Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].I[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:12][CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]1=[O:21]>O1CCCC1>[C:8]([O:7][C:5]([CH2:4][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:13]([Br:12])[C:14]1=[O:21])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1NCCCCCC1Br
Reactant: CC(C)(C)OC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCCCCC(Br)C1=O

Procedure:
To a vigorously stirred suspension of 0.55 g sodium hydride in 30 ml tetrahydrofuran add over 20 min. a solution of 5.0 g t-butyl iodoacetate and 4.12 g 3-bromoperhydroazocin-2-one [Nagasawa et al., J. Med. Chem., 14 501 (1971)] dissolved in 35 ml tetrahydrofuran. After the addition is completed stir the reaction at room temperature for 1.5 hours then quench by the addition of 5-6 ml of saturated NH4Cl solution. Filter the reaction and concentrate the filtrate. Add ether to the residue, filter and wash the filtrate with H2O and brine. Dry the ether solution and concentrate to obtain 1-t-butoxycarbonylmethyl-3-bromoperhydroazocin-2-one. Prepare an analytical sample by silica gel chromatography. M.p. 107.5-109. Anal. (C13H22BrNO3). Calc: C, 48.75; H, 6.93; N, 4.37. Found: C, 48.78; H, 7.12; N, 4.26.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=Cc1ccncc1
Reactant: Nc1cccc(F)c1C(=O)O
Product: O=C(O)c1c(F)cccc1NCc1ccncc1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-6-fluorobenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 167.7, 162.7, 150.6, 149.5, 148.6, 133.8, 121.9, 107.3, 102.6, 101.9, 45.0.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 20.4 %

Procedure:
A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (150 ml.). Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 40°-60° C). The solid thus obtained was recrystallised from petroleum ether (b.p. 60°-80° C.) to give hexanoylmethylenetriphenylphosphorane (17 g.), m.p. 73°-74° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C:19]2[N:23](C)[C:22]([CH:25]=[O:26])=[CH:21]N=2)CC1>>[CH2:1]([O:8][CH2:9][C:10]([C:11]1[N:23]([CH3:19])[C:22]([CH:25]=[O:26])=[CH:21][N:13]=1)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: CC(C)(COCc1ccccc1)C(N)=O
Product: Cn1c(C=O)cnc1C(C)(C)COCc1ccccc1

Procedure:
2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 3-benzyloxy-2,2-dimethyl-propionamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[C:13](O)(=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:4])#[N:2]
Reactant: CCCCCCCCCC(=O)O
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCCCC(=O)N[C@@H](C)C#N
Yield: 54.3 %

Procedure:
General procedure D was used to deprotect 0.160 g (0.94 mmols) of 4. The product was immediately carried on using general procedure F and coupled to decanoic acid (0.94 mmol, 0.162 g). The product was purified via flash chromatography to yield 0.115 g (0.51 mmols) of the title product. 1H NMR (300 MHz, CDCl3) δ 6.07 (s, 1H), 4.94 (dq, J=7.2, 14.5, 1H), 2.26-2.16 (m, 2H), 1.69-1.58 (m, 2H), 1.54 (d, J=7.2, 3H), 1.26 (d, J=6.4, 12H), 0.86 (t, J=6.7, 3H).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH3:17])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][NH:22][NH2:23]>>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][N:22]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]3[O:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:23]1
Reactant: CN(C)CCNN
Reactant: Cc1ccc(Cl)c2c(=O)c3ccccc3oc12
Product: Cc1ccc2c3c(nn2CCN(C)C)-c2ccccc2Oc13

Procedure:
By condensation of 1-chloro-4-methyl-9-xanthenone with 2-(dimethylamino)ethylhydrazine was obtained 2-(2-(dimethylamino)ethyl)-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole. To 0.11 g. of this base in ethanol (10 ml.) was added 30% aqueous hydrogen peroxide (0.2 ml.). After 22 hours at room temperature the solution was evaporated to dryness under reduced pressure and the residue crystallized from ethanol-ether to give 2-(2-(dimethylamino)ethyl)-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole N-oxide sesquihydrate, m.p. 139° - 140° (decomp.).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:19]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:22])[NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([N:19]([C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[S:22])[NH:20][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN(Cc1ccccc1)C(=S)Nc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1C(=O)NN(Cc1ccccc1)C(=S)Nc1ccccc1
Temperature: 90 °C

