Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]([N+:24]([O-])=O)[CH:14]=2)=[C:7]([Br:27])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].CCCCCCC>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]([NH2:24])[CH:14]=2)=[C:7]([Br:27])[CH:6]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2cc(C(C)C)c(OC)c([N+](=O)[O-])c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1cc(Br)c(Oc2cc(N)c(OC)c(C(C)C)c2)c(Br)c1
Yield: 44.2 %

Procedure:
Methyl[3,5-dibromo-4-(5-isopropyl-4-methoxy-3-nitrophenoxy)phenyl]acetate (1.1 g, 2.12 mmol) was dissolved in ethanol (50 mL) and sodium hydrosulfite (1.85 g, 10.6 mmol) was added. The reaction mixture was heated at reflux for 48 hours. The reaction monitored by TLC (65:35 n-heptane: EtOAc) and when complete, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified on column (silica gel, n-heptane/EtOAc 1:1) to yield methyl[3,5-dibromo-4-(3-amino-5-isopropyl-4-methoxyphenoxy)phenyl]acetate (457 mg, 44%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2cnccn2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(/C=C/c3cnccn3)n[nH]c2c1

Procedure:
A degassed mixture of (E)-3-((3-((E)-2-(pyrazin-2-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (20 mg, 0.040 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 0.6 mL, 0.6 mmol) in anh. THF (10 mL) was refluxed under Ar for 1 d. The reaction mixture was then concentrated under reduced pressure and purified by prepTLC (SiO2 12% MeOH/DCM) and trituration with DCM to provide the title compound as a 1.5:1.0 (E:Z) mixture of isomers: a yellow solid (1.7 mg, 12%). 1H NMR (400 MHz, DMF-d7) δ ppm 9.33 (s, 0.35H), 9.16 (d, J=1.51 Hz, 1.0H), 8.84-8.87 (m, 1.1H), 8.70 (t, J=2.26 Hz, 1.0H), 8.60 (d, J=8.78 Hz, 0.6H), 8.51 (d, J=8.28 Hz, 0.45H), 8.37-8.46 (m, 1.6H), 8.26 (d, J=5.52 Hz, 1.0H), 8.04 (s, 0.6H), 8.02 (d, J=7.53 Hz, 0.39H), 7.92-7.98 (m, 1.7H), 7.79 (d, J=8.03 Hz, 0.60H), 7.41-7.49 (m, 1.1H), 7.05-7.25 (m, 2.1H); MS ESI 366.2 [M+H]+, calcd for [C22H15N5O+H]+ 366.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[CH2:24]([C:20]1[CH:19]=[C:18]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:26][CH:27]=[N:28][CH:29]=4)[CH:3]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:23]=[CH:22][N:21]=1)[CH3:25]
Reactant: OB(O)c1cncnc1
Reactant: CCc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Product: CCc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3ccccc32)ccn1
Yield: 58 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-ethylpyridin-4-yl)-1H-isoindol-3-amine (Example 110) as described in Example 67 Scheme #10, D in 58% yield using pyrimidine-5-boronic acid. 1H NMR (DMSO-d6) δ 9.11 (s, 1 H), 8.93 (s, 2 H), 8.28 (d, J=5.30 Hz, 1 H), 7.86 (dd, J=6.06, 1.77 Hz, 1 H), 7.80-7.68 (m, 1 H), 7.64-7.54 (m, 2 H), 7.47-7.36 (m, 4 H), 7.19-7.10 (m, 1 H), 7.07 (dd, J=5.18, 1.64 Hz, 1 H), 6.85 (br s, 2 H), 2.59 (q, J=7.58 Hz, 2 H), 1.08 (t, J=7.58 Hz, 3 H); MS (ESI) m/z 392 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Ni].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 94.9 %

