Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[N:19]=1>N1C=CC=CC=1>[NH2:17][C:18]1[N:19]=[C:20]([N:24]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(N)n1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: Nc1cccc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Temperature: 5 °C
Yield: 67.4 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (20 g) is added in small portions to a solution of 2,6-diaminopyridine (60 g) in pyridine (400 cc). The suspension passes rapidly into solution. After 15 hours at a temperature of about 20° C the solution is concentrated to dryness under reduced pressure (25 mm Hg). The residue is taken up in methylene chloride (500 cc); the insoluble material (47 g) consists of 2,6-diaminopyridine. The methylene chloride solution is washed with water (3 × 100 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (20 mm Hg). After addition to the residue obtained of a mixture (250 cc) of water and ethanol (4:1 by volume) the mixture is heated to the boiling point. After cooling to 5° C the resulting crystals are filtered off and washed with ethanol (50 cc) to give (S)-3-[(6-aminopyrid-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11 g) in the form of white crystals melting at 128° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:15]1([C:2]2[N:7]=[C:6]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:5]3=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(n1)oc1ccccc12
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ccc3c(n2)oc2ccccc23)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
2-chlorobenzofuro[2,3-b]pyridine (1.33 g, 6.53 mmol), phenylboronic acid (1.19 g, 9.80 mmol), potassium phosphate (4.51 g, 19.59 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.214 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.13 mmol) were to toluene (40 mL) and water (4 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.45 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:24]=[O:25])[CH:31]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(C=O)c4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 3-formylphenylboronic acid (330 mg, 2.2 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is recrystallized from ethyl acetate to provide 62 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 262-263° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.39 (s, 1H), 7.69-7.82 (m, 2H), 7.98 (s, 1H), 8.03-8.14 (m, 2H), 8.23 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 10.08 (s, 1H); MS 452.0, 453.9 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5])[CH3:2].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.N1C=CC=CC=1>C(Cl)Cl>[C:11]12([C:21]([O:10][C:8]3[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([CH2:1][CH3:2])[CH:9]=3)=[O:22])[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]3)[CH2:12]1)[CH2:20]2
Reactant: CCc1cc(O)ccc1O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(OC(=O)C23CC4CC(CC(C4)C2)C3)ccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Ethylhydroquinone (1.85 mmol) and 1-adamantanecarbonyl chloride (1.4 eq.) were suspended in CH2Cl2 (3 mL/mmol), pyridine (1 mmol) was added, and the mixture stirred at r.t. for 48 h.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:28][CH2:27][CH2:26][S:25]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=3)[S:28][CH2:27][CH2:26][S:25]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCCC2)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 12 was prepared from Compound 8 using the same procedure as described above for Compound 9. Yield 3.60 g (79.2%) as an oil. Rf=0.56 (hexane:ethyl acetate 92:8); IR (neat) 2925, 1206, 1067, 832, 693 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.31–3.10 (m, 4H), 2.40–2.32 (m, 1H), 1.96–1.30 (m, 12H). 13C NMR δ 160.38, 148.94, 106.52, 98.48, 81.99, 70.21, 55.60, 51.27, 45.22, 39.34, 32.82, 29.80, 28.04, 27.77; MS: (ESI, Pos.) m/z 361 ([M+23]+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[N:6]=1.Br[CH2:24][CH2:25][CH:26]1[O:30][CH2:29][CH2:28][O:27]1.Cl>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:24][CH2:25][CH:26]2[O:30][CH2:29][CH2:28][O:27]2)=[O:17])[N:8]=1
Reactant: BrCCC1OCCO1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCO2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
10 Milliliters of N,N-dimethylformamide in which 0.22 g of 60% sodium hydride in oil has been suspended was mixed with 5 ml of N,N-dimethylformamide solution of 1.38 g of 2-(4,6-dimethoxypyrimidin-2-yl)oxy benzoic acid. After stirring the mixture at room temperature for 30 minutes, 10 ml of N,N-dimethylformamide solution of 1.81 g of 2-(2-bromoethyl)-1,3-dioxolane was added thereto. The resulting solution was stirred at 100° to 110° C. for 2 hours. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 1.20 g of 2-(1,3-dioxolan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-2)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1
Yield: 59 %

