Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(O)(=O)C.BrBr>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(Cl)cn2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc(Cl)cn2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a dry 100 mL flask equipped with magnetic stirrer and reflux condenser was charged 2.0 g of 6-(5-chloropyridin-2-yl)-4,5-dihydropyridazin-3(2H)-one (0.00955 mol), and about 25 mL of glacial acetic acid (some solid did not dissolve). Bromine (0.5 mL; 0.00955 mol) was added in one portion, and the reaction was slowly heated to reflux. After about 15 minutes at reflux, the color discharged. An aliquot was analyzed by TLC which revealed no starting material remained, and one major product was formed. The reaction was cooled and stirred at ambient temperature overnight. The reaction mixture was poured into about 300 mL of water, and stirred to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried in vacuo at 40° C. overnight. Isolated 1.9 g of a tan solid was isolated. The NMR data is as follows: 300 MHz 1H NMR (DMSO d-6, TMS=0 ppm) 7.10 (d, AH); 7.75 (d, AH); 8.11 (d, 1H) 8.70 (d, AH); 13.4 (bs, 1H). The sample had 96% isolated yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][CH2:25][CH3:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:24]([CH2:25][CH3:26])[C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18])(=[O:38])[CH3:37]
Reactant: CCNc1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(C)=O)c1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a solution of compound (ii) (6 mg, 0.015 mmol) in DCM was added DIPEA (7 μL, 0.040 mmol), followed by acetyl chloride (7 μL, 0.098 mmol) and the reaction was stirred at RT for 20 min. After concentrating to dryness, the residue was purified by flash column chromatography eluting with MeOH/DCM (0-20%) to give Compound (48) as a white solid (4 mg, 61%). ESI-MS m/z calculated for [M+H]+: 455.1/457.1; found: 455.4/457.4; 1H NMR (400 MHz, CDCl3) δ 7.71-7.63 (m, 2H), 7.56 (brs, 1H), 7.52-7.46 (m, 2H), 7.43 (s, 1H), 5.77 (brs, 1H), 4.32 (dq, J=14.3, 7.2 Hz, 1H), 3.25 (dq, J=14.2, 7.1 Hz, 1H), 3.01 (d, J=4.9 Hz, 3H), 1.96-1.74 (m, 4H), 1.21 (t, J=7.2 Hz, 3H), 1.10-0.97 (m, 2H), 0.86-0.70 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2)[CH3:2].CO.[OH-].[K+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(CC)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of ethyl 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.64 g), methanol (20 mL), and tetrahydrofuran (40 mL) was added an aqueous solution (10 mL) of potassium hydroxide (1.6 g), and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (3.4 g, yield 100%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)Cl.[NH3:6]>C1(C)C=CC=CC=1>[CH3:1][Si:2]1([CH3:5])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6][Si:2]([CH3:5])([CH3:1])[NH:6]1
Reactant: N
Reactant: C[Si](C)(Cl)Cl
Solvent: Cc1ccccc1
Product: C[Si]1(C)N[Si](C)(C)N[Si](C)(C)N1
Yield: 42.1 %

Procedure:
A 500-ml, four-necked flask equipped with a stirrer, dry ice/acetone condenser, thermometer, and gas inlet tube was charged with 64.5 grams (0.5 mol) of dimethyldichlorosilane and 150 grams of toluene. Into the solution at 30° C., 52 grams (3.06 mol) of ammonia was blown over 2 hours for effecting reaction. At the end of reaction, the reaction solution was passed through a glass filter to remove ammonium chloride resulting from the reaction. The filtrate was subjected to vacuum distillation, obtaining 15.4 grams of hexamethylcyclotrisilazane (yield 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=O)[CH:41]=[CH:42][C:35]1=2>>[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([CH2:43][C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])[N:6]([C@@H:11]4[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]4[OH:13])[CH:5]=3)[CH:41]=[CH:42][C:35]1=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc2occc2c1
Product: Cc1cccc2c1c(Cc1ccc3occc3c1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The titled compound was prepared from 4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 23-(1) and benzo[b]furan-5-carbonyl chloride in a manner similar to Example 3 as a colorless powder. APCI-Mass m/Z 424 (M−H). 1H-NMR (DMSO-d6) δ 2.40 (s, 3H), 3.23 (td, J=8.9, 5.5 Hz, 1H), 3.39 (td, J=8.8, 5.1 Hz, 1H), 3.42-3.47 (m, 2H), 3.65-3.70 (m, 2H), 4.30 (s, 2H), 4.52 (t, J=5.5 Hz, 1H), 5.07 (d, J=5.3 Hz, 1H), 5.13 (d, J=5.0 Hz, 1H), 5.17 (d, J=5.8 Hz, 1H), 5.35 (d, J=9.0 Hz, 1H), 6.70 (d, J=7.1 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 6.98 (m, 1H), 7.14 (s, 1H), 7.17 (dd, J=8.6, 1.4 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1COCCN1
Solvent: CC#N
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 83.2 %