Procedure:
In a 50 mL volume pressure-resistant vessel were placed 2.02 g (6.58 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 2.0 g of a developed Raney nickel, and 40 mL of methanol. The atmosphere in the vessel was replaced with hydrogen, and the vessel was closed. The reaction was carried out at 90-100° C. for 24 hours at a hydrogen pressure of 0.9 MPa (gauge pressure). After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.71 g (reaction yield: 95.0%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: C([Li])CCC.[NH:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.Cl[CH2:12][CH2:13][CH2:14][Si:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C1COCC1>[CH2:20]([O:19][Si:15]([O:22][CH2:23][CH3:24])([O:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)[CH3:21]
Reactant: c1cc[nH]c1
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCO[Si](CCCn1cccc1)(OCC)OCC
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of butyllithium (1.6 M in hexane, 187 mL, 0.3 mol) is added in 1 hour to a solution of pyrrole (20 g, 0.3 mol) in THF (200 ml) cooled to −10° C. This solution is kept at 0° C. for 1 hour. 72.3 g of 3-chloropropyltriethoxysilane (0.3 mol) is added to this solution, then the temperature of the reaction mixture is raised to +65° C. for 8 hours. After the temperature of the reaction mixture has returned to 20° C., the THF is evaporated under vacuum. The raw product is taken up in cyclohexane (150 mL), the salts of lithium chloride are filtered and the aqueous solution is washed with 50 mL of distilled water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under vacuum. The desired product (57.8 g) is then recovered.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=O)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.ON1C2C=CC=CC=2N=N1.[CH2:34]([NH2:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:34]([NH:42][C:21]([C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:14][CH:13]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)O)c3)cc2)S1
Reactant: CCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCNC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
1 g (3.1 mmol) of 4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-carboxylic acid, 15 ml of dimethylformamide, 460 mg (3.4 mmol) of 1-hydroxybenzotriazole and 500 μl (3.1 mmol) of n-octylamine are introduced into a three-necked flask under a stream of nitrogen. At 0° C., 0.59 g (3.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added portionwise. The mixture is stirred for three days while allowing the temperature to rise. The reaction medium is poured into water and extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. 450 mg (33%) of the desired product are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[C:11]([O:12][CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Reactant: CCI
Product: CCOc1cc(C(=O)OC)cnc1Cl
Yield: 43 %

Procedure:
The title compound is prepared in 43% yield (0.68 g, a white solid) from methyl 6-chloro-5-hydroxynicotinate (1.37 g, 7.28 mmol) and iodoethane instead of iodomethane by the similar manner in Step-2 of Amine-4.
Reaction SMILES: [OH-].[Na+].[I-:3].[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].O>CO>[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[I:3])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cccc(O)c1
Reactant: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
21 g (520 mmol) of sodium hydroxide and then 79 g (520 mmol) of sodium iodide are added to a solution of 69 g (500 mmol) of 3-hydroxybenzoic acid in 700 ml of methanol. The reaction mixture is cooled to 0° C. and then Javel water (520 mmol) is added dropwise. The reaction mixture is stirred at 0-5° C. for 2 hours and then at room temperature for 15 h. After evaporating the methanol, the reaction mixture is acidified with a concentrated solution of hydrochloric acid. The precipitate is filtered, washed with water and dried. 41.9 g of 3-hydroxy-4-iodobenzoic acid is obtained in the form of a white solid with melting point of 218° C. The aqueous phase is extracted with ethyl acetate, the organic phase obtained is dried over magnesium sulfate, filtered, and evaporated. The residue obtained is taken up in heptane and the precipitate obtained is filtered.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21](=[N:33][O:34]C)[C:22]#[C:23][CH:24]1[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:36]Cl.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:22]([I:36])=[C:23]([CH:24]2[CH2:27][CH:26]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]2)[O:34][N:33]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClI
Reactant: CON=C(C#CC1CC(CC(C)(C)C)C1)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 1 h

Procedure:
tert-Butyl 3-(3-benzyloxypropyl)-6-[3-(2,2-dimethylpropyl)cyclobutyl]-4-methoxyimino-5-hexynoate (3.37 g) and methylene chloride (70 mL) were mixed. To the mixture was added iodine monochloride (1 M in methylene chloride) (7.66 mL) at ice temperature. The mixture was stirred at ice temperature for 1 hr, and then to the mixture was added aqueous solution of sodium sulfite. The mixture was extracted with chloroform. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (4.21 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5]([CH3:8])=[N:6][CH:7]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: Cc1ncc(F)cc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ncc(F)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 32 mg of (5-fluoro-2-methylpyridin-3-yl)methanol in 2 mL of dichloromethane, 80 mg of molecular sieves 3 A and 40 mg of 4-methylmorpholine N-oxide were added, and the mixture was stirred at room temperature for 30 minutes. Thereto was added 6.0 mg of tetrapropyl ammonium perruthenate, and the mixture was stirred at room temperature for 1 hour 30 minutes. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 20 mg of 5-fluoro-2-methylnicotinaldehyde as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2](=[CH2:36])[CH:3]([N:17]1[CH:20](S(O)=O)[CH:19]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:35])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5].[I:37]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][C:2](=[CH2:36])[CH:3]([N:17]1[CH:20]([I:37])[CH:19]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:35])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1I

