Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]2=[O:30])=[CH:11][C:10]=1[CH2:31][CH2:32][CH3:33])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]2=[O:30])=[CH:11][C:10]=1[CH2:31][CH2:32][CH3:33]
Reactant: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
To a solution of 0.334 g (0.71 mmol) of the product of step B in 1 mL of anhydrous THF was added 728 gL (0.73 mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF and the resulting mixture was stirred at room temperature for 10 minutes. The THF was then removed in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 40% EtOAc-hexane. Combination of the product containing fractions and evaporation in vacuo afforded 0.109 g (43%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[I:11])(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1I
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1I

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and 2-iodobenzenesulphonyl chloride.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CC1

Procedure:
The title compound, white solid (86 mg, 86%), MS (ISP) m/z=399.3 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclopropanecarboxylic acid.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH2:28][C:17]3=[CH:16]2)=[O:14])=[CH:9][CH:8]=1)C.C(O)(=O)C.[NH2:34]N>ClCCl>[CH:28]1[CH:27]=[CH:26][N:18]2[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]4[NH:34][N:2]=[CH:4][N:5]=4)=[CH:8][CH:9]=3)=[O:14])[CH2:16][C:17]=12
Reactant: CN(C)C=NC(=O)c1ccc(C(=O)N2C=C3CC=CN3Cc3ccccc32)cc1
Reactant: NN
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(-c2ncn[nH]2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 42.4 %

Procedure:
A mixture of N-(dimethylaminomethylene)-4-(5H,1 H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzamide (1.0 g) from Example 46, glacial acetic acid (15 ml), and anhydrous hydrazine (0.16 g) was refluxed for 15 hours and the volatiles removed in vacuo. Saturated aqueous sodium bicarbonate solution was added and the resultant solid was recovered by filtration. The solid was refluxed for 4 hours and the volatiles removed in vacuo to give a solid. The solid was dissolved in dichloromethane and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.39 g), m.p. 225-227° C.; MS, m/z: 355 (M)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18](O)=[O:19])[C:15]([OH:21])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[Cl-].[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH3+:54])=[C:49]([C:55]([NH:57][CH:58]([CH3:60])[CH3:59])=[O:56])[CH:48]=1.C(N(CC)CC)C.[OH-].[Na+]>O.CN(C=O)C>[O:1]=[S:2]1(=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:54][CH2:53][C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][C:49]=2[C:55]([NH:57][CH:58]([CH3:60])[CH3:59])=[O:56])=[O:19])[C:15]([OH:21])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: O=C(O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reactant: CC(C)NC(=O)c1cc(F)ccc1C[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)NC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reaction time: 0.5 h

Procedure:
5-(1,1-Dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxylic acid (200 mg, 0.62 mmol, prepared as described in Example 3, Step 7), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (154 mg, 0.80 mmol), and 1-hydroxy-7-azabenzotriazole (109 mg, 0.80 mmol) were added to dry DMF (15 mL) and stirred for 30 minutes to preform the activated ester. {4-Fluoro-2-[(isopropylamino)carbonyl]phenyl}methanaminium chloride (168 mg, 0.68 mmol) and triethylamine (95 μL, 0.68 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was poured into water, the pH was adjusted to ˜10 using 1N NaOH, and resulting solution was extracted several times with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was redissolved in basic water and CHCl3, acidified to pH=4 using 1N HCl and extracted several times with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to a whitish solid. Methanol was added to the flask and the flask was sonicated for 5 minutes. The resulting solids were collected by vacuum filtration to give the title compound as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[C:28]([C:31]1[N:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH3:41])[NH:34][C:35]=1[C:36]#[N:37])(=[O:30])[CH3:29]>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:31]1[N:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH3:41])[N:34]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=2)[C:35]=1[C:36]#[N:37])(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h
Yield: 45.6 %