Procedure:
Phthalic anhydride (3.7 g, 0.25 mole) and 2-benzyl-4-phenyl-3-thiosemicarbazide (6.43 g, 0.25 mole) were dissolved in 100 ml of dimethylformamide and heated at 90° C. for three hours. The solution was cooled then poured into ice water with stirring. The title product was filtered off as a solid material. Recrystallization gave a substance having a melting point of 140°-142°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].CC(C)([O-])C.[K+].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][C@@H:3]([OH:5])[CH3:4]
Reactant: Clc1ccccn1
Reactant: C[C@H](O)CN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](O)CNc1ccccn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
(S)-1-amino-2-propanol (43 g, 0.57M) was added to a stirred solution of potassium tertiary butoxide (64.2 g, 0.66M) in tetrahydrofuran (500 ml). 2-Chloropyridine (65.1 g 0.66M) was then added dropwise. After the exothermic reaction had subsided, the reaction was heated under reflux overnight, filtered to remove the potassium chloride and evaporated to an oil. The crude oil was dissolved in xylene (500 ml) and toluene-p-sulphonic acid (2 g) added and heated overnight under reflux under argon. After cooling to room temperature, the mixture was extracted with 2M hydrochloric acid. The acid extracts were basified with 2M sodium hydroxide and extracted into ethyl acetate. The ethyl acetate extracts were dried (MgSO4) and after removal of the acetic acid the product was distilled affording 73.5 g of the title compound, bp 100-110° C. at 0.2 mbar.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28](Cl)=[C:27]([Cl:33])[N:26]=1)=[O:24].C(N(C(C)C)CC)(C)C>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:21][O:22][C:23]([C:25]1[C:30]([Cl:31])=[N:29][C:28]([N:1]2[CH2:2][CH2:3][C:4](=[N:7][O:8][CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[CH2:5][CH2:6]2)=[C:27]([Cl:33])[N:26]=1)=[O:24]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1nc(Cl)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2d (99 mg, 0.35 mmol), 56a (92 mg, 0.35 mmol) and diisopropylethylamine (0.1 mL, 0.6 mmol) were combined in 0.5 mL of DMSO and stirred at room temperature for 18 h. The mixture was diluted with aqueous NaHCO3 (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated under vacuum to afford the crude 56b. 20 mg of this crude material was purified by preparative HPLC to afford 56b: LC-MS 488.3 (MH+).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+].O>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([Br:22])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(Br)n2c1COCC2)c1ccccc1
Temperature: -78 °C
Reaction time: 1.83 h
Yield: 93.3 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (9a) (2.50 g, 8.79 mmol) in dry dichloromethane (245 ml) at −78° C. was added N-bromo-succinimide (1.565 g, 8.79 mmol) in several portions (over 2 min) and the mixture was stirred for 110 min at −78° C., then aqueous 0.1 M sodium hydroxide was added, water was added, and the mixture was extracted 3 times with dichloromethane, the combined organic layers were dried over sodium sulfate, and evaporated to give 2.98 g (93%) of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.27 min; m/z=363.07 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:44]=[N+:45]=[N-:46])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:46][N:45]=[N:44][N:37]=3)=[CH:32][CH:31]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(C#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 1000 mg (1.91 mmol) of ethyl (7E)-8-{2-[(4-tert-butylbenzyl)oxy]phenyl}-6-(4-cyanobenzyl)oct-7-enoate in 70 ml of toluene is mixed with 3.8 ml (28.6 mmol) of trimethylsilyl azide and 713 mg (2.86 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 800 mg (1.4 mmol, 74% of theory) of a white foam are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([C:12]3(O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[O:9][C:8]=12.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[O:15]1[CH2:14][CH:13]=[C:12]([C:10]2[O:9][C:8]3=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=[C:7]3[CH:11]=2)[CH2:17][CH2:16]1
Reactant: COc1nccc2cc(C3(O)CCOCC3)oc12
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2cc(C3=CCOCC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
A solution of 4-(7-methoxyfuro[2,3-c]pyridin-2-yl)tetrahydopyran-4-ol (2.5 g) in dry dichloromethane (50 ml) was stirred at 0° C. under an atmosphere of dry nitrogen. Triethylamine (5.6 ml) was added followed by methanesulfonyl chloride (2.3 ml). The mixture was stirred overnight at room temperature. The solvent was removed in vacuo. Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate gave 2-(3,6-dihydro-2H-pyran-4-yl)-7-methoxyfuro[2,3-c]pyridine (2.5 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20](SC)[N:19]=2)=[CH:5][N:4]=1.[NH3:27]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:27])[N:19]=2)=[CH:5][N:4]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(OC)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(OC)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
A glass microwave reaction vessel was charged with 2-methoxy-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (41 mg, 0.110 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solid formed was filtered off and washed with EtOAc to give 4-(2-methoxy-4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (28 mg, 0.082 mmol, 74.5% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.98 (s, 1H); 9.25 (s, 1H); 8.53 (s, 1H); 8.16 (dd, J=8.84, 2.56 Hz, 1H); 7.84 (s, 1H); 7.68 (s, 1H); 6.88 (d, J=8.77 Hz, 1H); 5.76 (s, 1H); 3.89 (s, 3H); 3.86 (s, 3H); 2.40 (s, 3H). m/z (ESI, +ve ion) 341.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:15]O>S(=O)(=O)(O)O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:15])=[O:11]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1C(F)(F)F

