Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.O.[OH-].[Cs+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29]([C:31]#[CH:32])[S:30][C:21]=12>CN1CCCC1=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29](/[CH:31]=[CH:32]/[N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[S:30][C:21]=12
Reactant: c1c[nH]nn1
Reactant: C#Cc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2s1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/n4nccn4)sc23)c(Cl)cc1Cl
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a mixture of 1,2,3-triazole (50 μL, 0.81 mmol) and cesium hydroxide monohydrate (18 mg, 0.11 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is added slowly 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.54 mmol). The mixture is heated to 120° C. for 12 hours, cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of methanol in dichloromethane (0–2%) to provide 90 mg (38%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(E)-2-(2H-1,2,3-triazol-2-yl)vinyl]thieno[3,2-b]pyridine-6-carbonitrile as a yelllow solid, mp 315–316° C.; 1H NMR (DMSO-d6-TFA) δ 3.88 (s, 3H), 7.50 (s, 1H), 7.65 (d, J=14 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.15 (s, 2H), 8.32 (d, J=14 Hz, 1H), 9.01 (s, 1H); MS 443.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.C(O)CCC.Cl.[CH3:17][O:18][NH2:19]>O>[CH3:17][O:18][NH:19][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: CON
Reactant: Clc1nccc2ccoc12
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CONc1nccc2ccoc12
Temperature: 125 °C

Procedure:
A three-necked flask was charged with 7-chloro-furo[2,3-c]pyridine (40 g, 0.26 mol) and n-butanol (300 mL) and heated at 125° C. Methoxyamine hydrochloride (54 g, 0.65 mol) was added as a solid and then additional methoxyamine hydrochloride (54 g, 0.65 mol) dissolved in water (50 mL) was added slowly. The resulting mixture was heated at reflux overnight. After cooling to RT, the reaction mixture was concentrated in vacuo. The remaining aqueous solution was basified to pH ˜8.5 with saturated NaHCO3 and extracted several times with DCM. The combined DCM extracts were washed with saturated NaHCO3 and brine. This solution was concentrated in vacuo leaving a dark brown syrup which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:29][CH2:30][CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:22]([N:29]([CH2:30][CH3:31])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g, 1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) in methylene chloride (10 mL) were added N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was stirred at room temperature for three days. The resulting solution was diluted with methylene chloride (90 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.129 g (31%) of a whitish oil.
Reaction SMILES: N[N:2]([CH:10]=[NH:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=O.C(OCC)(=O)C.C[N:29](C)C=O>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:29]=[C:10]([NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[NH:11][CH:13]=1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccccn1
Reactant: CC(C)(C)OC(=O)N(N)C=N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccccn2)c[nH]1
Temperature: 25 °C
Reaction time: 143 h
Yield: 27 %

Procedure:
tert-Butyl amino(imino)methylcarbamate (33.4 g; 210 mmol) was dissolved in N,N-dimethylformamide (300 mL), 2-bromo-1-pyridin-2-ylethanone (17.4 g; 87 mmol) was added thereto, and the mixture was stirred for 143 hours at room temperature. To the reaction solution, ethyl acetate (2.0 L) was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution (three times). The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting oily substance was crystallized from diethyl ether and the resulting crystals were collected by filtration and dried to give 6.2 g of the title compound (yield 27%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=1)[O:7]2.I.C(O)(=O)C>O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[O:7]2