Procedure:
A solution of p-nitrobenzyl 3-methyl-2-(2-oxo-4-sulfino-3-phenoxyacetamido-1-azetidinyl)-3-butenoate in methylene chloride was cooled to 0° C. and one molar equivalent of N-iodosuccinimide was added with stirring. After 5 minutes the reaction mixture was washed with brine, dried and evaporated. The product obtained as a solid residue was shown by its nmr spectrum to contain about a 2:1 ratio of cis-isomer to trans-isomer contaminated with a trace of oxazolineazetidinone.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]2([CH3:26])[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH:12]=[CH:13][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]2([CH3:26])[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(Cc2cccc(N)c2)Cc2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(CC2(C)Cc3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (41.75 mL, 0.46 mol) was added to a stirred solution of 2-[(3-aminophenyl)methyl]-2-methyl-1-indanone (37.00 g, 0.147 mol) in ethyl acetate (800 mL) and this mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate (600 mL) was added to the resulting mixture, followed by successive washes of the aqueous layer with ethyl acetate. The combined organic extracts were washed with water (500 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as an oil: 1H NMR (CDCl3) 7.7 (doublet, 1H), 7.55-7.15 (multiplet, 5H), 7.1 (doublet, 1H), 6.85 (doublet, 1H), 3.25 (doublet, 1H), 2.9 (doublet, 1H), 2.7 (doublet, 1H), 2.1 (singlet, 3H), 2.1 (doublet, 1H), 1.2 (singlet, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Yield: 80.7 %

Procedure:
A mixture of 1.1 g (4.0 mmol) methyl 2-(4-fluorophenyl)benzo[d]oxazole-4-carboxylate 9d and 3.7 mL of 3N aqueous NaOH in 10 mL of THF was refluxed overnight. After cooling the reaction mixture was poured into water and acidified with conc. HCl. The resulting solid was filtered and dried to give 830 mg (79%) of 2-(4-fluorophenyl)-benzo[d]oxazole-4-carboxylic acid, 9e. MS m/z (M+H+) 258.1.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OC)(=[O:17])[CH:15]=[CH2:16].C[Sn](Cl)(Cl)C.C[O-].[Na+].COC1C=CC(O)=CC=1.C1(C=CC(O)=CC=1)O.[Sn]>CCCCCCC>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:17])[CH:15]=[CH2:16]
Reactant: CCCCCCCCCCCCO
Reactant: C=CC(=O)OC
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: C[Sn](C)(Cl)Cl
Solvent: CCCCCCC
Product: C=CC(=O)OCCCCCCCCCCCC
Yield: 93.2 %

Procedure:
In a similar manner, a mixture of 559 parts n-dodecyl alcohol, 387.4 parts methyl acrylate, 167 parts heptane, 1.5 parts dimethyltin dichloride, 0.4 parts sodium methoxide (molar ratio 1.08:1), 3.3 parts 4-methoxyphenol and 0.65 parts hydroquinone yielded, after work up, 672.2 parts (93.2 percent yield, based on n-dodecyl alcohol) of n-dodecyl acrylate, with a purity of 96.6 percent containing no detectable tin.
Reaction SMILES: F[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][C:2]2[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)=[O:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)s1

Procedure:
Dissolve 5-fluorothiophene-2-carbonitrile (0.541 g, 4.25 mmol) and 4-hydroxybenzaldehyde (0.519 g, 4.25 mmol) in DMF (11 mL). Add K2CO3 (1.469 g, 10.6 mmol) and heat at 100° C. for 1.5 hours. Concentrate the reaction mixture. Take the solid up in ethyl acetate (100 mL) and wash with water (2×25 mL). Dry the organic layer over MgSO4, filter and concentrate. Purify by chromatography eluting with 30% ethyl acetate in hexanes to give the title compound: 1H NMR (CDCl3): 9.96 (s, 1H), 7.98 (dd, J=6.6, 2.2 Hz, 2H), 7.86 (d, J=4.0 Hz, 1H), 7.40 (d, J=2.2 Hz, 2H), 6.96 (d, J=4.0 Hz, 1H); HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=17.4 min, 98.1% purity.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][N:21]2[CH2:22][CH2:23][CH:18]([NH:17][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:19][CH2:20]2)=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NC1CCN(CCc2ccncc2)CC1)c1ccccc1