Procedure:
A solution of 2-trifluoromethylphenylacetic acid (5.0 g) in methanol (30 ml) containing 5 drops of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 ml), washed with 1N sodium hydroxide (25 ml) then with brine (25 ml), dried over magnesium sulphate and evaporated to give the title compound (5.04 g) as a colourless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:14](=[O:17])[NH:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:16][NH:15][C:14]([C:11]1([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:17]
Reactant: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1(Cc2ccccc2)CCNCC1
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
4-Benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester (2.8 g) was dissolved in a mixture of TFA and methylene chloride and stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and pH was adjusted to 13 with aqueous sodium hydroxide (1N). The aqueous phase was extracted with methylene chloride (3×75 ml) and the combined organic phases were dried (MgSO4) and evaporated in vacuo to afford 1.50 g of 4-benzylpiperidine-4-carboxylic acid methylamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:20][NH:19][C:18]1[CH:17]=[CH:16][C:15]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:14][CH:13]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 86 %

Procedure:
The title compound was prepared from 5-methyl-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344–8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 86% yield: 1H NMR (DMSO-d6): δ 2.3 (s, 3H), 6.76 (d, J=7.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.20 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 8.02 (s, 1H), 10.51 (s, 1H), 10.62 (s, 1H); APCI-MS m/z 329 (M−1)−. Anal. Calcd for C15H14N4O3S: C, 54.54, H, 4.27; N, 16.96; S, 9.71. Found C, 54.54, H, 4.32; N, 16.87; S, 9.62.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/P(OCC)(OCC)=O)=[CH:7]\[CH3:8])=[O:5].[K].C([O-])(C)(C)C.[Br:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:30]/[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[N:29]=1)[CH3:1]
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 5.88 g of 4-phosphonocrotonic acid triethyl ester in 60 ml of tetrahydrofuran is mixed in portions with 2.5 g of potassium-tert-butanolate with stirring and under argon atmosphere at -20° C. After 30 minutes, a solution of 2.6 g of 6-bromopyridine-2-aldehyde is instilled at -20° C. and the mixture is stirred at this temperature for another hour. The reaction mixture is poured on ice, shaken out with diethyl ether, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 2.66 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienoic acid ethyl ester is obtained as crude product.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]([S:13](/[N:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])([CH3:12])[CH3:11]>CS(C)=O>[C:10]([S:13]([N:15]1[CH2:4][CH:16]1[C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])([CH3:9])([CH3:11])[CH3:12]
Reactant: CCCS(=O)(=O)c1ccc(/C=N/S(=O)C(C)(C)C)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCS(=O)(=O)c1ccc(C2CN2S(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Sodium hydride (0.33 g of a 60% dispersion in mineral oil, 8.37 mmol) was added portionwise to a stirred solution of trimethylsulphoxonium iodide (1.84 g, 8.37 mmol) in DMSO (30 mL). The mixture was stirred at room temperature for 1 h by which time effervescence had ceased and the mixture was mostly clear. 2-Methyl-N-{(1E)-[4-(propylsulphonyl)phenyl]methylene}propane-2-sulphinamide (1.76 g, 5.58 mmol) was added and the resulting solution stirred at room temperature overnight. The reaction mixture was quenched by addition of water and the product extracted into ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated to give the title compound (1.44 g, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH3:17])[C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([NH:35][NH2:36])=[O:34]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][NH:35][C:33]([C:29]2[O:28][CH:32]=[CH:31][CH:30]=2)=[O:34])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH3:17])[CH3:26])[C:6]=2[N:7]=1
Reactant: NNC(=O)c1ccco1
Reactant: CN(CCN(C)c1ccc(F)cc1F)CCn1ccc2c(Cl)nc(N)nc21
Solvent: CN1CCCC1=O
Product: CN(CCN(C)c1ccc(F)cc1F)CCn1ccc2c(NNC(=O)c3ccco3)nc(N)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The title B compound, N1-(2-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)-N2-(2,4-difluorophenyl)-N1,N2-dimethylethane-1,2-diamine (196.8 mg, 0.50 mmol) and 2-furoic hydrazide (126.0 mg, 1.0 mmol) are dissolved in 2.0 mL of NMP. The solution is stirred at 150.0° C. for 3 h before it is cooled down to RT. The solvent is removed to afford N′-(2-amino-7-(2-((2-((2,4-difluorophenyl)(methyl)amino)ethyl)(methyl)amino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide. LC/MS showed product as one peak.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:36]=[CH:35][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:14]2[CH:26]=[C:25](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccnc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2cccnc2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 15 ml solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(pyridin-3-yl)vinyl)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added to it, and it was adjusted to pH6.0 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-(4-fluoroanilino)-4-((E)-2-(pyridin-3-yl)vinyl)benzoic acid 46 mg of pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH3:14])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cccc(O)c1C

Procedure:
A solution of 3-Hydroxy-2-methylbenzoic acid (5.04 g, 33.12 mmol) and p-Toluenesulfonic acid monohydrate (0.741 g, 3.89 mmol) in abs ethanol (150 ml) was refluxed for 16 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with EtOAc (30 ml) and washed with water (20 ml). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.