Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:17][CH3:18])[S:12][C:13]([C:14](O)=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1.C(Cl)(=O)C(Cl)=O.C[N:26](C)C=O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:17][CH3:18])[S:12][C:13]([C:14]([NH2:26])=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CN(C)C=O
Reactant: CSc1sc(C(=O)O)c2c1-c1oc(C)nc1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CSc1sc(C(N)=O)c2c1-c1oc(C)nc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
4,5-Dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylic acid (0.47 g) was suspended in tetrahydrofuran (15 ml); oxalyl chloride (0.32 g) and then N,N-dimethylformamide (6 μl) were added. After this mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (5 ml) and cooled with ice; concentrated aqueous ammonia (4.0 ml) was added. After the reaction mixture was stirred at room temperature for 1 hour, it was poured over water (150 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxamide (0.27 g, 57%), which was then recrystallized from chloroform-methanol. Light-yellow needles. Melting point over 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1.[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]C.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCO
Reactant: COc1cscc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cscc1C

Procedure:
40 g of 3-methoxy-4-methylthiophene were dissolved in 120 cm3 of toluene together with 120 g of 1-dodecanol, and the solution was refluxed with 2 g of NaHSO4. 19 ml of a methanol/toluene mixture were separated off over a period of 3 hours. The solution was washed with water until neutral, dried over MgSO4 and subsequently fractionated. At 141° to 143° C. and 0.013 mbar, 55.6 g of 3-dodecyloxy-4-methylthiophene distilled over. 97% pure by GC, which corresponds to 63% of the theoretical yield. The substance was characterized by mass spectrum and 1H-NMR.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CS(C)=O.O>[CH3:1][S:2][C:3]1[N:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1
Reactant: CSc1cc(-c2cccnc2)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(-c2cccnc2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A solution of the above pyrazole(1.94 g, 10.15 mmol) and potassium t-butoxide (1.2 g, 10.6 mmol) in anhydrous DMSO (15 mL) was stirred at room temperature for 5 min and then 4-flouronitrobenzene (1.08 mL, 10.15 mmol) was added. The reaction mixture was heated to 100° C. in an oil bath for 5 h under argon. The reaction mixture was cooled, diluted with water, the yellow solid obtained was filtered, washed with water and dried. The residue obtained was recrystallized from ethyl acetate to give 5-methylthio-1-(4-nitrophenyl)-3-(3-pyridinyl)pyrazole (2.4 g).
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.Cl[Si](C)(C)C.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][CH2:24][C:25](O)=[O:26].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:25](=[O:26])[CH2:24][CH2:23][C:19]1[S:18][CH:22]=[CH:21][CH:20]=1)[CH2:7][CH2:6]2
Reactant: O=C(O)CCc1cccs1
Reactant: Oc1ccc2c(c1)CCNC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CCc1cccs1)N1CCc2cc(O)ccc2C1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-6-hydroxyisoquinoline hydrobromide (5.8g) in methylene chloride (100 mL) at 0° C. was treated with chlorotrimethylsilane (7.4 mL). After 4 hours, the reaction was filtered, washed with cold NaHCO3, brine, dried (MgSO4), filtered and evaporated to provide an oil. To a solution of the above oil in THF (100 mL), was added 3-(2-thienyl)propanoic acid (4.33 g) and 1-hydroxybenzotriazole (6.8 g) followed by the addition of dicyclohexylcarbodiimide (5.2 g). After 12 hours, the reaction was filtered and concentrated. The residue was taken up into EtOAc and refiltered. The organic solution was washed with 10% aq. NaHCO3, 1 N HCl, brine, dried (MgSO4), filtered and concentrated. Chromatography on silica gel (elution with 50% ethyl acetate/hexanes) provided 4.61 g of the desired product as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH3:18]I>>[CH3:17][O:16][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][CH3:18])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: CI
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Product: COCCCc1cc(C(=O)O)cc(OC)c1OC
Yield: 69 %

