

Procedure:
8.5 mg (0.03 mmol) of 2-iodobenzenesulfonic acid prepared by Preparation Example 1, 1.48 g (2.4 mmol) of Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added to 3.75 ml ethyl acetate, and the mixture was heated at 70° C. while being stirred for ten hours. After heating, the mixture was cooled to room temperature, and the insoluble substance was removed by means of filtering. The obtained filtrate was vacuum-concentrated, and diethyl ether is added in the residue, and then an insoluble material was removed by filtering. The obtained filtrate was vacuum-concentrated, and then 5-nonanone was obtained. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)#[N:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:12])[N:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CC(=O)c1cc(C#N)c(OCc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyano-5-acetyl-6-methyl-2(1H)-pyridinone (1.76 g, 0.01 mol) (L. Mosti et al, J. Het. Chem. 22, 1503 (1985)), benzyl bromide (2.12 g, 0.012 mol), silver carbonate (3.06 g, 0.011 mol) in benzene was stirred at room temperature under a nitrogen atmosphere overnight, while protected from light. The following day the mixture was filtered, and the solids washed well with benzene. Evaporation of the filtrate gave the desired intermediate, mp 94°-99° C.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C:19]([O:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@H:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][C:42](=[O:49])[C@@:41]2([CH3:50])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24]1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@H:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][C@H:42]([OH:49])[C@@:41]2([CH3:50])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 4.5 h
Yield: 91.5 %

Procedure:
A THF solution of lithium tri-tert-butoxyaluminum hydride (1 M, 22.4 mL, 22.4 mmol) was added drop wise to a solution of compound 2.0a (2.5 g, 5.6 mmol) in THF (25 mL) at ambient temperature. After stirring for an additional 4-5 h, the reaction was determined to be complete by TLC. The reaction was quenched by adding aqueous HCl (1 M, 10 mL) and the mixture was diluted with EtOAc (30 mL). The phases were separated and the organic phase was washed sequentially with water (15 mL) and saturated brine solution (10 mL). The organic phase was then dried over anhydrous Na2SO4 (3 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by column chromatography [29 mm (W)×500 mm (L), 60-120 mesh silica, 50 g], eluting with EtOAc/hexane (2:8) [5 mL fractions, monitored by TLC with p-anisaldehyde charring]. The fractions containing the product were combined and concentrated under vacuum to provide compound 2.1a (2.3 g, 91%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][O:24][CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CCNCCOC
Product: CCN(CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)ethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine, MS: 419 (MH+, 1Cl).
Reaction SMILES: CC(C)C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]2[CH2:18][NH:17][C:16](=[C:19]=[S:20])[CH:15]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][CH:7]=1>FC(F)(F)C(O)=O>[C:19](=[C:16]1[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]([CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:26])=[O:4])=[CH:11][CH:10]=2)[CH2:18][NH:17]1)=[S:20]
Reactant: CCOC(=O)C1C(=C=S)NCC1CCc1ccc(C(=O)OCC(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1C(=C=S)NCC1CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
A mixture of 4.17 grams (11.1 mmol) of 4-(2-[2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl]ethyl)benzoic acid 2,2-dimethylethyl ester and 20 ml of trifluoroacetic acid was stirred at room temperature until a clear solution was obtained plus an additional 5 minutes. Next, the resulting mixture was concentrated in a rotary evaporator and the residue therefrom was dissolved in 10 ml of methanol. This new solution was carefully added to a suspension of 2 grams of NaHCO3 in saturated NaHCO3 solution. The pH was adjusted to 5.7 with acetic acid and the resulting mixture extracted with 5×20 ml of ethyl acetate. The combined extracts were dried (MgSO4) and then concentrated to give 3.87 grams (109% crude yield) of 4-(2-(2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid as a foam which was sufficiently pure for use in Example 8. Crystalline 4-(2-(2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid was obtained from chloroform. Selected data: mp 145° -148° C.; 1H NMR DMSO-d6) δ 10.39 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.24 J=8.1 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.64 (dd, J=10.9, 8.9 Hz, 1H), 3.46 (d, J =8.5 Hz, 1H), 3.20 (dd, J=10.9, 8.0 Hz, 1H), 2.64 (q, J =8.0 Hz, 1H), 2.54 (t, J=7.4 Hz, 2H), 1.70 (m, 2H), 1.12 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 198.6, 169.5, 167.0, 146.2, 129.1, 128.6, 128.1, 65.0, 60.4, 52.9, 40.8, 33.5, 32.6, 13.7; IR (CHCl3) 3410, 2985, 1732, 1694, 1517 cm-1 ; UV (EtOH) 236 nm (ε 14 900), 271 (15 600); MS(FD) m/z 321 (M+). Anal. Calcd for C16H19NO4S: C, 59.79; H, 5.96; N, 4.36. Found: C, 59.77; H, 6.00; N, 4.37.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(I)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(I)cc1C(=O)O
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A mixture of methyl 5-iodo-2-methoxybenzoate (14 g, 48 mmol), 30% aqueous sodium hydroxide (40 mL) and methanol (200-300 mL) was allowed to stand approximately 2 hours and th&n heated 5 minutes at reflux. The mixture was concentrated and the residue was stirred with water (500 mL). The mixture was treated with 10% hydrochloric acid (200 mL) and then cooled to 10° C. and the solids were collected and dried under vacuum at 90° C. to give 5-iodo-2-methoxybenzoic acid (13.4 g, 48 mmol), m.p. 150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:31]([OH:33])[CH3:32]>>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:33][CH2:31][CH3:32])[N:3]=1
Reactant: CCO
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)n2nc(-c3ccco3)nc2n1