Procedure:
A mixture of 4-vinylpyridine (578 mg.), 4-benzamidopiperidine (1.02 g.), acetic acid (330 mg.) and methanol (5 ml.) was refluxed for 8 hours, cooled, and evaporated. The residue in water was basified with potassium carbonate and the resulting solid was collected. Recrystallisation from aqueous ethanol gave the product (1.24 g.) m.p. 193°-5° C. (Found: C, 73.3; H, 7.4; N, 13.3. C19H23N3O requires C, 73.75; H, 7.4; N, 13.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([N:70]1[CH2:73][CH:72]([C:74](O)=[O:75])[CH2:71]1)=O)(C)(C)C>CN(C=O)C.CO.Cl>[NH:70]1[CH2:73][CH:72]([C:74]([N:19]2[CH2:18][CH2:17][CH:16]([C:12]3[CH:11]=[C:10]([F:22])[C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:23][C:24]5[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=5)[C:2]([Cl:1])=[CH:7][N:6]=4)=[CH:14][C:13]=3[CH3:15])[CH2:21][CH2:20]2)=[O:75])[CH2:71]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)C5CNC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), di-isopropylethylamine (50 uL, 0.36 mmol) and HATU (55 mg, 0.14 mmol) in DMF (1.5 mL) was added 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (29 mg, 0.14 mmol). After stirring at room temperature for 4 hours, the mixture was diluted with methanol (1 mL) and conc. aqueous HCl (1 mL). The mixture was stirred at 50° C. for 30 min. The mixture was filtered and purified by preparative RP-HPLC to give azetidin-3-yl(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)methanone as white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.68 (d, 2H), 7.04 (d, 2H), 6.26 (s, 1H), 4.74-4.68 (m, 2H), 4.39-4.35 (m, 1H), 4.29-4.24 (m, 2H), 4.11-4.07 (m, 1H), 3.74-3.71 (m, 1H), 3.25-3.24 (m, 1H), 3.07-3.04 (m, 1H), 2.87-2.80 (m, 1H), 2.33 (s, 3H), 2.28 (s, 3H), 1.87-1.84 (m, 2H), 1.66-1.56 (m, 2H); ESMS m/z 499.2 (M+H+).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
250 mg (0.59 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 201 mg (0.71 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.615 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 4 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 210 mg (56% of theory) of the product as a solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
Amine preparation: 1-BOC-4-piperidone (500 mg) and 2-methoxyethylamine (218 μL) were stirred in MeOH at room temperature. After 16 h, sodium borohydride was added (190 mg) carefully. After a further 3 h, the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (560 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[S:9][C:10]([C:12](=[O:21])[NH:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]>C1COCC1.[OH-].[Na+]>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][NH:13][C:12]([C:10]1[S:9][C:8]2[CH:22]=[CH:23][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH:11]=1)=[O:21]
Reactant: COC(=O)c1ccc2sc(C(=O)NOC3CCCCO3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2sc(C(=O)NOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(tetrahydro-pyran-2-yloxycarbamoyl)-benzo[b]thiophene-5-carboxylic acid methyl ester (131.6 mg, 0.39 mmol) in THF (2 mL) and 1M aqueous NaOH (4 mL) was allowed to stir at rt for 18 h. After removal of THF, the aqueous phase was acidified with HOAc to pH≈3. The solid formed was filtered, collected and dried to give 2-(tetrahydro-pyran-2-yloxycarbamoyl)-benzo[b]thiophene-5-carboxylic acid as a white solid. 1H NMR (DMSO-d6, 200 MHz) δ 12.04 (brs, 1H), 8.54 (s, 1H), 8.22-8.08 (m, 2H), 7.97 (dd, J=8.4, 1.2 Hz, 1H), 5.01 (s, 1H), 4.18-3.94 (m, 1H), 3.68-3.46 (m, 2H), 1.88-1.40 (m, 6H). MS (EI): cal'd 322.1 (MH+), exp 322.2 (MH+).