Reactant: COc1ccc(-c2cc(=O)c3c(F)cc(F)cc3o2)cc1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)cc2)oc2cc(F)cc(F)c12
Temperature: 110 °C
Yield: 54.6 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one (0.425 g, 1.47 mmol), hydroiodic acid (10 mL) and acetic acid (5 mL). The reaction mixture was heated 110° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was filtered off, washed with water and dried to give the title compound (220 mg, 54%). Selected data for the title compound: MS (ES) m/z: 275.10 (M+1); 19F-NMR (DMSO-d6): δ −106.2, −113.4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]1[CH2:72][CH2:71][CH2:70][C@H:66]1[C:67](O)=[O:68]>CN(C=O)C.C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][N:45]([C:67]([C@@H:66]4[CH2:70][CH2:71][CH2:72][N:65]4[CH3:64])=[O:68])[CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)[C@@H]2CCCN2C)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
HATU (0.26 g) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg; prepared as described in Example 45), diisopropylethylamine (210 μl) and N-methyl-L-proline (0.120 g) in DMF (7.5 ml) and the mixture was stirred at room temperature for 2.5 hours. The DMF was removed under reduced pressure and the residue dissolved in methylene chloride (50 ml) and washed with sodium bicarbonate (50 ml) then water (50 ml). Purification by flash column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (9614). The fractions containing the expected product were evaporated to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (0.130 g). 1H NMR Spectrum: (DMSO d6) 1.43-1.62 (m, 2H), 1.66-1.95 (m, 4H), 1.96-2.18 (m, 4H), 2.20-2.29 (m, 2H), 2.67-2.80 (m, 1H), 2.96 (m, 1H), 3.03-3.20 (m, 1H), 3.51-3.80 (m, 2H), 3.80-4.05 (m, 4H), 4.51-4.68 (m, 1H), 7.22-7.31 (2H), 7.47-7.59 (m, 2H), 7.89 (m, 1H), 8.39 (s, 1H), 9.55 (m, 1H); Mass Spectrum: (M+H)+ 514.
Reaction SMILES: ClC(OC(Cl)=O)C.COC1C=C(OC)C=CC=1C[N:13]1[CH2:26][CH:25]([CH3:27])[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14]1.C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:27][CH:25]1[N:16]2[CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@@H:15]2[CH2:14][NH:13][CH2:26]1
Reactant: COc1ccc(CN2CC(C)N3Cc4ccccc4C[C@@H]3C2)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CNC[C@H]2Cc3ccccc3CN12
Temperature: 0 °C
Yield: 56 %

Procedure:
1-Chloroethylchloroformate (0.050 ml, 0.47 mmol) was added to a solution of (11aR)-2,3,4,6,11,11a-hexahydro-2-(2,4-dimethoxybenzyl)-4-methyl-1H-pyrazino[1,2-b]isoquinoline (53 mg, 0.15 mmol) in 1,2-dichloroethane (1 ml) stirring at 0° C. The ice bath was removed and the reaction stirred at ambient temperature for 30 min. After refluxing an additional 2 h, the reaction was evaporated in vacuo. Methanol (1.0 ml) was added to the residue and the reaction refluxed under nitrogen for 1 h. Evaporation in vacuo afforded 75 mg of crude product. This crude product was transferred to a separatory funnel with CH2Cl2 and saturated NaHCO3. Extraction with CH2Cl2 (2×) and drying of the combined organic layers over MgSO4 afforded 42 mg which was further purified by flash chromatography (SiO2, 0.2 to 10% 2N N3 in MeOH/CH2Cl2) to give pure product (17 mg, 55%). MS (ESI) 203 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-Methyl-3-nitroaniline (5 g, 32.9 mmol) was stirred in a solvent of dichloromethane (150 mL). The reaction solution was added with DIPEA (11.48 mL, 65.7 mmol) and 3-(trifluoromethyl)benzoylchloride (4.86 mL, 32.9 mmol), and stirred for about an hour at room temperature. The reaction mixture was washed with 1M aqueous HCl solution, an aqueous sodium bicarbonate and saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (10.6 g, 99%).