Procedure:
A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (80 mg, 0.14 mmol) and morpholine (150 μL, 1.73 mmol) in acetonitrile (2.5 mL) was heated at 100° C. for 70 minutes in a microwave reactor. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (gradient: 30-60% ethyl acetate in cyclohexane) to afford (R)-(1-(4-fluorophenyl)-6-((6-morpholinopyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a colourless glass (70 mg). LCMS (Method D, ESI): RT 4.94 min, m+H=601.0; 1H NMR (400 MHz, CDCl3): δ 8.63 (ddd, J=4.8, 1.7, 0.9 Hz, 1 H); 8.44 (d, J=2.5 Hz, 1 H); 7.84-7.85 (m, 2 H); 7.66 (dd, J=9.1, 2.5 Hz, 1 H); 7.44-7.45 (m, 3 H); 7.29 (s, 1 H); 7.16 (t, J=8.5 Hz, 2 H); 6.49-6.50 (m, 2 H); 5.49 (dd, J=12.1, 2.1 Hz, 1 H); 4.28 (d, J=16.9 Hz, 1 H); 3.80 (t, J=4.8 Hz, 5 H); 3.63 (t, J=4.8 Hz, 4H); 2.83-2.85 (m, 2 H); 2.71 (d, J=12.1 Hz, 1 H); 2.47-2.50 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccccc1OCc1ccccc1
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a suspension of benzyl (2-benzyloxyphenyl)acetate (100 g) in ethanol (500 ml) was added a solution of sodium hydroxide (36 g) in water (300 ml). After being stirred for 16 hours, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was washed with diethyl ether. The aqueous layer was acidified by concentrated-hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated in vacuo. The residual oil was crystallized from diisopropyl ether to afford (2-benzyloxyphenyl)acetic acid (28 g).
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8]3[C:11]([Si:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][CH:13]=[CH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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:34][C:35]1[CH:36]=[C:37]([C:2]2[C:10]3[O:9][C:8]4[C:11]([Si:15]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:12][CH:13]=[CH:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Ic1cccc2c1oc1c([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cccc12
Reactant: OB(O)c1cccc(Cl)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cccc(-c2cccc3c2oc2c([Si](c4ccccc4)(c4ccccc4)c4ccccc4)cccc23)c1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture solution of (6-Iododibenzo[b,d]furan-4-yl)triphenylsilane (6.60 g, 11.95 mmol), (3-chlorophenyl)boronic acid (2.80 g, 17.92 mmol), Pd(PPh3)4 (0.138 g, 0.119 mmol) and K2CO3 (3.30 g, 23.89 mmol) in toluene (100 mL) and water (15 mL) was refluxed under nitrogen for 24 hours. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1, v/v) as eluent to yield (6-(3-chlorophenyl)dibenzo[b,d]furan-4-yl)triphenylsilane (3.7 g, 58%) as a white solid.
Reaction SMILES: [CH:1]([C:9]([OH:11])=O)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.S(Cl)([Cl:19])=O>>[CH:1]([C:9]([Cl:19])=[O:11])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 25 °C

Procedure:
The styrene carboxylic acid copolymer (20.0g) from Example 7(b) was refluxed with stirring for 2 hours in thionyl chloride (300 ml.) containing N,N-dimethylformamide (3.0 ml.). After cooling to room temperature the mixture was filtered and the polymer washed with chloroform (5 × 100 ml., containing 2% v /v ethanol); and dried in vacuo at 40° to constant weight. The title polymer (21.80g) exhibited μ max (Nujol) 1770 and 1738 cm-1 (C=O) and was yellow-green in colour.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[N-]=[N+]=[N-].[Na+]>O.C(O)(=O)C.S(=O)(=O)(O)O>[OH:2][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9](=[O:18])[NH:8][C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2N)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2[nH]c(=O)c3cc(OC)ccc3c2O)cc1
Reaction time: 0.5 h

Procedure:
At 0° C., a solution of sodium nitrite (24.8 mg, 0.36 mmol) in water (0.5 mL) is added slowly to a solution of 4-amino-7-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (100 mg, 0.33 mmol) dissolved in acetic acid (1 mL) and sulphuric acid (0.5 mL). The mixture is left under stirring under cold conditions for 30 minutes then sodium azide (25.7 mg, 0.39 mmol) dissolved in a minimum amount of water (0.2 mL) is introduced slowly. Stirring, still under cold conditions, is maintained for another 3 hours, then water (10 mL) is poured onto the reaction mixture and the solid residue formed is collected by filtration. Silica gel column chromatography using a gradient of ethanol (0 to 2%) in CH2Cl2 as eluent makes it possible to isolate the compound possessing the greatest mobility which corresponds to the expected compound 41 (31 mg, 31%) in the form of a white solid, 1H NMR (CDCl3) 7.91 (1H, d), 7.74 (1H, d), 7.41 (2H, d), 7.16 (1H, dd), 6.85 (2H, d), 6.75 (1H, br s), 4.60 (1H, br s), 3.98 (3H, s), 3.78 (3H, s); MS 295 (M−2H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])[CH2:17][C@H:16]2[CH3:32])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43](C)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([N:43]4[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:45][CH2:44]4)=[CH:3][CH:4]=3)(=[O:14])=[O:13])[C@H:16]([CH3:32])[CH2:17]2)=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Yield: 66.9 %