Procedure:
The title compound was synthesized as described for Example 1 in 59% yield, starting from 1-(3-bromophenyl)-4-fluoro-1-(4-methoxyphenyl)-1H-isoindol-3-amine (0.13 g, 0.25 mmol) and 5-pyrimidinylboronic acid (0.037 g, 0.30 mmol):
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 190 °C
Yield: 42.6 %

Procedure:
A mixture of the compound 16 (1.52 g, 6.09 mmol), 2-fluoro-4-nitrophenol (3.87 g, 24.6 mmol) and K2CO3 (4.31 g, 31.2 mmol) in Ph2O (20 mL) was heated at 190° C. overnight. DCM (250 mL) was added to the resultant dark-brown mixture, which was then extracted with aqueous 1M HCl. The aqueous layer was collected, washed with DCM and basified with NH4OH. The resultant cloudy mixture was extracted with DCM. The organic phase was combined, filtered; the filtrate was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resultant yellow solid was purified by flash chromatography, eluent EtOAc/MeOH (80:20) to afford title-compound 17 as a yellow solid (0.96 g, 43% yield). MS (m/z): 371.0 (M+H).
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](O)(O)[CH2:6][CH2:5][N:4](C(=O)C(F)(F)F)[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1([F:1])[F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C(N1CCC(O)(O)C(F)(F)C1)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: FC1(F)CNCCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In a 100 mL flask, 2.00 g (8.0 mmol) of 3,3-difluoro-4,4-dihydroxy-1-trifluoroacetylpiperidine 13 (J. Org. Chem. 2010, 75, 929-932) and 2.15 g (20.0 mmol; 2.5 equiv) of benzylamine were dissolved in 50 mL of toluene. The mixture was heated under reflux with a Dean Stark trap during 15 hours. After cooling to room temperature, the solvent was removed in vacuo. The resulting oil was dissolved in 25 mL of absolute methanol and 0.56 g (8.8 mmol; 1.1 equiv) of sodium cyanoborohydride and 0.48 g (8.0 mmol; 1 equiv) of acetic acid were slowly added at room temperature. The solution was stirred during 4 hours at room temperature. After removing the solvent under vacuum, the crude oil was redissolved in 50 mL of dichloromethane and poured in 50 mL of a saturated aqueous NaHCO3 solution and was subsequently extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (EtOAc, Rf=0.03) yielding 1.32 g (5.8 mmol; 73% yield) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14 as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C>CN(C=O)C>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:26]([N:36]([CH3:37])[CH3:35])=[O:27])=[C:23]([CH3:25])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)O)s3)nc21
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C)c(C(=O)N(C)C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
A mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-methylthiazole-5-carboxylic acid (example 50B, 51 mg, 0.106 mmol), dimethylamine (40% in water, 0.027 mL, 0.213 mmol), HATU (52.6 mg, 0.138 mmol) and 2,6-lutidine (0.025 mL, 0.213 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 2-8% methanol/dichloromethane). The product was further purified by preparative HPLC. 2-(7-(Dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-N,N,4-trimethylthiazole-5-carboxamide (17 mg, 0.032 mmol, 30.0% yield) was obtained as a off-white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:20]=[C:21]([F:22])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:22][C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4C)cc(F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3C)cc(F)c2O1

Procedure:
The title compound was prepared (0.075 g, 75%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-fluoro-5-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.141 g, 0.32 mmol) and methylamine (0.20 g, 6.4 mmol). mp 212-217° C. (dec).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1cc(C=O)c[nH]1
Temperature: 105 °C
Yield: 67.6 %