Reaction SMILES: C(O)(=O)C.[Si]([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH:20]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:37][CH3:38])(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH:20]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: CCOP(=O)(CC(Nc1cccnc1)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(OC)c1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(Nc1cccnc1)c1cc(C)c(O)c(OC)c1)OCC
Temperature: 20 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Glacial acetic acid (130 ml) was added to 500 ml of a THF solution containing a mixture of diethyl β-(4-t-butyldimethylsilyloxy-3-methoxy-5-methylphenyl)-β-[N-(3-pyridyl)-amino]-ethylphosphonate (90.5 g, 0.18 mol) and tetrabutylammonium fluoride trihydrate (TBAF) (224.5 g, 0.71 mol). After stirring at 20° C. for 3 h a GLC test showed that the Tbs protected compound has entirely reacted. The reaction mixture was extracted with dichloromethane, the organic phase was washed with a saturated bicarbonate solution, dried over MgSO4 and evaporated. Purification by column chromatography (silica gel, 9/1 CH2Cl2/MeOH) gave 53 g of pure fractions. Recrystallization from a mixture of petroleum ether/CH2Cl2 gave 27 g (39%) of the title compound as a white solid, mp=156-158° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1.Br[C:14]1[N:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.[Pd](Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:14]3[N:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][CH:15]=3)=[CH:11][N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Fc1cncc(-c2nccs2)c1
Reactant: N#Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cnc(-c3cncc(F)c3)s2)n1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
Under argon, 3-fluoro-5-(1,3-thiazol-2-yl)pyridine (0.99 g, 5.47 mmol) and 6-bromopyridin-2-carbonitrile (1.0 g, 5.47 mmol) were initially charged in DMF (15 ml). After 10 min, at room temperature, tris(2-methylphenyl)phosphine (0.13 g, 0.23 mmol) and palladium(II) chloride (0.1 g, 0.55 mmol) were added. The reaction mixture was stirred at 130° C. for 14 h. After cooling, water and ethyl acetate were added and the precipitated product was filtered off with suction. The organic phase of the filtrate was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was stirred with dichloromethane and filtered off with suction. This gave a total of 0.94 g (61% of theory) of 6-[2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carbonitrile.
Reaction SMILES: C(O)C.O1CCCC1.C([Li])CCC.[C:14]1([C:20]2[O:21][C@H:22]([C:31]([O:33]CC)=[O:32])[C@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([C:20]2[O:21][C@@H:22]([C:31]([OH:33])=[O:32])[C@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethanol (0.1 ml) was mixed with tetrahydrofuran (1.0 ml), and the mixture cooled to -78° C. n-Butyllithium (n-BuLi) (2.12M, 0.050 ml) was added dropwise, and the mixture warmed to 0° C. Solid (4S-cis)-4,5-dihydro-2,4-diphenyl-5-oxazolecarboxylic acid, ethyl ester having the structure: ##STR34## (20 mg, 0.0678 mmol) was added and the reaction was stirred for 1 hour (a small amount of water was present). A mixture of cis oxazoline ethyl ester starting material and the corresponding trans oxazoline ethyl ester (5-position inversion) were observed by TLC (very little hydrolysis was noted at this point). The reaction mixture was stirred for another hour and then left with an ice bath overnight (0° C. to room temperature). After 18 hours TLC showed mostly the trans acid title product and a trace of the cis ester starting material (solvent systems hexane:EtOAc 2:1 (trace of cis ester) and EtOAc:acetone:H2O:MeOH 7:1:1:1 (title product)).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[N:7]=1)(=[O:5])[CH3:4].Br.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.C(OCC)(=O)C>[C:13]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(C(=O)CBr)n1

Procedure:
Bromine (1.9 ml) was added dropwise to a mixture of 2-acetyl-6-acetylaminopyridine (6.6 g) and 30 wt % hydrogenbromide-acetic acid solution (7.4 ml) in acetic acid (66 ml) at ambient temperature under stirring and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 2-acetylamino-6-bromoacetylpyridine (8.57 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:5]([NH:7][CH:8]1[CH:17]([OH:18])[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9]1)=O.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:17]3[CH2:16][CH2:15][C:10]4([O:14][CH2:13][CH2:12][O:11]4)[CH2:9][C:8]=3[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1
