Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:23]=1[CH3:33].[CH:34](O)=O.C=O.O>C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:11][CH:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH3:34])[CH2:29][CH2:28]2)=[N:24][C:23]=1[CH3:33]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCN(C)CC2)nc1C

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL CH2Cl2, was added trifluoroacetic acid (4 mL). The reaction stirred for 1.5 hours and concentrated under reduced pressure, neutralized with 10 mL Na2CO3 (1M) and lyophilized to afford 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile. The mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (135 mg, 0.31 mmol), formic acid (300 μL, 6.76 mmol), formaldehyde (37% in water, 300 μL, 3.41 mmol) and water (1.5 mL) was heated to reflux for 10 hours. The reaction was diluted with saturated NaHCO3 until pH 9 and extracted with CH2Cl2 (3×20 mL). The residue was purified by preparative TLC with 10% methanol and 1% ammonium hydroxide in dichloromethane and lyophilized to give 43 mg (30% two steps) of the title compound as a white solid. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (21 g, 54.5 mmol) and azetidine-3-carboxylic acid (6.61 g, 65.4 mmol) in ethanol (750 mL) and acetic acid (20 mL) was stirred at RT for 30 min. The reaction was cooled to 0° C. and a solution of sodium cyanoborohydride (caution: potential source of cyanide generation) (1.17 g, 27.3 mmol) in ethanol was added slowly. The reaction was warmed to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The solids were collected by filtration and washed with water. The product was purified by triturating once each with DCM:methanol (98:2), DCM:methanol (96:4) and ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (16 g, 34 mmol). The compound had an HPLC retention time=8.48 min.−Column: XbridgeA 4.6×150 mm Flow rate=1.0 mL/min. Buffer=0.05% TFA in water pH2.5. Solvent A=Buffer:Acetonitrile (95:5), Solvent B=Acetonitrile:Buffer (95:5). 0-100% B over 12 minutes. LC/MS M+1=471.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([CH:25]([CH2:28][CH3:29])[CH:26]=[O:27])[CH3:24].[NH4+].[Cl-]>C1COCC1>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([CH:25]([CH2:28][CH3:29])[CH2:23][CH3:24])[OH:27])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CCC(C=O)CC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: -70 °C
Yield: 67.9 %

Procedure:
The following reaction was performed under a N2 atmosphere. A mixture of N-(4-bromophenyl)-2-benzothiazolamine (0.492 mol) in THF (2700 ml) was stirred at −70° C. Butyllithium (0.984 mol; 2.5 M in hexane) was added dropwise at −65° C. The mixture was stirred for one hour. A solution of 2-ethyl-butanal (0.492 mol) in THF (300 ml) was added dropwise at −75° C. The mixture was allowed to warm to RT overnight. A 10% aqueous NH4Cl solution (3000 ml) was added and the mixture was stirred for 15 minutes. The separated aqueous phase was extracted with EtOAc (1000 ml). The separated organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from methyl isobutyl keton. The precipitate was filtered off and dried, yielding 109 g (68%) of (±)-4-(2-benzothiazolylamino)-α-(1-ethylpropyl)benzenemethanol (interm 28).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20](=O)[C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.[CH3:26][C:27]([S:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[C:27]([S:30]([N:32]=[C:20]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([CH3:12])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:21]([F:22])([F:24])[F:23])=[O:31])([CH3:29])([CH3:28])[CH3:26]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)C(F)(F)F
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoroacetyl)-1H-indole-1-carboxylate (0.45 g, 1.26 mmol) and 2-methyl-2-propanesulfinamide (0.46 g, 3.78 mmol) in toluene (12.6 mL), Zr(O-t-Bu)4 (2.52 mL, 6.30 mmol) was added at room temperature, and the reaction was heated to 100° C. After 15 minutes the reaction mixture was cooled to room temperature and diluted with EtOAc and sat. aq. brine. The resulting mixture was filtered and the layers separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 461.3 (M+H).
Reaction SMILES: CN1CCC[C@@H](OC(=O)C(O)(C2SC=CC=2)C2SC=CC=2)C1.O(CC[Br:32])C1C=CC=CC=1.[Br-].[OH:34][C:35]([C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)([C:55]1[S:56][CH:57]=[CH:58][CH:59]=1)[C:36]([O:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][N+:41]([CH3:54])([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40]1)=[O:37]>C(#N)C>[Br-:32].[OH:34][C:35]([C:55]1[S:56][CH:57]=[CH:58][CH:59]=1)([C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[C:36]([O:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][N@+:41]([CH3:54])([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40]1)=[O:37]
Reactant: BrCCOc1ccccc1
Reactant: C[N+]1(CCOc2ccccc2)CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Agent: CN1CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Agent: [Br-]
Solvent: CC#N
Product: C[N@+]1(CCOc2ccccc2)CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Temperature: 25 °C