Procedure:
3,4-Dimethoxy-5-(3-methoxypropyl)benzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-Dimethoxybenzoic acid (Example 10, Step 1) and methyl iodide by following Method I in 69% yield. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:22][C:23]2[C:24]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([S:22][C:23]2[C:24]3[CH2:32][NH:31][CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncnc(Sc3cc(Nc4nc(CCc5ccccc5)cs4)ncc3Br)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)cc1Sc1ncnc2c1CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
tert-Butyl 4-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-ylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.023 g, 0.037 mmol) was dissolved in TFA (2 mL) and stirred at ambient temperature for 2 hours. The solution was neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated to afford the desired product (0.010 g, 52% yield) as a white solid. 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.51 (s, 1H), 7.14-7.27 (m, 6H), 6.38 (s, 1H), 3.99 (s, 2H), 3.22 (t, 2H), 2.89-2.96 (m, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=1>C1COCC1>[NH2:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[N:13]=1
Reactant: N#Cc1cccc(Cl)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(Cl)n1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A 1M solution of lithium aluminium hydride in THF (2.88 ml, 2.88 mmol) was added dropwise to a solution of 6-chloro-2-cyanopyridine (532 mg, 3.84 mmol) in THF (10 ml) at −5° C. under an atmosphere of nitrogen. The mixture was stirred at −5° C. for two hours and the reaction quenched by careful, sequential addition of water (0.1 ml), 15% aqueous sodium hydroxide solution (0.1 ml) and then water (0.3 ml). The mixture was stirred for one hour at 0° C., the insolubles removed by filtration and the filter pad washed thoroughly with methanol. The resulting solution was evaporated and the residue purified by column chromatography on silica gel eluting with DCM/methanol/ammonia (95:5:0 increasing in polarity to 90:10:1) to give the title compound. (215 mg, 40%) as an oil. NMR (DMSO): 2.10 (br s, 2H), 3.75 (s, 2H), 7.30 (d, 1H), 7.55 (d, 1H), 7.80 (t, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:38][CH3:39])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]([CH3:22])[C:17](=O)[CH2:18][O:19][CH3:20])[CH3:15])=[CH:10][CH:9]=2)[N:5]([C:23]([NH:25][C@H:26]([CH2:34][CH2:35][CH3:36])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:24])[C:4]1=[O:37])[CH3:2].B.CSC>C1COCC1>[CH2:38]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH3:22])[CH3:15])=[CH:10][CH:9]=2)[N:5]([C:23]([NH:25][C@H:26]([CH2:34][CH2:35][CH3:36])[C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:24])[C:4]1=[O:37])[CH3:39]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)N(C)C(=O)COC)cc1)c1ccc(C)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)N(C)CCOC)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.5 %

Procedure:
To a solution of (4S)-3,3-diethyl-4-{(S)-4-[1-(N-methoxyacetyl-methylamino)ethyl]phenoxy}-1-[(R)-α-n-propyl-(4-methyl)benzylaminocarbonyl]azetidin-2-one (13 gm, 24 mmol) in THF (150 mL) was added a 2M solution of borane-methyl sulfide in THF (36 mL, 72 nmmol) and the reaction stirred at rt for 7 hrs. The reaction was then quenched with methanol (20 mL) and then dimethylaminoethanol (17 mL) added to decompose the borate complex. After stirring at rt for 16 hrs most of the THF was evaporated in vacuo and the residue was taken up in ether, washed twice with potassium carbonate solution and brine. The aqueous layers were reextracted with another portion of ether and the pooled ether layers were then dried over sodium sulfate and evaporated. The residue was purified by preparative chromatography using 1.5-4% methanol/methylene chloride to afford 11 gm (86%) of the title compound as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:25]=[CH:24][C:15]3[N:16]=[C:17]([NH:19]C(OC)=O)[NH:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N#CBr>CO>[NH2:19][C:17]1[NH:18][C:14]2[CH:13]=[C:12]([O:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH:25]=[CH:24][C:15]=2[N:16]=1
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Agent: N#CBr
Solvent: CO
Product: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2[nH]1