Reactant: O=C(NC1CC2(CCC1O)OCCO2)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(-c2nc3c(o2)CCC2(C3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 3-chloro-4-(cyclopropylmethoxy)-N-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzamide (19.4 g) in dimethyl sulfoxide (100 mL) were added triethylamine (22.2 mL) and sulfur trioxide-pyridine complex (25.4 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (100 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (19.0 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:46](=O)[CH2:47][CH2:48][CH3:49]>>[CH2:46]([NH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:47][CH2:48][CH3:49]
Reactant: CC(C)Cc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1N
Reactant: CCCC=O
Product: CCCCNc1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)ccc1CC(C)C

Procedure:
5-{-4-[2-(3′-Amino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-[1,2,5]thiadiazolidin-3-one-1,1-dioxide (22 mg, 0.03 mmol) was reacted with butyraldehyde (2.2 mg, 0.03 mmol) according to general procedure X to give 5-{4-[2-(3′-butylamino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:14]>>[Cl-:14].[CH2:1]([NH2+:8][CH2:9][CH2:10][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCC[NH2+]Cc1ccccc1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [H][H].[CH:3]([CH:5]=[O:6])=[O:4].[CH2:7]([OH:11])[CH2:8][CH2:9][CH3:10]>>[C:5]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:6])[CH:3]=[O:4]
Reactant: O=CC=O
Reactant: [H][H]
Reactant: CCCCO
Product: CCCCOC(=O)C=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
300 g of 1-butanol was added to 60 g of a 40 wt % glyoxal aqueous solution (Wako Pure Chemical), and most of the water was distilled off as an azeotropic composition with the 1-butanol at normal pressure and 90° C. with an evaporator. This gave a butanol solution of glyoxal (containing 19.4 wt % glyoxal and 80.6 wt % butanol). 5.17 g of the above-mentioned butanol solution, 8.90 g of 1-butanol, and 0.6 g of the above-mentioned metal-loading carrier were then put into an autoclave equipped with a condenser, the system was maintained at an internal pressure of 0.5 MPa at 80° C. under stirring while a mixed gas of hydrogen and nitrogen (hydrogen:nitrogen=1:9 (volumetric ratio)) was bubbled into the solution at a flux of 500 mL/minute, and the reaction was allowed to continue for 5 hours. After the reaction, the reaction solution was analyzed, which revealed the glyoxal conversion to be 87%, and the 1-butyl glyoxylate (the product) selectivity and yield to be 73% and 64%, respectively.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25](N)=[O:26])=[CH:20][CH:19]=1.CN1[C:35](=[O:36])CCC1>>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:29])([CH3:28])[C:25]([O:36][CH3:35])=[O:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: CN1CCCC1=O
Reactant: CC(C)(C(N)=O)c1ccc(N)cc1
Product: CCc1cc(Nc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 100 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.075 g, 0.29 mmol) in NMP (3 mL) was reacted with 2-(4-aminophenyl)-2-methylpropanamide (0.069 g, 0.36 mmol) to afford the title compound (0.105 g, 100%) as an amber oil. MW=409.91. 1H NMR (CDCl3, 300 MHz) δ 8.44-8.39 (m, 1H), 8.33-8.26 (m, 1H), 7.43-7.40 (m, 1H), 7.40-7.35 (m, 4H), 6.77 (s, 1H), 6.52 (s, 1H), 4.12 (q, J=7.1 Hz, 1H), 3.69 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 2.61 (s, 6H), 1.59 (s, 3H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NCC(O)=O)(OC(C)(C)C)=O.C(O)C1C=CC=CC=1>CO.C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:29])[CH2:27][NH:28][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: OCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCc1ccccc1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldrich) using General Procedure X, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=167.5° C.). The reaction was monitored by tlc (Rf=0.35 in 2% MeOH/CH2Cl2) and the product was purified by flash chromotography using 2% MeOH/CH2Cl2 as the eluent.