Procedure:
Hydroxy-di-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester (0.57, 0.00169 mol) is dissolved in acetonitrile (3 ml) at 60° C. and 2-phenoxyethyl bromide (0.51 g, 0.00254 mol) in Acetonitrile (1 ml) is added dropwise. The reaction mixture is refluxed for 96 hours, cooled to room temperature and left in the refrigerator. This gives an approximately 1:1 mixture of isomers (1R/S,3R)-3-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (97a). The suspension is filtered off and washed with cold acetonitrile to yield (1R,3R)-3-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (97b) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=c1cc(-c2cccnc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (86 mg, 0.362 mmol) and K2CO3 (250 mg, 1.81 mmol) in acetone (3 mL) was added nicotinoyl chloride hydrochloride (0.71 mL, 0.399). The reaction vessel was sealed and heated to 85° C. for 24 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 100% EtOAc to yield 14 mg (12%) of 5-hydroxy-7-morpholin-4-yl-2-pyridin-3-yl-chromen-4-one. Rf=0.22 (100% EtOAc).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.CI>CN(C)C=O.C(C(C)=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:17]([O:19][CH3:1])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Yield: 96.3 %

Procedure:
To a 3 liter flask stirring under nitrogen was charged 276 g (2.0 mole) of potassium carbonate and 1000 mL of methyl ethyl ketone. The mixture was stirred for 10 minutes, then a cloudy solution of 356 g (1.0 moles) of 4-(4-chlorophenyl)-2-phenyl-2-[(1,2,4-triazol-1-yl)-methyl]-butanoic acid in 2000 mL of dimethyl formamide was charged and stirred at room temperature for 30 minutes. To the mixture was added 284 g (2.0 moles) of methyl iodide in 125 mL of methyl ethyl ketone over 1 hour. The reaction was stirred at room temperature for 16 hours after which TLC indicated the reaction was complete. The solvent was removed under vacuum, then the residue was treated with 2000 mL of ethyl acetate and washed with 2×1000 mL of water, dried and concentrated. The residue crystallized on concentration and was washed several times with hexane, filtered and washed with additional hexane and gave 356 g (96% yield) of pale yellow solid, Example 127 of Table 1.
Reaction SMILES: [Cl:1]C1C(C#N)=NC(Cl)=C(Cl)C=1Cl.F[C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#Cc1nc(F)c(F)c(F)c1F
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1nc(F)c(F)c(F)c1Cl
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4,5,6-tetrachloropicolinonitrile (16.1 g, 66 millimoles (mmol)) and 3,4,5,6-tetrafluoropicolinonitrile (5.9 g, 33 mmol) were heated to 160° C. under nitrogen to form a solution. To this stirred solution was added tetrabutyl phosphonium chloride (Bu4PCl; 0.36 g, 1.2 mmol), and the solution was held at 160° C. for 1 h. An aliquot was dissolved in methylene chloride (CH2Cl2) and passed through a short pad of silica gel before GC analysis. The profile of halogenated picolinonitriles was: 11.2% Cl4—PN; 11.3% 4,6-F2—PN; 2.3% 5,6-F2—PN; 19% 3,6-F2—PN; 52.6% 6-F—PN and 3.6% 4-F—PN. About 80% of the mixture is useful in the halogen exchange reaction to produce 3-chloro-4,5,6-trifluoropicolinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCN=C=NCC.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][C:33]=1[Cl:44]>ClCCl.O>[Cl:44][C:33]1[CH:34]=[C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:36]=[CH:37][C:32]=1[NH:31][C:4]([C:3]1[CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: CCN=C=NCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (230 mg, 0.77 mmol) in dichloromethane (3 ml) was treated with N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (178 mg, 0.93 mmol, 1.2 eq) and stirred at room temperature for 30 minutes. A solution of ethyl (4-amino-3-chlorophenyl)acetate (198 mg, 0.93 mmol, 1.2 eq) in dichloromethane (2 ml) was added and the resulting mixture heated at 40° C. overnight. As some starting material was still present, another 100 mg of N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride were added and the mixture heated at 40° C. for another 2 hours. On cooling, the mixture was diluted with dichloromethane (50 ml) and water (30 ml), the layers separated and the aqueous layer extracted again into dichloromethane (50 ml). Organic layers combined, washed with brine, dried over magnesium sulphate and evaporated to afford the title compound as a yellow oil. The aqueous layer containing an insoluble solid was evaporated in vacuo, the residue purified by SCX cartridge eluting with methanol to afford a further crop of the title compound as a yellow oil (72 mg total). MS (ES+) m/z 492 [M+H]+ (C24H2035Cl3NO4). 1H-NMR (400 MHz, d6-DMSO) δ 1.20 (3H, t, J 7.2), 3.72 (2H, s), 4.10 (2H, q, J 7.2), 5.20 (2H, s), 7.15-7.62 (10H, m).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](=[O:27])[CH:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:19]=2[F:26])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4](=[O:27])[CH:5]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[F:26])[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:29]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(C=O)cc2F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(CO)cc2F)CC1
Reaction time: 72 h
Yield: 95.2 %