Procedure:
14.1 g of 1,2-diamino-4-(4-fluorophenylsulfonyloxy)benzene (see Example 1) and 5.8 g of cyanogen bromide in 150 ml of methanol are heated to reflux for 6 h, then the mixture is cooled and concentrated. The residue is dissolved in water, and ammonia is added with cooling. The precipitated 2-aminobenzimidazole derivative is filtered off with suction, washed with water, dried and recrystallized from ethyl acetate and diisopropyl ether, with the addition of active charcoal; melting point 192° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH2:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH2:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(CO)nc5nc(C(=O)NO)nn45)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(C(=O)NO)nn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (45 mg) (0.074 mmol) and 31 mg (0.096 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the reddish solution is concentrated in a high vacuum. The residue is suspended in 6 ml of water and the product is filtered off under suction. After washing with water and diethyl ether and subsequently drying in a high vacuum there are obtained 50 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOCC.[OH-].[Na+]>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([CH:11]=[CH:10][N:9]=2)[CH:14]=[O:15])[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(CO)ccn2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(Nc2cc(C=O)ccn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
A solution of (2-(4-methylthiazol-2-ylamino)pyridin-4-yl)methanol (0.210 g, 0.949 mmol) in THF (5 mL) was added to a solution of Dess-Martin periodinane (0.604 g, 1.42 mmol) in THF (5 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 minutes, then diluted with ether and 1N NaOH (40 mL). The reaction mixture was stirred for 30 minutes, then extracted with ether, washed with water, brine, dried and concentrated to afford 2-(4-methylthiazol-2-ylamino)isonicotinaldehyde (0.197 g, 94.7% yield) as a yellow wax/powder. The crude product was used in the next step without purification.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=CC=1.O=C(CC)CC#[N:30]>>[CH2:1]([C:7]1[CH:20]=[C:25]([NH2:30])[N:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:8]=1)[CH3:6]
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Reactant: CCC(=O)CC#N
Product: CCc1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 85.3 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 3-oxo-pentanenitrile (1.3 g, 1.1 eq) were combined to yield 5-ethyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (2.5 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (dd, J=7.8, 1.8 Hz, 1H), 8.39 (dd, J=8.4, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06-8.03 (m, 2H), 7.54 (dd, J=8.4, 1.2 Hz, 1H), 5.46 (br s, 2H), 5.40 (s, 1H), 2.49 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:3][N:4]1[CH:10]2[CH:8]([CH2:9]2)[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[OH:35][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30].[CH:10]12[CH2:9][CH:8]1[NH:7][CH2:6][CH2:5][N:4]2[CH2:3][C@@H:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[OH:1]
Reactant: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3CC32)ccc2c1COC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c([C@@H](O)CN2CCNC3CC32)ccc2c1COC2=O