Procedure:
0.87 g of potassium carbonate and 2.4 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate were added to a solution of 1.2 g of 4-acetyl-2-butyl-5-cyanoimidazole (prepared as described in Preparation 5) in 12 ml of N,N-dimethylacetamide, and the resulting mixture was shirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was once again extracted with 50 ml of ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.31 g of the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CNCC(F)(F)F)ccc1-2
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde (180 mg, 0.53 mmol) in DCE (7 mL+5% AcOH) was added trifluoroethylamine (46 μL, 0.58 mmol) and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (134 mg, 0.64 mmol) was added and the solution was stirred under nitrogen for 65 hours. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution and DCM and the phases were separated. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% 2M NH3/MeOH in DCM) to give a colourless oil. The oil was triturated with ether/cyclohexane to give 119 as a grey solid (138 mg, 61%). LCMS: RT=9.52 min, [M+H]+=424. 1H NMR δ (ppm) (DMSO-d6): 8.91 (1 H, s), 8.22 (1 H, d, J=8.10 Hz), 7.09 (1 H, dd, J=8.16, 1.68 Hz), 7.00 (1 H, d, J=1.64 Hz), 5.49-5.39 (1 H, m), 4.33-4.27 (2 H, m), 3.74 (2 H, s), 3.40-3.32 (2 H, m), 3.21-3.09 (2 H, m), 2.92 (1H, s), 1.52 (6H, d, J=6.71 Hz)
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16]>>[CH:15]([O:19][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)O
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCC(C)Oc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as example 161c from 2,6-dinitrobenzonitrile and sec-butanol to provide 2-sec-butoxy-6-nitrobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.98 (t, J=7.5 Hz, 3H), 1.33 (d, J=5.9 Hz, 3H), 1.73 (m, 2H), 4.76 (sext, J=5.9 Hz, 1H), 7.78 (dd, J=6.8, 2.8 Hz, 1H), 7.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(NS(=O)(=O)c2cc(F)ccc2F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of methyl 3-amino-4-fluorobenzoate (25 g, 149 mmol) in DCM (150 mL) were added pyridine (35.3 g, 446 mmol) and a catalytic amount of DMAP (1.8 g, 14.9 mmol). The mixture was cooled to 0° C. 2,5-Difluorobenzene-1-sulfonyl chloride (34.7 g, 212 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (300 mL), and extracted with DCM (2×400 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether to afford the title compound of Step A (48.2 g, 94.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.12-8.18 (m, 1H), 7.73-7.80 (m, 1H), 7.47-7.53 (m, 1H), 7.10-7.25 (m, 1H), 7.00-7.07 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:15])=[C:6]([CH3:16])[N:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[CH3:16][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[CH3:15])=[C:2]([CH3:1])[N+:3]([O-:22])=[CH:4][N:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(O)ccc1-c1c(C)ncnc1C
Solvent: ClCCl
Product: Cc1cc(O)ccc1-c1c(C)nc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol (1.0 g, 4.7 mmol) in dichloromethane (25 mL) was added 3-chloroperoxybenzoic acid (887 mg, 5.14 mmol) at 0° C. The reaction was stirred at 0° C. for 2 hours, then at room temperature for 14 hours. After removal of solvent in vacuo, purification by chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in petroleum ether) provided the product. Yield: 742 mg, 3.22 mmol, 69%. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 6.82-6.91 (m, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.97 (s, 3H).
Reaction SMILES: C1(SC2C=CC(S([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=O)=O)=CC=2)CCCCC1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CN(C)C(=O)C>O>[N:35]1([CH2:34][CH2:33][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CNCCN1CCOCC1
Temperature: 60 °C
Yield: 57 %