Procedure:
A solution of N,N-diethyl-2-[4-(2-fluoro-4-formyl-phenyl)-piperazin-1-yl]-2-phenyl-acetamide (0.76 g, 1.92 mmol) in ethanol (35 mL) was treated with NaBH4 (0.11 g). After 3 d, the solvent was removed and water (5 mL) and 1 M NaOH were added (˜pH 10). The mixture was extracted with DCM and the solvent removed. Purification on SiO2EtOAc/hexanes) provided 0.73 g of the title compound. MS (ESI): mass calcd. for C23H30FN3O2, 399.5. m/z found, 400.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.C([CH2:16][S:17]([CH2:20][S:21]([CH2:24][C:25](O)=O)(=[O:23])=[O:22])(=[O:19])=[O:18])(O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1/[CH:5]=[CH:16]/[S:17]([CH2:20][S:21](/[CH:24]=[CH:25]/[C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=1[O:11][CH3:12])(=[O:22])=[O:23])(=[O:18])=[O:19]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1cccc(OC)c1C=O
Solvent: CC(=O)O
Product: COc1cccc(OC)c1/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c1c(OC)cccc1OC
Yield: 74 %

Procedure:
A solution of 2,6-dimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 74% yield. m.p. 118-120° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:22][C:21]=3[C:32]([OH:34])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N.O1CCOCC1>CN(C=O)C>[C:32]([C:21]1[N:22]=[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)(=[O:34])[NH2:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cccnc4)nc3C(=O)O)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cccnc4)nc3C(N)=O)cc2)CC1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(pyridin-3-ylamino)oxazole-4-carboxylic acid (0.046 g, 0.1 mmol) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.065 g, 0.17 mmol), diisopropylethylamine (0.03 ml, 0.17 mmol) and 0.5M NH3 in dioxane (0.6 ml, 0.3 mmol) and the resultant mixture stirred at room temperature overnight. A further portion of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.020 g, 0.05 mmol), diisopropylethylamine (0.01 ml, 0.056 mmol) and 0.5M NH3 in dioxane (0.2 ml, 0.1 mmol) was added and the reaction stirred for 1 hour. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(pyridin-3-ylamino)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.006 g, 0.013 mmol, 13%). LCMS (2) Rt: 2.64 min; m/z (ES+) 465.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12]1>>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:15]2[NH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: COC(=O)c1c[nH]c(C(=O)c2ccc(C)cc2)c1

Procedure:
Following the procedure of Example 64, p-toluoyl chloride (3.09 g., 20 mmoles) and methyl pyrrole-3-carboxylate were reacted to form methyl 5-(4-methylbenzoyl)pyrrole-3-carboxylate (2.9 g., m.p. 155°-159° C., m/e 243).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:28][CH3:29])[C:11]1[C:12]([O:23][CH3:24])=[CH:13][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 103 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester and 17.3 g. of sodium hydride (50% dispersion in oil) in 1 liter of absolute dimethylformamide was stirred at room temperature for 4 hours and subsequently treated with 56.2 g. of ethyl iodide with stirring and ice-cooling. After stirring at room temperature for 30 minutes, the dimethylformamide was removed at 60° C. under vacuum. Then, 1 liter of water was added to the residue and the mixture was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 700 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained N-ethyl-2,6-dimethoxy-4-(methoxycarbonyl)-carbanilic acid benzyl ester having a melting point of 85°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.[N:26]#[O+:27].[OH2:28]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27]
Reactant: CCC(c1ccc(Cl)cc1)C1(C(=O)OC(C)(C)C)CC1
Reactant: O
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
262 mg (0.89 mmol) of tert-butyl 1-[1-(4-chlorophenyl)propyl]cyclopropanecarboxylate were dissolved in 8 ml of dichloromethane, the mixture was cooled to 0° C. and 284 mg (2.14 mmol) of nitrosyl tetrafluoroborate were added a little at a time. The reaction solution was then stirred at a temperature between −10° C. and 0° C. for four hours. The reaction mixture was then added to water and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 262 mg of the target product, which was used without further purification in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:34])=[N:31][C:32]=1[CH3:33])#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:34])=[N:31][C:32]=3[CH3:33])[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(N)ccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (59 mg, 0.21 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (1 mL) were added 5-ethynyl-6-methyl-pyridin-2-ylamine (22 mg, 0.16 mmol) described in Manufacturing Example 187-1-2 and triethylamine (46 μL, 0.33 mmol), which was stirred for 2 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (35 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].O.NCC(O)=O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:10]([C:9]#[N:13])[C:11]#[N:12])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: N#CCC#N
Agent: NCC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(C#N)=Cc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-thiophenecarboxaldehyde (6.92 g, 36.2 mmol) and malononitrile (2.39 g, 36.2 mmol) were dissolved in 100 mL 1:1 EtOH:H2O. A small spatula of glycine was added and the reaction was stirred at ambient temperature for 30 min. The precipitated product was collected by suction filtration, washed with water, and dried under vacuum overnight. The result was 8.38 g (97% ) 4bromo-2-(2,2-dicyanoethenyl)thiophene as a light green solid. MS 238/240 (M+H)+.