Procedure:
A solution of 7-amino-2-(2-furyl)-5-methylsulphonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine (1.6 g) in ethanol (40 ml) containing DBU (1.0 ml) was heated under reflux until no starting material remained by TLC analysis. The solvent was removed by evaporation and the residue purified by chromatography on silica using 5-10% v/v ethyl acetate in dichloromethane as eluant, followed by crystallisation from ethanol to give 7-amino-5-ethoxy-2-(2-furyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine as hygroscopic crystals, m.p. 211°-213° C.; microanalysis, found: C, 48.7; H, 4.5; N, 31.4; H2O, 1.2%; C10H10N6O2.0.33C2H5OH. 0.165H2O requires: C, 48.4; H, 4.7; N, 31.8; H2O, 1.1%; NMR: 1.05(t, 1H, CH3CH2OH), 1.35(t, 3H, CH3CH2), 3.4(q, CH3CH2OH), 4.3(q, 2H, CH3CH2O--), 6.7(dd, 1H, furyl-4H), 7.1(d, 1H, furyl-3H), 7.9(d, 1H, furyl-5H), 8.5-9.0(d, 2H, NH2); m/e 246 (M+).
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=O)=[O:11])=[CH:6][CH:5]=1.[Na+].O.S(Cl)([Cl:18])=O.CN(C=O)C>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([Cl:18])(=[O:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
5 g (21.5 mmol) sodium 4-hydroxy-benzenesulfonate dihydrate were suspended in 50 ml toluene and refluxed for 2 hours using a Dean-Stark trap (a water separator used in chemical reactions). The solvent was evaporated, replaced by 12.8 g (108 mmol) thionyl chloride and 160 mg DMF and the mixture stirred for 4 hours at 60° C. and over night at room temperature. After evaporation, the residue was quenched with ice water, extracted thrice with dichloromethane and the extracts died and evaporated. Yield 4.78 g (quant.) raw product as white gum.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[CH2:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:32]1[CH2:37][CH2:36][C:35]([OH:38])([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A 1.6M solution of n-butyllithium in hexane (39 ml, 63 mmol) was added to a stirred solution of 4-bromobiphenyl (11.7 g, 50 mmol) in anhydrous tetrahydrofuran (50 ml), under nitrogen, at about −50° C., whilst ensuring that the reaction temperature was kept below −40° C. After a further 1 hour, a solution of 1-benzyl-4-oxopiperidine (10.4 g, 55 mmol) in anhydrous tetrahydrofuran (30 ml) was added at such a rate that the reaction temperature was maintained below −40° C. The cooling bath was then removed and, after a further 1 hour, the reaction mixture was partitioned between dichloromethane (400 ml) and brine (200 ml). The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure, then the residue crystallised from ethyl acetate to provide the title compound (13.9 g) as a colourless solid. δ(DMSOd6): 1.80 (d,2H), 2.52 (m,2H), 3.24 (m,4H), 4.33 (d,2H), 7.28-7.75 (m,14H), 11.30 (brs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:40][CH2:39][C:12]2[N:13]=[C:14]([NH:16][C:17]([C:19]3[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=3)[CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=3)=[O:18])[S:15][C:11]=2[CH2:10]1.CCN(C(C)C)C(C)C.Br[CH2:51][CH2:52][O:53][CH2:54][CH2:55]Br>CN(C=O)C>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[C:24]([NH:23][CH2:22][C:21]1[CH:36]=[CH:37][CH:38]=[C:19]([C:17](=[O:18])[NH:16][C:14]2[S:15][C:11]3[CH2:10][C@H:9]([N:8]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH2:40][CH2:39][C:12]=3[N:13]=2)[CH:20]=1)=[O:35]
Reactant: BrCCOCCBr
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N)CC4)c2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)C[C@H](N3CCOCC3)CC4)c2)cc1OC
Temperature: 70 °C

Procedure:
Dissolved N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide trifluoroacetate (50.0 mg, 0.09 mmol) in 1.5 mL of dry DMF. To this was added DIPEA (0.05 mL, 0.26 mmol) and the 1-bromo-2-(2-bromo-ethoxy)-ethane (0.02 mL, 0.12 mmol). The mixture was heated at 70° C. overnight. LC-MS analysis indicted the desired material. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give the desired product with one major impurity. Applied to a SiO2 prep plate. Eluted with (10% MeOH/1% NH3/CH2Cl2) to give 18.9 mg of N-[3-((R)-6-Amino-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide. MS, electrospray 537.6 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CC[O:14]C(C)=O>>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc2ncccc2c1
Product: O=Cc1ccc2ncccc2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of SeO2 (10.89 g, 99 mmol) and 6-methylquinoline (12.87 g, 90 mmol) was heated to 150° C. and stirred for 16 h. Then it was cooled to room temperature and EtOAc (400 ml) was added. After filtration, the filtrate was concentrated to obtain the crude compound, which was purified by chromatography (silica gel, petroleum ether/EtOAc 5:1 to 2:1) to afford the title compound (2.87 g, yield 20%). LC-MS (ESI) m/z: 158 (M+1)+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.[NH:28]1[CH2:41][CH2:40][CH2:39][C@@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C1COCC1>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:28]1[CH2:41][CH2:40][CH2:39][C@@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])=[O:17]
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
201 mg (1.05 mmol) of EDCl was added to 5 ml of THF solution of 100 mg (0.526 mmol) of Boc-Pro-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 113 mg (0.526 mmol) of H-D-Pro-NHPh (manufactured by Tokyo Chemical Industry Co., Ltd), followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 160 mg of the product with a yield of 73.6%.