Procedure:
In a round bottom flask charged with stirring bar, tert-butyl (±)5-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (502 mg, 1.292 mmol) was dissolved in DCM (5 mL) and was treated with TFA (2 mL, 26.0 mmol) at room temperature for 3 hours. Then solvent was removed on rotavapor. Residue was re-dissolved in small amount of DCM and evaporated to take out remained TFA. Then it was dried on high vacuum pump for 4 hours to remove extra TFA. Without further purification, crude product was used to make ROMK inhibitors. LC/MS: (M+1)+=289.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH2:12])[CH3:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH:10]([NH:12][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH3:11]
Reactant: CCOC(=O)Cl
Reactant: COC(OC)C(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(C)C(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 g (0.73 mol) of ethyl chloroformate are added dropwise to 86.2 g (0.72 mol) of 2-aminopropionaldehyde dimethyl acetal in 350 ml of toluene and 32 g (0.8 mol) of NaOH in 300 ml of water. The mixture is stirred at room temperature for a further 2 hours, the organic phase is separated off, the aqueous phase is extracted with toluene and the toluene solutions are dried over K2CO3. The solution is concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35].O>C(Cl)Cl.C1COCC1>[C:34]([O:26][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:16]([C:13]2[N:12]=[N:11][N:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH3:15])=[O:17])[CH:20]=1)(=[O:36])[CH3:35]
Reactant: Cc1c(C(=O)Nc2cccc(CO)c2)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1cccc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[(3,4-dichlorophenyl)methyl]-N-[3-(hydroxymethyl)phenyl]-5-methyl-1H-1,2,3-triazole-4-carboxamide (Example 24) (0.1 g, 0.25 mmol) in a mixture of DCM/THF were added NEt3 (75 μL, 2 eq) and acetyl chloride (25 μL, 1.2 eq). The reaction was stirred at room temperature for 2 hours. Water was added and the product was extracted with ether, dried over sodium sulphate and evaporated in vacuo. The title compound was obtained as a white solid after recrystallisation from isopropyl ether (a couple drops of DCM) (60 mg, 54.5%). HRMS calculated for C20H18Cl2N4O3 (M+H)+433.0834. found: 433.0812, Rt: 3.14 min. MP: >70° C. (sticky).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:33][CH2:32]2)[CH:21]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH:31]2[CH2:32][CH2:33]2)[CH:21]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cl)c12
Temperature: 40 °C
Reaction time: 28 h
Yield: 77.1 %

Procedure:
To 311 mg (0.624 mmol) of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 2-(a) was added 15 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at 40° C. for 28 hours. After completion of the reaction, the reaction suspension was cooled by allowing to stand, and precipitated solid was collected by filtration and washed with diisopropyl ether. To the obtained solid were added 22 ml of methanol and 1.5 ml of 28% aqueous ammonia, and the mixture was stirred under room temperature for 3 hours. Then, the solution was concentrated under reduced pressure, diisopropyl ether and hexane were added to the obtained solid, a treatment with ultrasonic wave was carried out, and precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether and dried under reduced pressure to obtain 177 mg of the title compound as a white solid. (Yield: 77%)
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:31][C:32]#[N:33])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(O)ccc3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC#N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (1.29 g, 3.37 mmol), prepared in the previous step, bromoacetonitrile (282 μL, 4.05 mmol) and of potassium carbonate (2.33g, 16.8 mmol) in 100 mL of DMF was stir under nitrogen overnight at room temperature. The reaction was diluted with ethyl acetate, extracted three times with water, dried (MgSO4), filtered and the solvent was removed under reduced pressure to give ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (1.12 g, 79%) as a white solid, mp 127-127° C. Elemental Analysis for C27H22N2O3 Calc'd: C, 76.76; H, 5.25; N, 6.63. Found: C, 76.53; H, 5.22; N, 6.59.
Reaction SMILES: [O-][Mo:2]([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[CH2:13]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([C:25]1[CH:26]=[CH:27][C:28]([NH2:29])=[CH:30][CH:31]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Mo:2]
Reactant: O=[Mo](=O)([O-])[O-]
Agent: CCCCCCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: [Mo]

Procedure:
The procedure is as in Example A, but an aqueous solution containing 48.4 g of sodium molybdate is acidified with 65.4 g of 30% sulphuric acid. While the solution is kept at 60° C., 52.2 g of p-dodecylaniline are added.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5].[CH:14]([NH2:17])([CH3:16])[CH3:15].Cl.CCOCC>CO>[ClH:1].[C:8]1([CH2:7][S:4]([CH2:3][CH2:2][NH:17][CH:14]([CH3:16])[CH3:15])(=[O:6])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)N
Reactant: O=S(=O)(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)NCCS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
A mixture of 51.49 g (0.236 mole) of benzyl 2-chloroethyl sulfone and 600 ml of isopropylamine was stirred at room temperature for 72 hr. The solvent was removed in vacuo, and the residue was partitioned between ether and dilute sodium hydroxide. The ether solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in methanol, and excess ethereal hydrogen chloride was added. Ether was added, and a white solid precipitated to give 43.11 g (65.8%) of a white crystalline solid, m.p. 180.5°-181.5° C.