Procedure:
A mixture of (2R)-1-[(4-bromo-1-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (250 mg, 0.47 mmol), 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (175.1 mg, 0.94 mmol), tris(dibenzylidineacetone)dipalladium (0) (4.3 mg, 0.0047 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (8.78 mg, 0.014 mmol) and sodium tert-butoxide (56.5 mg, 0.59 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl 4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-1-naphthyl]piperazine-1-carboxylate as yellow gum (200.1 mg, 66.9% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1.[NH2:43][C:44]1[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56](O)=[O:57])=[CH:46][C:45]=1[Cl:67]>C1COCC1>[NH2:43][C:44]1[C:49]([C:50]([F:51])([F:52])[F:53])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56]([N:40]2[CH2:41][CH2:42][CH:37]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[CH2:38][CH2:39]2)=[O:57])=[CH:46][C:45]=1[Cl:67]
Reactant: Nc1c(Cl)cc(C[C@@H](OCc2ccccc2)C(=O)O)cc1C(F)(F)F
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.35 g (4.20 mmol) TBTU, 0.70 mL (5.0 mmol) triethylamine and 0.75 g (4.01 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 1.5 g (4.01 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid in 50 mL THF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was combined with 200 mL EtOAc and 200 mL saturated NaHCO3 solution, the organic phase was separated off and extracted with 100 mL of 5% citric acid solution. The citric acid extract was made alkaline with K2CO3 and extracted twice with 100 mL EtOAc in each case. The combined organic phases were evaporated down i.vac. and the residue further reacted without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[O:4][N:3]=1.C(C1C=C(N[C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)ON=1)(C)C>>[OH:9][CH2:8][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(CO)c1cc(N)no1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 72 %

Procedure:
Prepared from 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol (100 mg, 0.60 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (120 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.30 (brs, 1H), 7.42-7.43 (m, 2H), 7.26 (m, 1H), 7.18-7.21 (m, 2H), 6.65 (s, 1H), 3.67 (s, 2H), 1.98 (brs, 1H), 1.32 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(#N)C>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine at about 0° C. to about 80° C. in acetonitrile and water to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 40° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:14]Cl>>[Cl:14][NH:11][C:9](=[O:10])[C:8]1[C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=[N:6][CH:7]=1
Reactant: ClCl
Reactant: NC(=O)c1cnccc1C(F)(F)F
Product: O=C(NCl)c1cnccc1C(F)(F)F

Procedure:
in which A is a non-oxidizable organic or inorganic anion can be prepared by chlorinating 4-trifluoromethylnicotinamide with Cl2 in aqueous acid and, if desired, subsequent anion exchange and/or, if desired, reaction with a base to give N-chloro-4-trifluoromethylnicotinamide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: COCCN
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 71 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of 2-methoxyethanamine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc:EtOH:NEt3=10:1:0.5 solvent mixture. N4-(2-Methoxyethyl)-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH:23]=1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1cccnc1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cccnc2)c1
Yield: 40.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (152 mg, yield: 40.3%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1[C:21]2[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][NH:17][CH2:16][C:15]=2[S:14][CH:13]=1>N1C=CC=CC=1.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:17]2[CH2:16][C:15]3[S:14][CH:13]=[CH:12][C:21]=3[N:20]3[CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: c1cc2n(c1)-c1ccsc1CNC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3sccc3-n3cccc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
An excess of para-toluenesulfonyl chloride is added to a solution of 1 g (0.0053 mol) of 5,6-dihydro -4H-pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine in 10 ml of pyridine, and the reaction mixture is then stirred at room temperature for one hour. The pyridine is then removed under reduced pressure and the oil residue obtained is ground in 100 ml of water. The emulsion formed is extracted with 3 times 100 ml of ethyl ether. The organic phases are separated after settling has taken place, combined, dried, washed with acidulated water, dried over magnesium sulfate and evaporated under vacuum. The solid residue is recrystallized. 0.4 g of 5-(p-tolylsulfonyl)-5,6-dihydro-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is thereby obtained in the form of yellow crystals, melting point 165° C. (ethyl ether).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.[C-]#N.[K+].[CH3:28][N:29](C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:28]#[N:29])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCBr)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl bromide (1.5 g), powdered potassium cyanide (1.52 g) and N,N-dimethylformamide (30 ml) was stirred for 3 hours at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), which was then concentrated to give 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyronitrile (1.2 g, 92%). Recrystallization of the product from ethyl acetate--hexane gave colorless needles, m.p.73°-74° C.