Procedure:
The N-[[4-(cyclohexylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, from Example 5b (3.34 mmol, 1.145 g), dried 325 mesh K2CO3 (13.4 mmol, 1.84 g), N-(chloroethyl)morpholine (10 mmol, 1.86 g), and N,N-dimethyacetamide (13 mL) were combined and heated at 60° C. under an inert atmosphere for 16 hours, then an additional 4 hours at 80° C. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (100 mL, then 50 mL). The combined organic phases were dried (MgSO4), filtered through a silica plug, concentrated, and subjected to chromatography (ethyl acetate:toluene 1:1), to afford N-[[4-(cyclohexylthio)phenyl]phenyl]sulphonyl]-N-[2-(4-morpholinyl)ethyl]-glycine, 1,1-dimethylethyl ester (954 mg, 57%) as an oil. The structure was verified spectroscopically. MS MH+ calcd. for C24H38N2O5S2 : 499, found: 499. Elemental anal. calc'd for C24H38N2O5S2.0.25H2O: C, 57.29; H, 7.71; N, 5.57. Found: C, 57.32; H, 8.21; N, 5.27.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:55])[CH2:52][C:53]#[N:54])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][C:32]=3[F:44])[C:23]=12>C(Cl)Cl.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH2:45][C@@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51]([C:52](=[CH:3][C:2]([CH3:5])([NH:6][CH:7]3[CH2:10][O:9][CH2:8]3)[CH3:1])[C:53]#[N:54])=[O:55])[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][C:32]=3[F:44])[C:23]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)NC1COC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC1COC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
To a solution of 2-methyl-2-(oxetan-3-ylamino)propanal (106.3 mg, 0.7400 mmol) in DCM (5 mL) was added pyrrolidine (0.07 mL, 0.890 mmol). The reaction mixture was cooled to 0° C., followed by addition TMS-Cl (0.08 mL, 0.59 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 10 minutes before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (70 mg, 0.1500 mmol). The mixture was stirred for 50 minutes at which point it was deemed finished by checking TLC and LC-MS. The mixture was washed with saturated Na2HCO3 and the layers separated. The aq. layer was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent removed. The residue was loaded on silica gel plate, flashed by [MeOH:CH2Cl2(1:4)}: EtOAc 50%, 60% to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(oxetan-3-ylamino)pent-2-enenitrile (35.6 mg, 0.0597 mmol, 40.2% yield) as an off white solid. LC-MS (ES, m/z): 598 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:11][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=2[CH3:10])=[CH:21][CH:22]=1)[CH3:28]
Reactant: CCOc1ccc(CCl)cc1
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc(C=O)c(O)c2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzaldehyde (1.00 g, 6.57 mmol) in DMF (20 mL) were added potassium carbonate (1.36 g, 9.86 mmol) and 1-(chloromethyl)-4-ethoxybenzene (1.23 g, 7.23 mmol), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:2) to give the title compound (336 mg, yield 18%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([CH2:27][NH:28][C:29]2[CH2:33][S:32][C:31](=[O:34])[N:30]=2)[CH2:26][CH2:25]1.CC(C)([O-])C.[K+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][CH:24]3[CH2:25][CH2:26]3)=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NCC2CC2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1N=C(NCC2CC2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
1-[2,4-Bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (200 mg) and 4-[(cyclopropylmethyl)amino]-1,3-thiazol-2(5H)-one (100 mg) were suspended in ethanol (3 mL), potassium tert-butoxide (66.1 mg) was added, and the reaction mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (180 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:21]([O-:23])=[O:22])[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: O=[N+]([O-])O
Reactant: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)ccc21
Agent: O=S(=O)(O)O
Product: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc21
Yield: 50 %

Procedure:
100 mg of 6-trifluoromethyl-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is suspended in 1 ml of concentrated sulfuric acid, mixed at 4° C. with 0.1 ml of a mixture of concentrated sulfuric acid:concentrated nitric acid=1:1 and stirred for 1 hour at 4° C. Then, everything is dissolved. Then, it is poured on ice and the settled precipitate is suctioned off. 59 mg (50% of theory) of 6-trifluoromethyl-7-nitro-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17]CC2C=CC=CC=2)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:5]>C1COCC1>[OH:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100497.4 %

Procedure:
Methyl 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate (50.0 g, 0.152 mmol) was dissolved in a mixture of THF:ethanol (600 mL) and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (5.0 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (36.7 g).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)=[CH:11][CH:10]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18](=[O:20])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)no1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2noc(=O)[nH]2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
6.5 g (29 mmol, 4 eq.) of tin(II) chloride dihydrate were added to a solution of 1.5 g (7.2 mmol) of 3-(4-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one in 75 ml of ethanol, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was poured into ice-water, and sodium bicarbonate was added carefully until a pH of 8 had been reached. The mixture was filtered through a filter layer and the residue was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was stirred with dichloromethane and methanol, treated in an ultrasonic bath for 10 min and then filtered. The filtrate was concentrated under reduced pressure and dried. Yield: 1.4 g (quant.)
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([OH:20])=O)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1([NH2:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:18]([NH:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(NN1CCOCC1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid and 4-morpholinamine (CAN 4319-49-7) as starting materials; MS (ESI) 372.1 (M−H)−.