Procedure:
5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2-methylphenylboronic acid (94 mg) and sodium carbonate (146 mg) were suspended in a mixed solvent of 1,2-dimethoxyethane (5 mL) and water (2 mL), and the mixture was sufficiently degassed under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (33 mg) was added, and the mixture was further degassed and refluxed at 105° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, and the mixture was extracted with water and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as colorless crystals (yield 72 mg, 68%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[C:7]([CH2:9][OH:10])#[N:8].C(N(CC)CC)C>C(COC)OC>[C:7]([CH2:9][O:10][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:8]
Reactant: N#CCO
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(Br)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
215.9 g (1 mole) of α-bromopropionyl bromide are dissolved in 500 ml of dimethoxy ethane and to the resulting solution are slowly added 62.8 g (1.1 moles) of cyanomethanol at 10° C. Then 111.3 g (1.1 moles) of triethylamine are added dropwise at 10°-20° C. The reaction mixture is stirred for 10 minutes at room temperature and filtered over hyflo. The filtrate is concentrated and the residue is distilled in a water jet vacuum, yielding as main fraction 107 g (55.7%) of α-bromopropionic acid cyanomethyl ester with a boiling point of 109° C./17 torr and having the formula ##STR6##
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of formic acid (15.3 mL, 0.4 mol) in dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.75 mL, 60 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cyclohexanecarboxylic acid from Preparation 19 (4.41 mmol theoretical) in dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 18 h and was concentrated in vacuo. Brine (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale, orange oil (1.77 g, 100%). MH+292.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[N+:18]([C:8]1[CH:9]=[C:10]([O:13][C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][C:7]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:20])=[O:19]
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1I
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1-n1ccnc1
Yield: 69.3 %

Procedure:
1H-imidazole (818 mg, 12 mmol, 4 eq) and 1-iodo-2-nitro-4-(trifloromethoxy)benzene (1.0 g, 3 mmol, 1 eq) under argon are heated with a heat-gun at between 300 and 500° C. for 45 min until 1-iodo-2-nitro-4-(trifluoromethoxy)benzene has completely reacted on TLC monitoring. The crude mixture is cooled to room temperature, diluted in ethyl acetate and washed with a saturated solution of ammonium chloride. The organic phase is dried over sodium sulfate and concentrated under vacuum. Purification on silica gel (95/05 dichloromethane/methanol) afforded the title compound (570 mg, 2.08 mmol, 69%) as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.O.[NH2:12][NH2:13].O>C(O)C>[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1)[NH2:13]
Reactant: NN
Reactant: Cc1nc(Cl)ccc1C#N
Solvent: O
Solvent: CCO
Product: Cc1nc(NN)ccc1C#N
Temperature: 80 °C
Yield: 59.9 %

Procedure:
To a suspension of 6-chloro-2-methylnicotinonitrile (6.2 mmol) in 6.2 mL of ethanol, hydrazine monohydrate (9.3 mmol) was added. The resulting mixture was then heated to 80° C. overnight. The mixture was cooled to room temperature and 2 mL of water was added. It was heated to 80° C. again to a clear solution and then allowed to cool down to room temperature and finally in an ice-bath. The solid was collected by filtration, washed with cold 50% ethanol, and dried under vacuum to give 550 mg of the desired solid product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 4.41 (s, 2H), 6.60 (br. s., 1H), 7.66 (d, J=8.59 Hz, 1H), 8.47 (s, 1H); ES-MS m/z 149 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][C:12]1([O:15][CH2:14]1)[CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][C:12]([CH3:14])([OH:15])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)CSc1ccc(Br)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 4-bromothiophenol (9.45 g, 50.0 mmol) in tetrahydrofuran (150 mL) was added sodium hydride (60% in oil, 2.20 g, 55.0 mmol) at 0° C. by small portions, and the resulting mixture was stirred for 1 hr. To this reaction mixture was added isobutylene oxide (4.91 mL, 55.0 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (11.6 g, yield 89%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=O)[CH3:8].Cl.[NH2:17][OH:18]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[C:7](=[N:17][OH:18])[CH3:8]
Reactant: CC(=O)c1sc(-c2cccnc2)nc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone (0.5 g, 2.1 mmol) in a mixture of pyridine (2 ml) and methanol (15 ml) was added hydroxylamine hydrochloride (0.29 g, 4.2 mmol). The resluting solution was stirred at ambient temperature for 18 hours. The precipitated white solid was filtered and dried at vacuum to afford the desired 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime. 1H NMR (300 Mz, DMSO-d6): δ:12.2 (s, 0.29H), 11.89 (s, 0.69H), 9.10 (s, 1H), 8.70 (d, 1H, J=4.8 Hz), 8.30 (m, 1H), 7.55 (m, 1H), 2.41 (s, 1H), 2.29 (s, 2H).